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These authors contributed equally to this work.
Epidemiologic studies have shown that in the aging society, a person dies from stroke every 3 minutes and 42 seconds, and vast numbers of people experience depression around the globe. The high prevalence and disability rates of stroke and depression introduce enormous challenges to public health. Accumulating evidence reveals that stroke is tightly associated with depression, and both diseases are linked to oxidative stress (OS). This review summarizes the mechanisms of OS and OS-mediated pathological processes, such as inflammation, apoptosis, and the microbial-gut-brain axis in stroke and depression. Pathological changes can lead to neuronal cell death, neurological deficits, and brain injury through DNA damage and the oxidation of lipids and proteins, which exacerbate the development of these two disorders. Additionally, aging accelerates the progression of stroke and depression by overactive OS and reduced antioxidant defenses. This review also discusses the efficacy and safety of several antioxidants and antidepressants in stroke and depression. Herein, we propose a crosstalk between OS, aging, stroke, and depression, and provide potential therapeutic strategies for the treatment of stroke and depression.
Epidemiologic studies demonstrate that 11% of the world’s population is over 60 years of age and this percentage will double to about 22% by 2050 . A significant percentage of older individuals develop one or more age-related diseases, which may include two leading diseases characterized by high incidence and disability: stroke  and depression . Stroke is classified into ischemic stroke and hemorrhagic stroke; the latter consists of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). It is estimated that on average, a person died from stroke every 3 minutes and 42 seconds in 2016 . Global Burden of Disease 2017 identifies stroke as the third leading cause of years of life lost and disability-adjusted life years [5, 6]. Between 2006 and 2016, the actual number of stroke deaths increased 3.7%, although the age-adjusted mortality rate decreased 16.7% due to the large increase in the number of elderly people [4, 7]. Like stroke, another disease that affects a significant proportion of the population is depression, a psychiatric disorder characterized by inactivity and negative feelings of inadequacy. The 12-month prevalence of major depressive disorder (MDD) is about 6%, while the lifetime risk of MDD is nearly 15-18% [8-10]. Moreover, older age is identified as a consistent and important risk factor for a worse prognosis. This phenomenon may be associated with the effect of cognitive impairment . As the World Health Organization (WHO) predicted depression to be the leading cause of global burden by 2030, attention should be paid to depression treatment [10, 11].
Over the past two decades, studies have identified the role of OS in these two diseases. Recently, preclinical experiments and clinical trials have focused on studying the efficacy of antioxidants and combined therapy with antidepressants in stroke or depressed patients. We review the results of experiments within the last 5 years, providing a comprehensive and novel overview of this interesting field.
Figure 1. Schematic model of the main source of ROS and redox reaction. ROS are generated mainly from enzymatic reactions in the cytoplasm, endoplasmic reticulum, mitochondria, and peroxisome [
OS describes a state in which the body produces excessive ROS and RNS in response to deleterious substances. Under normal conditions, OS and the anti-OS system are beneficial to physiological functions, such as respiration, circulation, etc. Mitochondrial dysfunction and internal environment disturbance can arise from multiple cellular molecules and signaling pathways as a result of imbalanced redox reactions, characterized by increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Fig. 1), as well as decreased antioxidant defenses. The most important ROS are mitochondrial ROS (mitoROS) produced from enzymes of the mitochondrial respiratory chain. Overproduced mitoROS can affect metabolic pathways, leading to a compromised function of organelles . Another significant source of ROS is NADPH oxidase (NOX). When the complex of NOX is assembled, it transports an electron from the cytosolic NADPH to oxygen to then form superoxide on the extracellular side . The antioxidant system consists of enzymes and nonenzymatic substances, among which nuclear factor erythroid 2-related factor (Nrf2) is the most important factor. Nrf2 is a transcription factor and can recognize the antioxidant response element (ARE) to regulate several genes, such as heme oxygenase 1 (HO-1). Activation of the Nrf2-ARE pathway increases antioxidants and protects the cells from free radical (FR) accumulation .
Under physiological conditions, moderate OS activity is necessary for body health. Toxic effects derived from ROS and RNS can be ameliorated or neutralized by FR scavengers and the antioxidant system. However, when a large number of ROS and RNS are generated, excessive FR then induce molecular oxidation, cell membrane modification, and enzyme inactivation, resulting in cellular damage and functional decline . Overactive OS with an imbalanced redox state can induce many injuries, especially to the brain, partly expounding the role of OS in both stroke and depression.
Ischemia-hypoxia often occurs in ischemic stroke, while intracerebral bleeding in the brain parenchyma can be found in ICH, and blood clots can be found in the subarachnoid space of SAH patients. Once cerebral ischemia occurs, it impairs cellular metabolism and triggers pathological pathways, such as immune responses, inflammatory reactions, OS, autophagy, and apoptosis, leading to irreversible neuronal damage and brain injuries accompanied by blood-brain barrier (BBB) disruption (Fig. 2) . Particularly, the release of FR further damages the brain. Different from ischemia, both primary and secondary brain injury (SBI) occur in ICH and SAH. Mechanisms participating in post-ICH include the coagulation cascade (particularly thrombin), hemoglobin degradation, inflammation, apoptosis, necrosis, OS, and hematoma expansion . Post-ICH events lead to SBI, which manifests as brain edema, BBB disruption, brain atrophy, vasospasm, neurological deficits, and even death . Compared with ischemic stroke, the results of OS activity in the studies were similar in ICH. Indeed, this kind of behavior exhibited by OS also occurs in SAH . Furthermore, brain injury involved in SAH is divided into two stages: an early stage within the first 72 hours, called early brain injury (EBI), and the delayed stage. OS plays a direct and indirect role in both stages, and many recent studies demonstrate efficacy of antioxidants in animal models, especially in EBI [19, 20].
In comparison with stroke, the main factors promoting MDD are psychosocial stressors, and the main pathophysiology of depression is associated with decreased monoamine levels, an altered hypothalamic-pituitary-adrenal axis , inflammation , neuro-plasticity and neurogenesis controlled by BDNF , and structural and functional brain changes (Fig. 2) [23, 24]. Apart from inflammation and neurogenesis, OS also plays a crucial role in depression. The role of OS in depression is supported by many studies that show upregulated OS activities and downregulated anti-OS responses [25-27]. In addition, the antioxidants may ease depressive symptoms [28, 29]. In summary, there is a close relationship between depression and OS.
As mentioned above, OS not only exists in stroke, but also occurs in depression. Moreover, many clinical trials have proved that stroke increases the incidence of depression, which inversely acts as an independent risk factor for stroke. On one hand, both ischemic and hemorrhagic stroke increases the prevalence of depression. A multicenter study found that approximately one-fifth of patients developed depression after stroke at a 12-month follow-up . In addition, 757 patients with first-ever minor ischemic stroke were followed for one year and analysis showed that nearly 30% of patients developed depression . However, the incidence rates of depression in ischemic stroke survivors aged 18-50 years and in the control group were 16.8% and 6.1%, respectively . A similar relationship is also seen in ICH  and SAH . On the other hand, an Australian longitudinal study with a 12-year follow-up suggested that depression caused a 2-fold increase in the odds of stroke . In addition, Pan did a meta-analysis consisting of 28 prospective cohort studies illustrating that the risk of ischemic stroke was exacerbated by depression , whereas another meta-analysis found that patients experiencing stressful life events had a 33% increased risk of total stroke  (Fig. 2).
Following ischemic stroke, an excess of ROS and RNS causes an ascending concentration of H+ and H2O2, leading to DNA damage, endothelial impairment, and mitochondrial dysfunction (see below for details). Furthermore, they exacerbate the damage through OS-mediated inflammation, apoptosis, autophagy, and the microbial-gut-brain axis. Apart from the mechanisms shown in ischemic stroke, the ROS and RNS, derived from the hemoglobin-heme-iron axis and activation of NOX, increase glutamate and inflammatory activities in ICH, and they disrupt BBB integrity to influence EBI and SBI in SAH. It is unsurprising to find semblable outcomes and pathological processes of OS in depression.
Figure 2. Pathogenesis and correlation between stroke and depression. There are different mechanisms in ischemic stroke [
Because the human brain requires constant oxygen and nutrients to maintain its function, it is vulnerable to FR attack. The depletion of energy in ischemic stroke can cause a series of damage to promote the development or recurrence of stroke, and OS is involved in all stages of ischemic stroke progression (Fig. 3). Firstly, energy expenditure leads to the accumulation of H+ concentration and H2O2. Studies on a mouse model of focal ischemia found that extracellular proton induce neuronal necroptosis via acid-sensing ion channel 1a/receptor interaction protein 1 association . Secondly, ROS have effects on cerebral blood flow. ROS stimulates vasoconstriction and increases platelet aggregation and endothelial cell permeability, thereby affecting blood circulation . Thirdly, RNS play a role in mitochondrial functions, such as reducing DNA and suppressing enzymes of the mitochondria. This is favored by a case-control study, in which a low mitochondrial DNA content in peripheral blood leukocytes is significantly related to ischemic stroke . Lastly, ROS and RNS bring about DNA damage, protein destruction, lipid peroxidation, and cell death, leading to poor outcomes [41, 42]. The results of clinical studies have demonstrated that higher plasma levels of oxidized low-density lipoprotein reveal a worse prognosis , a higher prevalence of cognitive impairment , and an increased risk of death .
Hemorrhagic stroke is a common, serious neurological disease associated with high disability and mortality, especially when associated with ICH. One of the main underlying mechanisms is OS. ROS and RNS usually come from the metabolite axis of hemoglobin-heme-iron, NOX activation, increased glutamate and inflammatory activities. Upon the onset of ICH, bleeding into the brain parenchyma is commonly observed. Then, several biological events associated with hemoglobin oxidation and released iron occur, resulting in neurological damage (Fig. 4) [46, 47]. What’s more, the results suggest that iron chelators could attenuate ROS generation to improve neurological function following ICH, further supporting the hemoglobin-heme-iron axis . Additionally, there are other mechanisms participating in the process of ICH, such as glial glutamate transporter responses  and mitochondria-dependent apoptosis . The effects caused by other pathological events are similar to those in ischemic stroke [51, 52]. Besides neuronal injuries, those pathological events contribute to SBI, including brain edema, BBB breakdown, and vasospasm. Interruption of the BBB facilitates ROS and RNS accumulation, which amplifies brain injuries .
In SAH, EBI is identified as the immediate injury accompanied by subsequent events (brain edema, inflammation, apoptosis, etc.) in the first 72 hours, and EBI plays a vital role in the pathological processes (Fig. 4). After the occurrence of SAH, the intracranial pressure will rise to the pressure of the diastolic artery, which reduces cerebrospinal fluid pressure and disturbs cerebral autoregulation before BBB breakdown and occurrence of cerebral edema . Due to erythrocytosis, the central nervous system (CNS) is exposed to high levels of Hb and Hb-degradation products in the subarachnoid space. This pathological process produces excess ROS and RNS, and promotes cerebral vasospasm, cerebrovascular stenosis, and delayed cerebral ischemia . Furthermore, several harmful events occur in SAH survivors, including altered ionic homeostasis, excitotoxicity, destruction of vascular integrity, OS, inflammation, apoptosis, autophagy, and activation of the NOS pathway [56-62].
The impact on stroke pertains to an abundance of ROS and RNS, as well as OS-induced cell death pathways. So, what role could OS have in depression? Depression involves several pathological processes that include an imbalance of neurotransmitters, inflammation, OS, apoptosis, glutamate excitotoxicity, and the microbiota-gut-brain axis [10, 63-65]. Although there is a deficiency of direct evidence exhibiting mechanisms between OS and depression, numerous animal and human studies have reported functions of OS in depressed patients via various OS-associated molecules [66-69]. For example, Pasquali et al. conducted a longitudinal study and described a series cascade of pro-oxidative and pro-inflammatory events contributing to the development of MDD in middle-aged women . Besides hyperactive OS, reduced antioxidant activity may exacerbate depression, but antioxidant treatment shows anti-depressant effects [71-74]. Wigner et al. proved that the polymorphisms of antioxidant enzymes (e.g., superoxide dismutase (SOD) and catalase (CAT) or glutathione peroxidase (GPx)) could regulate the risk of depression . Parallel results in the clinical trial were found to reach a consistency in the effects of OS in depression .
In previous sections, it is mentioned that OS-mediated pathological mechanisms (e.g., inflammation and apoptosis) act as a bridge and exert functions in stroke and depression (Fig. 5). Details about common OS-induced mechanisms are shown as follows.
Overproduction of ROS and RNS can activate inflammatory processes to aggravate brain damage through glycogen synthase kinase 3 (GSK-3) and endothelial injury. ROS stimulate the phosphorylation of GSK-3 to negatively affect the cyclic adenosine monophosphate response element-binding protein (CREB) by suppressing its nuclear translocation, resulting in an increased expression of pro-inflammatory cytokines and brain dysfunction in ischemic rat [76, 77]. To be specific, activated GSK-3 downregulates Nrf2-ARE binding activity and decreases the expression levels of genes downstream of Nrf2-ARE , but it stimulates the Toll-like receptors (TLRs) in the peripheral blood mononuclear cells . Experiments indicate that TLR 4 induces the expression of inflammatory elements through activation and nuclear translocation of NF-κB, while deletion of TLR 4 attenuates ischemic cerebral injury . Additionally, GSK-3 could boost inflammation by interrupting CREB binding proteins, which are the co-activators of CREB and NF-κB in the nucleus [76, 81]. Inversely, inhibition of GSK-3β improves the transcription and expression of anti-inflammatory cytokines and reduces pro-inflammatory cytokine production . Therefore, the results of GSK-3 activation and GSK-3 suppression confirm the role of OS-induced inflammation in ischemic brain injury. In addition to GSK-3, oxidative injury of platelet and endothelium cells also participate in inflammation. Following endothelial impairment, P-selectin is highly expressed to induce the rolling of leukocytes on the endothelium, facilitating stable adhesion between leukocytes and endothelial cells [82, 83]. Afterwards, the adhered leukocytes release matrix metalloproteinase, break down the BBB, and enter into the brain parenchyma to trigger a series of inflammatory processes . In ICH, a similar process occurs . In SAH, free Hb stimulates endothelial cells to express cell adhesion molecules to attract neutrophils. Cells trapped in the subarachnoid space then undergo an oxidative burst, which releases ROS-mediated inflammatory cytokines or other molecules to further damage the brain .
Figure 4. Schematic model of oxidative mechanisms in ICH and SAH, especially associated with hemoglobin (Hb). During the hemoglobin-heme-iron axis, Hb is released into the extracellular space and is accompanied by an abundance of superoxide generated from the non-enzymatic oxidation of Hb [
In depressed individuals, ROS and RNS have effects on inflammatory reactions via NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3). After sensing mitochondrial dysfunction of ROS, activated NLRP3 inflammasome induce the maturation of procaspase-1, which is an initiating process of interleukin (IL)1β and IL-18, to initiate inflammatory responses. Nevertheless, IL-1β knock-down in the hippocampus attenuate depression-like behaviors induced by LPS in mice . However, these changes are reversed by treatment with amitriptyline [87, 88]. In addition, pattern recognition receptors recognize PAMPs and DAMPs to trigger MAPK and/or NF-κB to activate immune-inflammation [89, 90].
Figure 5. Mechanisms of oxidative stress and OS-mediated cell death pathway in depression.
Accumulating evidence has shown that apoptosis, necrosis, and their combined pathway, “necroptosis”, participated in ischemic stroke stimulated by ROS and RNS . Experimental data obtained from ischemic mouse models suggest that the nuclei of neurons exhibit apoptotic morphology after four hours of ischemia . Mechanistically, under pathological conditions, cellular stress stimulates an apoptotic signaling pathway to activate the caspase protease and cause mitochondrial dysfunction, resulting in characteristic changes of apoptotic cell morphology, such as cell rounding, plasma membrane blebbing, and nuclear fragmentation. Apoptosis can be induced by extrinsic and intrinsic stimuli. The extrinsic stimuli are triggered by the death receptor signaling pathway , while the intrinsic stimuli involve a mitochondrial signaling pathway and released cytochrome c (Cytc) . When ischemic stroke occurs, OS initiates the apoptosis pathway mainly through intrinsic stimulation. OS also regulates apoptotic activities through modulating the balance between the anti-apoptotic protein, Bcl-2, and the pro-apoptotic regulator, Bax protein . In ICH, Cytc-mediated and mitochondria-dependent apoptosis is also demonstrated to be an important part of the OS-mediated mechanisms. Additionally, Hb-induced ROS, NO, and peroxynitrite (ONOO-) are shown to directly or indirectly activate matrix metalloprotein 9, leading to apoptosis [95, 96]. Meanwhile, there is a significant increase in the number of apoptotic neural cells in the rat brain after SAH .
Parallel to OS-mediated apoptosis in stroke, intrinsic apoptosis associated with mitochondria occupies an important position in the development of depression. When exposed to chronic stress, overactive apoptosis stimulated by OS in neurons promotes the neurodegeneration in depressed animals . Mechanistically, Bcl-2-mediated damage and excess levels of Ca2+ trigger various kinases, leading to a loss of the mitochondrial membrane potential, and an increased release of intermembrane proteins into the cytoplasm. In the presence of dATP, the released Cytc binds to the cytosolic Apaf 1 to activate caspase-9 and promote apoptosome formation. Meanwhile, enhanced permeability of the outer membrane of the mitochondria allows apoptosis-inducing factor (AIF) and endonuclease G to move to the nucleus and regulate chromatinolysis . In addition, chronic mild stress suppresses the expression of Bcl-2-associated athanogene-1, a gene involved in anti-apoptosis, resulting in the activation of caspases, BAX, and Bcl-2 antagonists in the mitochondria. Consequently, there is an excess of neuronal death . Moreover, it is highlighted that polymorphisms of apoptotic protein genes may be associated with MDD .
Recently, the microbiota-gut-brain axis has gained extensive attention as a channel for communication and physiological regulation. Activities of the intestinal microbiome might promote abnormal protein aggregation and oxidative responses to impair the brain. Inversely, the brain can either directly or indirectly impact commensal organisms or gastrointestinal functions through the release of signaling molecules from cells in the lamina propria [100, 101]. After an ischemic stroke, there is an increase of gastrointestinal complications such as dysphagia , fecal incontinence , gastro-intestinal hemorrhage , and constipation . Wen et al. revealed that ischemic stroke exacerbates gut barrier breakdown and microbiota alterations. Subsequently, the translocation of a selective bacterial strain from the host intestinal microbiota to the surrounding tissues promotes post-stroke infections . Furthermore, Benakis C et al. suggested that intestinal dysbiosis disequilibrates the intestinal immune homeostasis by inhibiting interleukin-17-positive γδ T cells, and suppressing the trafficking of effector T cells from the gut to the leptomeninges . Moreover, vagal afferent innervation of the enterochromaffin cells provides direct signaling to the neuronal circuits, leading to changes of the immune-response and other homeostatic functions . Due to lack of data showing the relationship the among gut-brain axis and ICH or SAH, further studies are needed.
In depression, the changes of microbiota, intestinal composition, and the resultant bacterial translocation expand the content of two-way interaction of the gut-brain axis. Zhang P et al. recognized the gut microbiome as an environmental factor that can shape the brain through this axis. Data from clinical sampling showed a significant difference of gut microbiota compositions between MDD patients and healthy controls, demonstrating that gut dysbiosis may mediate the host's metabolism to promote depressive-like behaviors . In addition, gut dysbiosis could have an impact on the biology of MDD through several pathways involving immune activation, ROS and RNS, and neuroplasticity cascades . Therefore, the microbiota-gut-brain axis may play a key role in the pathophysiological process of MDD. This axis opens a new preventative and therapeutic perspective for depression. However, due to methodological inconsistencies and limitations, more fundamental and clinical research should be undertaken.
The preceding content shows us a close connection between stroke and depression via the OS system and OS-mediated biological processes. Moreover, numerous studies have proved that aging or senescence is a risk factor that aggravates stroke and depression. For example, the population-based multiethnic cohort reported that the risk effect of physical inactivity is modified by age, and there is a conspicuous risk found only in stroke patients >80 years of age [111, 112]. Population-based surveillance studies predicted that the number of strokes will double by 2050, with incidence occurring primarily in the elderly (>age 75) groups . Although depression prevalence in the elderly varies across studies, Sjoberg L et al. indicated that older adults with poor physical function have a higher prevalence of depression . Herein, there is an “aging-stroke-depression” network and OS seems to be the center of this network. So, what relationship does aging have with oxidative stress, stroke, and depression?
There is a close link between oxidative stress and aging, and this link can be proven through many related mechanisms [115, 116]. Firstly, age-related cognitive decline is a consequence of increased OS and neuroinflammation activity in the the aging hippocampus, and a consequence of reduced neurogenesis and synaptic plasticity . Furthermore, mutual effects of inflammation and OS are observed to exacerbate the aging brain. Inflammation stimulates both macrophages and microglia to generate mitoROS to cause cognitive decline, whereas OS-damaged cells produce inflammatory mediators to promote microglial aging . Secondly, aging and OS can damage the brain by negatively affecting neuroplasticity, brain homeostasis, and cognitive function [119, 120]. The third factor is glutathione. In animal experiments, glutathione deficiency might compromise the ability of the aging brain to meet the demands of OS, leading to impaired physiological functions .
Normally, physiological events of aging involve a decline of innate functions, including shortened telomeres, dysregulated hormones, and dampened immune responses. Under pathological conditions, aging stimulates and exacerbates cellular injuries, such as DNA damage and FR accumulation, to increase the vulnerability of the brain . Mattson MP et al. depicted ten hallmarks of brain aging (e.g., OS and impaired DNA repair), among which, dysregulated energy metabolism is the core factor . When exposed to ischemia, aging impairs the integrity of the neurovascular unit and damages brain tissues . Aging can also destroy collateral circulation and revascularization of the brain through increased FR and inflammatory responses to aggravate stroke . Age-related cognitive deteriorations also exist in the ICH mice model. Researchers showed a delayed neurological improvement and decreased levels of antioxidants in senescence-accelerated mice than senescence-accelerated resistant mice, though the time period in which the neurological deficits occurred and increased remains the same. To conclude, these results implied a key role of OS in senescence and stroke.
Apart from OS, several other mechanisms are involved in OS and stroke. The ubiquitin proteasome pathway protects neurons by removing abnormal or toxic proteins located in the axons and dendrites, and ischemia may exacerbate injury of an aged brain through impairing ubiquitin proteasome function . Furthermore, aging is detrimental to ischemic stroke recovery due to its role in altering astrocytic proliferation, inhibiting vascular endothelial growth factor (VEGF) production, and upregulating the release of inflammatory cytokines [126, 127]. What about aging in hemorrhagic stroke? Apart from the direct effects of aging in ICH, senescence may contribute to ICH progression by changing the body physiology and increasing the risk of multiple chronic health conditions and comorbidities, such as hypertension and diabetes . However, the exact mechanism remains unclear. To our knowledge, there is no clear evidence explaining a relation between SAH and aging.
In the process of aging, biological changes in depression include mitochondrial dysfunction, dopamine dysfunction, and increased proinflammatory cytokines involved in the cellular senescence cycle. In general, mitochondrial abnormalities can be measured in peripheral blood mononuclear cells . For instance, the clinical study by Karabatsiakis et al. depicted higher levels of mitochondrial impairments in older folks with depression when compared with healthy controls . A systematic review and meta-analysis also supported this connection, indicating that late-life depression may be associated with a decreased hippocampal volume, though the relationship was not straightforward .
Different from other mechanisms in stroke, the pathological process of depression during aging is significantly affected by dopamine dysfunction, inflammation, and psychological stressors. In regards to dopamine, the availability of D2 receptors in the caudate and shell nuclei is attenuated in older adults, leading to decreased motor speed and impaired frontal functioning . Worse still, dopamine levels in the striatum of the elderly are only 40% of those found in young adults, and the D1/D2 receptor density and dopamine transporter expression decreased approximately 10% per decade, throughout the life cycle [133, 134]. Secondly, studies have found that inflammatory processes, especially high expression levels of IL-6, TNF-α, and C-reactive protein contribute to the depressive symptoms in elderly adults, with clinical manifestations of lethargy, slowing, and weakness . Most importantly, psychological well-being is largely associated with the onset and progression of depression among the elderly population . As the relationship between physical health and subjective well-being is bidirectional, elderly people with chronic diseases (e.g, coronary heart disease and chronic lung disease) have higher levels of unhappiness and are more likely to have depression . Fourthly, a cross-sectional survey showed that malnutrition increased the prevalence of depression in the elderly Nepali population. . Lastly, low folate levels result in increased mild cognitive impairment, dementia, and depression in older individuals . In summary, aging and depression are closely linked through OS, OS-related inflammation, and dopamine dysfunction, although social life and malnutrition play a crucial role in this link.
There are some changes of molecules and signaling pathways in aging. Under ischemia/hypoxia conditions among elderly individuals, silent information regulator 1 (SIRT1) expression and the mitochondrial unfolded protein response are reduced with age, leading to impairment of mitochondrial function . This condition also occurs in another study, indicating that the post-translational regulation of molecular mediators, such as hypoxia-inducible factor 1α and SIRT1, and the glycolytic-mitochondrial energy axis are critical in response to hypoxic-ischemic injury . Moreover, E2f transcription factor 1 enhances the cellular senescence in human fibroblast cells, while transcription factor FOXO3 plays against senescence by regulating ROS scavenging proteins. E2f transcription factor 1 could inhibit FOXO3-dependent transcription by directly binding to FOXO3 in the nucleus to expedite the aging process . Interestingly, the telomerase reverse transcriptase (TERT), a catalytic subunit of telomerase, exerts neuroprotective effects in the mitochondria of neurons by decreasing the ROS and protecting DNA. Nevertheless, recent studies observe the neuroprotective effects of TERT in cellular and animal models after aged brain injury, but it is unclear about TERT’s effects in the human CNS . In regards to aging, OS, and depression, glutathione captures our attention. In a study enrolling 58 depressed older patients and 12 controls, glutathione was measured in the anterior cingulate cortex, and the data showed that increased glutathione/creatine ratios are associated with greater depressive symptoms than the control group . In conclusion, OS lies in the center of the “aging-stroke-depression” network (Fig. 6). First, when stroke occurs in animals or patients, excessive generation of ROS follows, leading to cellular damage and brain injury. Second, OS mediates inflammation, apoptosis, and the microbiota-gut-brain axis to increase the accumulation of ROS, followed by brain deterioration. Third, aging acts as a risk factor and aggravates the development of stroke and depression via OS and OS-induced pathways. Due to the central role of OS in this network, administration of antioxidants seems to provide therapeutic ways for stroke and depression. So, are antioxidants safe and effective in these two disorders?
Figure 6. Proposed crosslink and interplay among aging, oxidative stress, stroke and depression.
In the last 5 years, mountains of preclinical and clinical studies have found that the application of antioxidants inhibits stroke and depression in patients with either, or both diseases, although the therapeutic effects and safety are under consideration. What’s more, the main pharmacotherapy for depression patients focuses on antidepressants , and the selective serotonin reuptake inhibitors (SSRIs) have been used as first-line antidepressants in recent decades. However, SSRIs have shown moderate efficacy and significant side-effects . Variability in efficacy and acceptability are large in head-to-head trials . Therefore, development of an accurate and effective antidepressant regimen requires our constant efforts. Herein, we list most of the relative studies about antioxidants and antidepressants used in treating stroke/depression, in order to find potential therapies.
Antioxidants or anti-oxidative systems have neuroprotective effects through different anti-activities and various signaling pathways, especially the Nrf2 pathway found in either ischemic stroke or hemorrhagic stroke (Table 1). Firstly, antioxidants alleviate ischemic stroke by attenuating the OS activity, and by protecting the mitochondrial function and BBB. For example, fucoxanthin , Sirtuin 6 , protocatechualdehyde , mangiferin , Korean Red Ginseng , 11-Keto-β-boswellic acid , metformin , s-allyl cysteine , monomethyl fumarate, dieckol , and fumarate  are reported to protect the brain by activating the Nrf2/HO-1 pathway. As such, uric acid (UA) , HP-1c , andrographolide , 2,2,6,6-tetramethyl-1-piperidinoxyl , and 3H-1,2-Dithiole-3-thione are associated with Nrf2 . Secondly, protecting mitochondrial function is beneficial to ischemic stroke treatment, such as 3-n-butylphthalide  and 5-methoxyindole-2-carboxylic acid .
Melatonin activates the silent information regulator 1 signaling , and progesterone suppresses mtROS production and blocks MPTP, to exert mitochondrial protection . SkQR1 is a mitochondrial-targeted antioxidant, and it is effective in protecting newborn brains before and after ischemic stroke . Thirdly, antioxidant systems also exert protective effects on blood vessels. For instance, ginkgolide  and leonurine  promote angiogenesis via upregulated VEGF expression. Fourthly, BBB integrity can be protected by several antioxidants, including astragaloside IV , Osthole  and the Chinese herbal medicine formula, Tao Hong Si Wu Decoction[170, 171]. All of these antioxidants are correlated with Nrf2 signaling.
Table 1 Antioxidants in Stroke.
|Stroke||Antioxidants||Anti-OS activity||Mechanism of anti-OS activity and others|
|Ischemic stroke||fucoxanthin||anti-OS||inhibit OS via Nrf2/HO-1 signaling pathway|
|Korean Red Ginseng|
|ursolic acid||upregulate Nrf2 pathway and expression levels of BDNF|
|HP-1c||AMPK-Nrf2 pathway activation, without any toxicity after penetrating the brain|
|andrographolide||up-regulate Nrf2/HO-1 expression via regulation of p38 MAPK|
|2,2,6,6-tetramethyl-1-piperidinoxyl||inhibit p38 MAPK and p53 cascades|
|3H-1,2-Dithiole-3-thione||suppress microglia activation; inhibit CNS peripheral cell infiltration|
|3-n-butylphthalide||anti-OS; attenuate mitochondrial dysfunction||inhibit OS; activate Nrf2/HO-1/AMPK pathway; improve MMP and complexes I-IV|
|melatonin||activate SIRT1 signaling|
|progesterone||suppress mtROS production and block MPTP|
|5-methoxyindole-2-carboxylic acid||increase antioxidative capacity via the Nrf2 signaling pathway; reduce OS|
|GK||anti-OS; protect blood vessels||faciliate angiogenesis through HIF-1α/VEGF and JAK2/STAT3 pathway|
|leonurine||upregulate VEGF expression by Nrf-2 pathway|
|astragaloside IV||anti-OS; protect BBB||Nrf2 signaling pathway|
|Tao Hong Si Wu Decoction||anti-OS|
|schizandrin A||anti-OS; anti-inflammation||AMPK/Nrf2 pathway|
|tryptanthrin||decrease pro-inflammatory cytokines in BV2 microglia cells via Nrf2/HO-1 signaling and NF-κB|
|3, 14, 19-triacetyl andrographolide||inhibit TLR4/NF-κB; upregulate Nrf2/ARE|
|quercetin||suppress LPS-induced oxidant production and expression of adhesion molecules|
|apelin 13||affect AMPK/GSK-3β pathway activated by AR/Gα/PLC/IP3/CaMKK signaling;|
|diosgenin||suppress TLR4/MyD88/NF-kB-induced inflammation|
|irisin||regulate ROS-NLRP3 inflammation|
|TPEN||inhibit OS and inflammation|
|N-acetyl lysyltyrosylcysteine amide|
|berberine||reduce the infarct volume and brain edema; improve motor function;|
|melilotus officinalis||reduce cerebral thrombosis and inflammatory mediators|
|DHC||protect BBB; inhibit inflammation by affecting ROS, NOX2, NOX4, NF-ĸB, and NO|
|resveratrol||modulate intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift|
|EPO-cyclosporine||suppress the innate immune response to OS, inflammation and MAPK family signaling|
|rhein||anti-OS; anti-apoptosis||inhibit OS and apoptosis|
|deuterohemin His peptide-6|
|adiponectin||attenuate mitochondrial vulnerability through the JAK2/STAT3 pathway|
|YiQiFuMai||reduce PKCδ/Drp1-mediated mitochondrial fission|
|withania somnifera||inhibit PARP1-AIF-Mediated caspase-independent apoptosis|
|SMXZF||suppress H2O2-induced neuronal apoptosis through caspase-3/ROCK1/MLC pathway|
|diallyl trisufide||suppress OGD-induced apoptosis via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway|
|plumbagin||anti-OS; anti-inflammation; anti-apoptosis||inhibit OS, inflammation and apoptosis|
|hollow prussian blue nanozymes|
|Sirt3||promote autophagy||regulate the AMPK-mTOR pathway; decrease H2O2; increase ATP generation|
|β-arrestin-1||interact two major components of the BECN1 autophagic core complex|
|vitexin||anti-autophagy||inhibit autophagy through the mTOR/Ulk1 pathway|
|silibinin||suppress the mitochondrial and autophagic cell death pathways|
|3-methyladenine||inhibit expression of LC3 and Beclin-1|
|astragalosides||block OGD-R-induced apoptosis and autophagy by inhibiting OS and ER stress|
|isoquercetin||anti-OS; anti-inflammation; anti-apoptosis; anti-autophagy||influence TLR4, NF-κB and caspase-1; ERK1/2, JNK1/2, and MAPK; TNF-α, IL-1β and IL-6; NOX4/ROS/NF-κB signaling pathway; CREB, Bax, Bcl-2, and caspase-3|
|ECGG||affect PI3K/AKT/eNOS and NRF2/HO-1 signaling pathway; promote neovascularization and cell proliferation|
|ICH||green tea||anti-OS||reduce EBI|
|mammalian sterile 20-like kinase-1|
|melatonin||reduce DNA damage and MPTP opening|
|dexmedetomidine||inhibit PGC-1α pathway inactivation and mtROS|
|oleuropein||alleviate brain edema; preserve the BBB|
|isoliquiritigenin||anti-OS; anti-inflammation||ROS/NF-κB, NLRP3 inflammasome pathway and Nrf2-mediated activities|
|Sirt3||suppress NLRP3 and IL-1β levels|
|Sodium Benzoate||anti-OS; anti-apoptosis||regulate DJ-1/Akt/IKK/NFκB pathway to inhibit neuronal apoptosis and mtROS|
|carnosine||decrease brain edema, BBB disruption, OS and neuronal apoptosis|
|metformin||anti-OS; anti-inflammation; anti-apoptosis;||inhibit OS, apoptosis and neuroinflammation|
|hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) metalloenzymes||abolish ATF4-dependent neuronal death|
|SAH||dimethyl formamide||anti-OS||improve EBI and cognitive dysfunction via the Keap1-Nrf2-ARE system|
|telmisartan||anti-OS; inhibit cerebral vasospasm||decrease TXNIP expression|
|nebivolol||increase GSH-Px activity|
|curcumin nanoparticles||anti-OS; anti-inflammation||keep BBB integrity; activate glutamate transporter-1; inhibit inflammation and OS|
|UA||suppress the TLR4-mediated inflammatory pathway|
|pterostilbene||inhibit NLRP3 inflammasome and Nox2-related OS|
|apigenin||anti-OS; anti-apoptosis||inhibit EBI through the dual effects of anti-oxidation and anti-apoptosis|
|AVE 0991||decreases OS and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway|
|allicin||extenuate brain edema and BBB dysfunction;|
|regulate the mitochondrial apoptosis pathway, NLRP3 and NF-κB.|
|memantine||inhibit inflammation-mediated BBB breakdown and ER stress-based apoptosis|
|Salvianolic acid B||activate Nrf2 signaling pathway|
|Salvianolic acid A||associate with Nrf2 signaling, the phosphorylation of ERK and P38 MAPK signaling|
|mitoquinone||promote autophagy||activate mitophagy via Keap1/Nrf2/PHB2 (prohibitin 2) pathway|
|melatonin||promote autophagy||stimulate autophagy to inhibit apoptotic death of neural cells|
Moreover, the anti-OS and anti-inflammatory effects are beneficial for post-ischemic treatment. Schizandrin A inhibits inflammation and OS through the AMPK/Nrf2 pathway . Tryptanthrin , 3, 14, 19-triacetyl andrographolide , quercetin , diosgenin  and irisin  reduce the production of proinflammatory cytokines by inhibiting the NF-κB-related signaling pathways and suppressing ROS generation. In addition, the Zinc ion chelating agents, TPEN , N-acetyl lysyltyrosylcysteine amide , Tanshinone IIA , resveratrol  and EPO-cyclosporine combination therapy  preserve neuronal function through anti-OS and anti-inflammatory mechanisms of action. Furthermore, many antioxidants have effects on neuroprotection via anti-OS and anti-apoptosis. Rhein , deuterohemin His peptide-6 , acteoside , Radix scrophulariae , pomalidomide , and Clostridium butyricum  protect the brain against cerebral I/R injury by inhibiting apoptosis and OS. Similarly, adiponectin , YiQiFuMai , epigallocatechin-3-gallate (EGCG) , Withania somnifera , SMXZF , and diallyl trisulfide  lessen neuronal impairment by attenuating mitochondrial caspase-independent apoptosis. Besides, plumbagin , hollow prussian blue nanozymes , geniposide , curcumin , and hexahydrocurcumin  play a role in neuronal protection by anti-OS, anti-inflammatory, and anti-apoptotic activities. In addition, as autophagy is a double-edged sword, promoting or inhibiting autophagy to exert neuroprotective effects depends on different conditions. On one hand, Sirt3  and β-arrestin-1  promote autophagy to play a neuroprotective role. On the other hand, vitexin , silibinin . 3-methyladenine , and astragalosides  inhibit autophagy to protect the brain. It is also worth mentioning that isoquercetin [205, 206] and EGCG  alleviate brain impairment via anti-OS, anti-inflammatory, anti-apoptotic, and anti-autophagocytic properties.
Like ischemic stroke, antioxidant defenses involving OS and OS-related processes are also found in ICH and SAH. Green tea [208, 209], cofilin , and mammalian sterile 20-like kinase-1  play a major role in ICH-induced SBI. Melatonin  and dexmedetomidine  reduce mitochondrial impairments and ameliorate SBI. Analogously, oleuropein  and adiponectin  attenuate brain edema and preserve the BBB structure in a dose-dependent manner. In addition, isoliquiritigenin  and Sirt3  improve ICH by inhibiting inflammatory and OS activities, whereas Sodium Benzoate  and carnosine  attenuate SBI and brain edema through suppression of neuronal apoptosis. As such, metformin , baicalein , hydrogen gas , protocatechuic acid , and hypoxia-inducible factor prolyl hydroxylase domain metalloenzymes  prevent neurological deficits after ICH by inhibiting apoptosis, OS, and neuroinflammation in rats.
Table 2 Antioxidants in Depression.
|Antioxidants||Anti-OS activity||Mechanism of anti-OS activity and others|
|Depression||bay 60-7550||anti-OS||downregulate gp91phox; activate the cAMP/cGMP-pVASP-CREB-BDNF signaling pathway|
|p-chloro-diphenyl diselenide||modulate glutamate neurotransmission|
|homocysteine||inhibit ROS by activating NMDA receptors|
|vitamin D||suppress OS|
|2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside||anti-OS; anti-inflammation||reduce proinflammatory factors; restore the diminished Akt signaling pathway; faciliate astrocyte proliferation and neurogenesis|
|vorinostat||modulate NF-κB p65, COX-2 and phosphorylated JNK levels|
|melatonin||inhibit OS and inflammation|
|ketamine||increase glutamate release; affect energy metabolism|
|mitochondrial uncoupling protein 2||anti-OS; anti-inflammation; anti-apoptosis||downregulate the activation of NLRP3 inflammasome; suppress the ROS-TXNIP-NLRP3 pathway in astrocytes|
|dl-3-n-butylphthalide||inhibit OS, inflammatory responses and apoptosis|
|allicin||reduce neuroinflammation, OS, iron overaccumulation; inhibit neuronal apoptosis in the hippocampus|
|AVLE||suppress the apoptosis of hippocampus cells via regulation of Bcl-2/Bax pathways|
Many preclinical experiments in SAH have demonstrated that inhibiting OS and OS-mediated pathological processes alleviates alleviates EBI, SBI, and neuronal deficits. Dimethyl formamide improves cognitive dysfunction via the Keap1-Nrf2-ARE system . Telmisartan , nebivolol  and curcumin  can ameliorate cerebral vasospasm, and Pterostilbene can attenuate EBI by inhibiting the NLRP3 inflammasome . Some antioxidants (e.g., apigenin , peroxiredoxin1/2 , docosahexaenoic acid , sodium hydrosulfide , cysteamine , gastrodin , naringin , and progesterone ) play a neuroprotective role in EBI through the effects of anti-apoptosis after SAH, but other antioxidants (e.g. AVE 0991 and mangiferin [56, 236] memantine [59, 237], salvianolic acid B [238, 239], salvianolic acid A , and allicin ) protect against SAH-induced oxidative injury via inhibition of oxidative, inflammatory, and apoptotic pathways. Stimulating autophagy to inhibit apoptosis of neural cells also works in improving neurological outcome with administration of mitoquinone  and melatonin .
Table 3 Co-antioxidants in stroke and depression from experiments.
|Clinical trials and outcomes in stroke||Clinical trials and outcomes in depression|
|flavonoid||meta-analysis||high flavonoid reduces risk of stroke||RCT||higher flavonoid links to lower depression risk especially among women|
|UA||RCT and URICOICTUS||UA is safe; UA enhances outcomes of stroke||cohort studies and meta-analysis||UA are associated with low risk of depression hospitalization and lower MDA levels|
|melatonin||RCT||early melatonin usage ameliorates the brain injury of asphyxial newborns||RCT||buspirone-melatonin therapy benefits cognitive function|
|Review||melatonin does not affect mood disorders|
Apart from stroke, using antioxidants may help improve depression. Generally, antioxidants exert antidepressant effects through their anti-OS characteristics (Table 2). Bay 60-7550 , p-chloro-diphenyl diselenide , homocysteine , and vitamin D  can attenuate depressive-like behaviors and improve depression. In a sense, the latest studies have focused on antioxidants that act against OS-induced inflammation. Examples of this include 2,3,5,4'-tetrahydroxystilbene-2-O-β-D- gluco-pyranoside  and vorinostat , which ameliorate inflammatory damage and OS to exert the antidepressant effect. Moreover, naringenin [250, 251], iptakalim , silymarin , resveratrol , honokiol , ketamine , melatonin , oxytocin , vanillin , trigonelline , quercetin , α-tocopherol , baicalin  and selenium-containing compounds  have neuroprotective effects in the hippocampus of mice due to their antioxidant and anti-inflammatory properties. Particularly, ketamine is involved in inducing the rapid antidepressant effects through increasing the release of glutamate in the body  and affecting energy metabolism in MDD . Furthermore, some antioxidants with multifunctional properties demonstrate anti-OS, anti-inflammatory, and anti-apoptotic characteristics in depression. These antioxidants include mitochondrial uncoupling protein 2 , dl-3-n-butylphthalide , indole-3-carbinol , or 25-methoxyhispidol A  and allicin . Of note, AVLE treatment has similar effects compared to fluoxetine on depression in the rat hippocampus .
Thus far, the use of antioxidants in animals has been successful in treating stroke or depression. According to the previous summarization, we have found some co-antioxidants (Table 3). Additionally, several clinical trials show that co-antioxidants exert protections in stroke and depression, including flavonoid and melatonin.
In stroke, high dietary flavonoid intake may modestly lower the risk of stroke due to its role in constraining OS-induced mitochondrial lipid peroxidation . In depression, flavonoids can limit ROS production and promote the chelation of transition metal elements [273, 274]. Also, flavonoids act as reversible and competitive human monoamine oxidase inhibitors in the CNS, leading to increased central neurotransmission . Moreover, a study enrolling 10,752 depressed individuals shows that higher flavonoid intake may be linked to lower depression risk, especially among older women .
UA is the primary endogenous antioxidant in blood. A randomized, double-blind phase 2b/3 trial (URICOI-CTUS) indicates that UA is safe without any concerns regarding safety, although the addition of UA to thrombolytic therapy does not raise the proportion of patients with excellent outcome after stroke . However, a reanalysis of the URICOICTUS trial suggests that UA suppresses infarct growth, and is more effective than the placebo in reaching an excellent outcome in patients who are treated with alteplase following acute ischemic stroke . Another clinical study supports the efficacy of UA therapy by showing decreased infarct growth and enhanced outcome in stroke survivors . In depression, researchers have found that UA is associated with a low risk of hospitalization for depression after examining the plasma levels of UA in 96,989 depressed subjects . Moreover, the efficacy of UA in depressed patients is supported by another large-scale study .
To our knowledge, few clinical trials have studied the neuroprotective effects of melatonin on cerebral ischemia prevention. A prospective trial involving 45 neonates indicates that it is practicable to provide early administration of melatonin to ameliorate brain injury in a choking newborn infant . In regards to treatment of MDD, preliminary findings of a study reveal that a combination of buspirone with melatonin can partially benefit cognitive function .
Table 4 Antidepressants in PSD treatment.
|Antioxidants in PSD||Clinical trials||Outcomes|
|fluoxetine||FOCUS||not support routine use of fluoxetine in preventing PSD or promoting function recovery|
|fluoxetine/paroxetine||meta-analysis of 12 trials||fluoxetine is the worst choice for PSD treatment; paroxetine is the best drug in terms of efficacy and acceptability|
|meta-analysis of 20 RCTs||citalopram has similar efficacy and safety as other SSRIs but acts faster than them|
|fluoxetine||FLAME||exhibit a positive connection between motor recovery|
|escitalopram||Cochrane review||escitalopram is the best tolerated SSRI, followed by sertraline and paroxetine for PSD|
|escitalopram||RCT||not take effects on depressive symptoms; diarrhea is more likely to occur|
|escitalopram||RCT||effective at decreasing the incidence of depression in nondepressed patients|
|Citalopram||RCT||safe for patients with acute ischemic stroke|
|Citalopram||RCT||different effects in different stages of PSD|
|citalopram||RCT||SSRI treatment is well tolerated and beneficial in PSD|
|SSRI||registry-based score-matched follow-up study||pre-stroke SSRI use increases risk of the hemorrhagic stroke; no increased stroke severity and mortality ischemic stroke|
|milnacipran||RCT||milnacipran prevents post-stroke depression; safe to use without serious adverse events|
Although many co-antioxidants are found in animal models of both diseases, only a few clinical trials have confirmed the efficacy of antioxidants in stroke and depression. The difficulty of antioxidants acting through the BBB in patients may be the reason for this result. Nevertheless, OS and OS-mediated pathways are co-mechanisms of stroke and depression. So, what is the role of antidepressants in stroke survivors?
At present, antidepressant drugs are widely used for treating post-stroke depression (PSD), but there are many adverse reactions at the same time. These events include gastroenterological symptoms, falls/fracture, and epilepsy . Therefore, future clinical trials should emphasize their focus on the efficacy and safety of antidepressant drugs in preventing or treating stroke (Table 4). Herein, we summarize some clinical trials in recent years with the objective of determining whether antidepressants (e.g., fluoxetine, escitalopram, milnacipran) are necessary for PSD patients. Results of FOCUS (effects of fluoxetine on functional outcomes after acute stroke) represent a lower incidence of new depression and a higher risk of bone fractures in the group in which fluoxetine is allocated, when compared with the controls. Those outcomes do not support the routine use of fluoxetine in preventing PSD or promoting function recovery . In addition, a meta-analysis of 12 suitable trials demonstrated that fluoxetine is the worst choice for PSD treatment, while paroxetine is an effective and acceptable drug . However, FLAME (fluoxetine for motor recovery after acute ischemic stroke) exhibits a positive connection between motor recovery and fluoxetine use in PSD patients . The second drug is escitalopram. Kim K et al. did a Cochrane systematic review of 13 trials of antidepressant drugs, and confirmed that escitalopram is the most tolerated SSRI . Another study also indicates that escitalopram was well-tolerated, though it does not have any effects on the depressive symptoms in PSD patients . Robinson et al. illustrated that escitalopram is significantly effective at decreasing the incidence of depression in patients with recent stroke over 12-month therapy . Thirdly, citalopram is reported to be a safe medication in patients with acute ischemic stroke , and it improves PSD . In conclusion, fluoxetine is not necessary for PSD treatment, but it is good for motor recovery. Escitalopram and citalopram are both tolerated and may have benefits in PSD patients. However, the question of whether to allocate antidepressants in post-stroke patients is still controversial, when considering efficacy and safety. Additionally, is pre-stroke SSRI therapy useful for patients with stroke? Mortensen et al. conducted a study enrolling hemorrhagic stroke patients and ischemic stroke patients. They found that pre-stroke SSRI use increased severity and mortality in patients with hemorrhagic stroke, but there was no increase in ischemic stroke patients . Finally, milnacipran also plays a role in preventing PSD and it is safe to use, without any serious adverse events, according to an RCT performed by Ching-Shu Tsai . Due to the limited data showing a relationship between depressants and PSD, more multicenter clinical trials should be conducted.
This review discusses the central role of OS in the “aging-stroke-depression” network and antioxidants in treating stroke or depression, as well as antidepressant in PSD. Although all of the studies have immeasurable contributions to scientific exploration, there are some limitations in the current studies. First, depression is a psychiatric disorder lacking effective biomarkers or methods, and depressive symptoms may be less apparent, making it difficult to procure an accurate diagnosis for depression . Relatively uniform and accurate diagnostic criteria for depression must be improved . Second, this review focuses on major depression, leaving an unclear relationship between other depression phases and stroke. Third, although this review suggests aging as a risk for stroke and depression, the link is often found in aged adults, but not analyzed in other age groups [296, ]33]. For future studies, it is suggested that there should be an emphasis on certain age demographics. Fourth, human brains have a natural and complex protective barrier, which prevents antioxidant drugs from entering into the CNS, partially explaining the reduced efficacy of these drugs in experimental models . Finding carriers that can penetrate the blood-brain barrier, such as nanoparticles, may address this problem. Fifth, there are data deviations due to the lack of dose-response analysis, limitations on sample size, representativeness of the sample, statistical methods, inclusion criteria, and follow-up [37, 298, 299]. Therefore, studies should be conducted in a more precise manner. Furthermore, drug dose, window time, and methods of administration also warrant our attention. All things considered, further studies are required to improve the diagnosis of depression, to find drugs directed at overproduced ROS with higher efficacy and safety, and to enhance the quality of life after diseases.
This work was funded by the China Postdoctoral Science Foundation (2017M612010), National Natural Science Foundation of China (81701144, 81371433, and 8187 0916), and Major Science and Technology project in medical and health of Zhejiang Province (WKJ-ZJ-1615:2016149634). Wish the global epidemic of 2019 novel coronavirus pneumonia ends soon.
Conflict of interest
The authors state that there was no conflict of interest in the preparation of this review.
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Neuroprotective mechanisms of dieckol against glutamate toxicity through reactive oxygen species scavenging and nuclear factor-like 2/heme oxygenase-1 pathway. ,
Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. ,
Uric Acid Protects against Focal Cerebral Ischemia/Reperfusion-Induced Oxidative Stress via Activating Nrf2 and Regulating Neurotrophic Factor Expression. ,
A Dual AMPK/Nrf2 Activator Reduces Brain Inflammation After Stroke by Enhancing Microglia M2 Polarization. ,
Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats. ,
Nitroxide antioxidant as a potential strategy to attenuate the oxidative/nitrosative stress induced by hydrogen peroxide plus nitric oxide in cultured neurons. Nitric Oxide-Biology and,
3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway. ,
3-n-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke. ,
Post-ischemic administration of 5-methoxyindole-2-carboxylic acid at the onset of reperfusion affords neuroprotection against stroke injury by preserving mitochondrial function and attenuating oxidative stress. ,
Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. ,
Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats. ,
Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic(-)Ischemic Brain Injury. ,
Ginkgolide K promotes angiogenesis in a middle cerebral artery occlusion mouse model via activating JAK2/STAT3 pathway. ,
Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2-related factor 2 pathway.
Astragaloside IV protects blood-brain barrier integrity from LPS-induced disruption via activating Nrf2 antioxidant signaling pathway in mice. ,
Osthole, a natural coumarin improves cognitive impairments and BBB dysfunction after transient global brain ischemia in C57 BL/6J mice: involvement of Nrf2 pathway. ,
Panax notoginseng Saponins Protect Cerebral Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Reperfusion-Induced Barrier Dysfunction via Activation of PI3K/Akt/Nrf2 Antioxidant Signaling Pathway. ,
Chinese herbal medicine formula tao hong si wu decoction protects against cerebral ischemia-reperfusion injury via PI3K/Akt and the Nrf2 signaling pathway. ,
Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation. ,
Tryptanthrin Suppresses the Activation of the LPS-Treated BV2 Microglial Cell Line via Nrf2/HO-1 Antioxidant Signaling. ,
Neuroprotective effects of andrographolide derivative CX-10 in transient focal ischemia in rat: Involvement of Nrf2/AE and TLR/NF-kappaB signaling. ,
Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. ,
Dioscin inhibits ischemic stroke-induced inflammation through inhibition of the TLR4/MyD88/NF-B signaling pathway in a rat model. ,
Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury. ,
The Zinc Ion Chelating Agent TPEN Attenuates Neuronal Death/apoptosis Caused by Hypoxia/ischemia Via Mediating the Pathophysiological Cascade Including Excitotoxicity, Oxidative Stress, and Inflammation. ,
Inhibition of Myeloperoxidase by N-Acetyl Lysyltyrosylcysteine Amide Reduces Oxidative Stress-Mediated Inflammation, Neuronal Damage, and Neural Stem Cell Injury in a Murine Model of Stroke. ,
Tanshinone IIA Elicits Neuroprotective Effect Through Activating the Nuclear Factor Erythroid 2-Related Factor-Dependent Antioxidant Response. ,
Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis. ,
EPO-cyclosporine combination therapy reduced brain infarct area in rat after acute ischemic stroke: role of innate immune-inflammatory response, micro-RNAs and MAPK family signaling pathway. ,
Rhein protects against cerebral ischemic/reperfusioninduced oxidative stress and apoptosis in rats. ,
Cancer stemness and metastatic potential of the novel tumor cell line K3: an inner mutated cell of bone marrow-derived mesenchymal stem cells.
Acteoside Attenuates Oxidative Stress and Neuronal Apoptosis in Rats with Focal Cerebral Ischemia-Reperfusion Injury. ,
Neuroprotective Effects of Radix Scrophulariae on Cerebral Ischemia and Reperfusion Injury via MAPK Pathways. ,
Pomalidomide Ameliorates H(2)O(2)-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects. ,
Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. ,
Adiponectin Attenuates Oxygen-Glucose Deprivation-Induced Mitochondrial Oxidative Injury and Apoptosis in Hippocampal HT22 Cells via the JAK2/STAT3 Pathway. ,
YiQiFuMai Powder Injection Protects against Ischemic Stroke via Inhibiting Neuronal Apoptosis and PKCdelta/Drp1-Mediated Excessive Mitochondrial Fission. ,
Epigallocatechin-3-Gallate Reduces Neuronal Apoptosis in Rats after Middle Cerebral Artery Occlusion Injury via PI3K/AKT/eNOS Signaling Pathway. ,
Withania somnifera Improves Ischemic Stroke Outcomes by Attenuating PARP1-AIF-Mediated Caspase-Independent Apoptosis. ,
Cocktail of Four Active Components Derived from Sheng Mai San Inhibits Hydrogen Peroxide-Induced PC12 Cell Apoptosis Linked with the Caspase-3/ROCK1/MLC Pathway. ,
Diallyl trisufide protects against oxygen glucose deprivation -induced apoptosis by scavenging free radicals via the PI3K/Akt -mediated Nrf2/HO-1 signaling pathway in B35 neural cells. ,
Hollow Prussian Blue Nanozymes Drive Neuroprotection against Ischemic Stroke via Attenuating Oxidative Stress, Counteracting Inflammation, and Suppressing Cell Apoptosis. ,
Geniposide protects against hypoxia/reperfusion-induced blood-brain barrier impairment by increasing tight junction protein expression and decreasing inflammation, oxidative stress, and apoptosis in an in vitro system. ,
Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. ,
Hexahydrocurcumin protects against cerebral ischemia/reperfusion injury, attenuates inflammation, and improves antioxidant defenses in a rat stroke model. ,
Sirt3 confers protection against neuronal ischemia by inducing autophagy: Involvement of the AMPK-mTOR pathway. ,
ARRB1/beta-arrestin-1 mediates neuroprotection through coordination of BECN1-dependent autophagy in cerebral ischemia. ,
Vitexin reverses the autophagy dysfunction to attenuate MCAO-induced cerebral ischemic stroke via mTOR/Ulk1 pathway. ,
Silibinin Prevents Autophagic Cell Death upon Oxidative Stress in Cortical Neurons and Cerebral Ischemia-Reperfusion Injury. ,
Folic acid deficiency increases brain cell injury via autophagy enhancement after focal cerebral ischemia. ,
Beneficial effect of astragalosides on stroke condition using PC12 cells under oxygen glucose deprivation and reperfusion. ,
Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-kappaB pathway. ,
Isoquercetin Ameliorates Cerebral Impairment in Focal Ischemia Through Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Effects in Primary Culture of Rat Hippocampal Neurons and Hippocampal CA1 Region of Rats. ,
Epicatechin Gallate Protects HBMVECs from Ischemia/Reperfusion Injury through Ameliorating Apoptosis and Autophagy and Promoting Neovascularization. ,
Short-term green tea supplementation prevents recognition memory deficits and ameliorates hippocampal oxidative stress induced by different stroke models in rats. ,
Green Tea and Red Tea from Camellia sinensis Partially Prevented the Motor Deficits and Striatal Oxidative Damage Induced by Hemorrhagic Stroke in Rats. ,
Cofilin Knockdown Attenuates Hemorrhagic Brain Injury-induced Oxidative Stress and Microglial Activation in Mice. ,
Exploration of MST1-Mediated Secondary Brain Injury Induced by Intracerebral Hemorrhage in Rats via Hippo Signaling Pathway.
Dexmedetomidine Protects Against Neurological Dysfunction in a Mouse Intracerebral Hemorrhage Model by Inhibiting Mitochondrial Dysfunction-Derived Oxidative Stress. ,
Oleuropein protects intracerebral hemorrhage-induced disruption of blood-brain barrier through alleviation of oxidative stress. ,
Overexpression of adiponectin alleviates intracerebral hemorrhage-induced brain injury in rats via suppression of oxidative stress. ,
Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-kappaB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway. ,
Sirt3 Ameliorates Oxidative Stress and Mitochondrial Dysfunction After Intracerebral Hemorrhage in Diabetic Rats. ,
Sodium Benzoate Attenuates Secondary Brain Injury by Inhibiting Neuronal Apoptosis and Reducing Mitochondria-Mediated Oxidative Stress in a Rat Model of Intracerebral Hemorrhage: Possible Involvement of DJ-1/Akt/IKK/NFkappaB Pathway. ,
Carnosine Attenuates Brain Oxidative Stress and Apoptosis After Intracerebral Hemorrhage in Rats. ,
Metformin Attenuates Neurological Deficit after Intracerebral Hemorrhage by Inhibiting Apoptosis, Oxidative Stress and Neuroinflammation in Rats. ,
Baicalein Promotes Neuronal and Behavioral Recovery After Intracerebral Hemorrhage Via Suppressing Apoptosis, Oxidative Stress and Neuroinflammation. ,
Neuroprotective effects of hydrogen inhalation in an experimental rat intracerebral hemorrhage model. ,
Protocatechuic acid exerts protective effects via suppression of the P38/JNK- NF-kappaB signalling pathway in an experimental mouse model of intracerebral haemorrhage. ,
Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. ,
Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system. ,
Telmisartan ameliorates oxidative stress and subarachnoid haemorrhage-induced cerebral vasospasm. ,
Nebivolol attenuates cerebral vasospasm both by increasing endothelial nitric oxide and by decreasing oxidative stress in an experimental subarachnoid haemorrhage. ,
Curcumin mitigates cerebral vasospasm and early brain injury following subarachnoid hemorrhage via inhibiting cerebral inflammation. ,
Pterostilbene Attenuates Early Brain Injury Following Subarachnoid Hemorrhage via Inhibition of the NLRP3 Inflammasome and Nox2-Related Oxidative Stress. ,
Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage. ,
Peroxiredoxin 1/2 protects brain against H2O2-induced apoptosis after subarachnoid hemorrhage. ,
Docosahexaenoic Acid Alleviates Oxidative Stress-Based Apoptosis Via Improving Mitochondrial Dynamics in Early Brain Injury After Subarachnoid Hemorrhage. ,
Hydrogen Sulfide Ameliorates Early Brain Injury Following Subarachnoid Hemorrhage in Rats. ,
Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. ,
Effect of Gastrodin on Early Brain Injury and Neurological Outcome After Subarachnoid Hemorrhage in Rats. ,
Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model. ,
AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats. ,
Memantine alleviates brain injury and neurobehavioral deficits after experimental subarachnoid hemorrhage. ,
Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways. ,
Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. ,
Salvianolic acid A attenuates early brain injury after subarachnoid hemorrhage in rats by regulating ERK/P38/Nrf2 signaling. ,
Allicin attenuates early brain injury after experimental subarachnoid hemorrhage in rats. ,
Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in Rats. ,
Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. ,
Inhibition of phosphodiesterase 2 reverses gp91phox oxidase-mediated depression- and anxiety-like behavior. ,
4,4'-Dichlorodiphenyl diselenide reverses a depressive-like phenotype, modulates prefrontal cortical oxidative stress and dysregulated glutamatergic neurotransmission induced by subchronic dexamethasone exposure to mice. ,
Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. ,
Vitamin D Supplementation Affects the Beck Depression Inventory, Insulin Resistance, and Biomarkers of Oxidative Stress in Patients with Major Depressive Disorder: A Randomized, Controlled Clinical Trial. ,
2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside Reverses Stress-Induced Depression via Inflammatory and Oxidative Stress Pathways. ,
Antidepressant activity of vorinostat is associated with amelioration of oxidative stress and inflammation in a corticosterone-induced chronic stress model in mice. ,
Naringenin protects against oxido-inflammatory aberrations and altered tryptophan metabolism in olfactory bulbectomized-mice model of depression. ,
Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. ,
Activation of ATP-sensitive potassium channel by iptakalim normalizes stress-induced HPA axis disorder and depressive behaviour by alleviating inflammation and oxidative stress in mouse hypothalamus. ,
Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response. ,
Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior. ,
Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. ,
Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system. ,
Postnatal melatonin treatment protects against affective disorders induced by early-life immune stimulation by reducing the microglia cell activation and oxidative stress. ,
Oxytocin improves animal behaviors and ameliorates oxidative stress and inflammation in autistic mice. ,
Effects of vanillin on potassium bromate-induced neurotoxicity in adult mice: impact on behavior, oxidative stress, genes expression, inflammation and fatty acid composition. ,
Trigonelline mitigates lipopolysaccharide-induced learning and memory impairment in the rat due to its anti-oxidative and anti-inflammatory effect. ,
Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. ,
alpha-Tocopherol Ameliorates Redox Equilibrium and Reduces Inflammatory Response Caused by Chronic Variable Stress.
Baicalin ameliorates chronic mild stress-induced depression-like behaviors in mice and attenuates inflammatory cytokines and oxidative stress. ,
The selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole reverses depressive-like behavior induced by acute restraint stress in mice: modulation of oxido-nitrosative stress and inflammatory pathway.
The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. ,
Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression. ,
Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-kappaB pathways. ,
Effects of indole-3-carbinol on clonidine-induced neurotoxicity in rats: Impact on oxidative stress, inflammation, apoptosis and monoamine levels. ,
Effect of 25-methoxy hispidol A isolated from Poncirus trifoliate against bacteria-induced anxiety and depression by targeting neuroinflammation, oxidative stress and apoptosis in mice. ,
Allicin attenuated chronic social defeat stress induced depressive-like behaviors through suppression of NLRP3 inflammasome. ,
Apocynum venetum leaf extract reverses depressive-like behaviors in chronically stressed rats by inhibiting oxidative stress and apoptosis. ,
Dietary flavonoid intake and the risk of stroke: a dose-response meta-analysis of prospective cohort studies. ,
Protective Effect of Quercetin against Oxidative Stress-Induced Cytotoxicity in Rat Pheochromocytoma (PC-12) Cells. ,
Gaultheria trichophylla (Royle): a source of minerals and biologically active molecules, its antioxidant and anti-lipoxygenase activities. ,
Inhibition of Human Monoamine Oxidase: Biological and Molecular Modeling Studies on Selected Natural Flavonoids. ,
Dietary flavonoid intake and risk of incident depression in midlife and older women. ,
Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. ,
Uric Acid Therapy Improves Clinical Outcome in Women With Acute Ischemic Stroke. ,
Uric acid improves glucose-driven oxidative stress in human ischemic stroke. ,
Association between the antioxidant uric acid and depression and antidepressant medication use in 96 989 individuals. ,
Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression. ,
Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. ,
Changes in cognitive symptoms after a buspirone-melatonin combination treatment for Major Depressive Disorder. ,
Post-stroke depression: Mechanisms and pharmacological treatment. ,
Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. ,
Comparative efficacy and acceptability of antidepressant treatment in poststroke depression: a multiple-treatments meta-analysis. ,
Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. ,
Management of post-stroke mood and emotional disturbances. ,
Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study. ,
Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. ,
Efficacy of Citalopram on Acute Ischemic Stroke Outcome: A Randomized Clinical Trial. ,
TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke. ,
Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality. ,
Prevention of poststroke depression with milnacipran in patients with acute ischemic stroke: a double-blind randomized placebo-controlled trial. ,
Neuropsychiatric sequelae of stroke. ,
Depression predictors within six months of ischemic stroke: The DEPRESS Study. ,
Blood-Brain Barrier: From Physiology to Disease and Back. ,
Dietary flavonoid intake and the risk of stroke: a dose-response meta-analysis of prospective cohort studies. ,
Melatonin as a treatment for mood disorders: a systematic review. ,
Free radicals and antioxidants in normal physiological functions and human disease. ,
Reactive Oxygen Species in Metabolic and Inflammatory Signaling. ,
NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. ,
Pharmacological applications of antioxidants: lights and shadows. ,
Inflammatory Pathways Following Subarachnoid Hemorrhage.