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Aging and disease    2018, Vol. 9 Issue (4) : 729-744     DOI: 10.14336/AD.2017.1014
Review Article |
Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease
Eckert Schamim H1, Gaca Janett1, Kolesova Nathalie1, Friedland Kristina1,2, Eckert Gunter P1,3, Muller Walter E1,*
1Department of Pharmacology, University of Frankfurt/M, Biocenter, D-60438 Frankfurt, Germany
2Deparment of Molecular and Clinical Pharmacy, University of Erlangen, D-91058 Erlangen, Germany
3Department of Nutricional Sciences, University of Giessen, D-35392 Giessen, Germany
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Abstract  

Dimebon (latrepirdine), an old antihistaminic drug, showed divergent results in two large clinical trials in Alzheimer disease (AD), which according to our review might be related to the specific pharmacological properties of the drug and the different patient populations included in both studies. Out of the many pharmacological effects of Dimebon, improvement of impaired mitochondrial function seeems to be most relevant for the substantial effects on cognition and behaviour reported in one of the studies, as these effects are already present at the low concentrations of dimebon measured in plasma and tissues of patients and experimental animals. Since impaired mitochondrial function seems to be the major driving force for the progression of the clinical symptoms and since most of the clinical benefits of dimebon originate from an effect on the symptomatic deterioration, mitochondrial improvement can also explain the lack of efficacy of this drug in another clinical trial where symptoms of the patiets remained stable for the time of the study. Accordingly, it seems worthwhile to reevaluate the clinical data to proof that clinical response is correlated with high levels of Neuropsychiatric Symptoms as these show a good relationship to the individual speed of symptomatic decline in AD patients related to mitochondrial dysfunction.

Keywords Alzheimer disease      mitochondrial dysfunction      dimebon      latrepirdine      cognitive decline     
Corresponding Authors: Muller Walter E   
About author:

These authors equally contributed to this work.

Issue Date: 01 August 2018
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Eckert Schamim H
Gaca Janett
Kolesova Nathalie
Friedland Kristina
Eckert Gunter P
Muller Walter E
Cite this article:   
Eckert Schamim H,Gaca Janett,Kolesova Nathalie, et al. Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease[J]. Aging and disease, 2018, 9(4): 729-744.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1014     OR     http://www.aginganddisease.org/EN/Y2018/V9/I4/729
Figure 1.  Effects on respiratory activity (adapted and mofified from Eckert et al. [<xref ref-type="bibr" rid="b36-ad-9-4-729">36</xref>])

HEKsw cells were incubated for 6 h with dimebon (0.1 µM) and oxygen consumption (respiration [pmolx s-1 x mill-1 cells]) was measured in different mitochondrial stages by injecting several substrates and inhibitors in an Oxygraph 2k (Innsbruck, Austria). CIOXPHOS, CI dependent oxidative phosphorylationdetermined with complex I related substrates glutamate, malate and ADP; CI+IIOXPHOS, oxidative phosphorylation providing CI and CII substrates by addition of succinate; CI+IIETS, non-coupled respiration with CI and CII substrates, is considered as maximum capacity of the ETS by uncoupling with carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP, injected stepwise up to 1-1.5 µM); CIIETS, non-coupled CII dependent respirationby subsequent inhibition of complex I with rotenone; CIVETS, non-coupled respiration with CIV substrates, applying tetramethylphenylenediamine (TMPD) as an artificial substrate and ascorbate to keep TMPD in the reduced state. Values represent the means ± SEM from n = 6-9 experiments per protocol, Two-way ANOVA with Bonferroni post-tests, *p<0.05, **p<0.01, ***p<0.001.

Figure 2.  Effects on mitochondrial morphology (adapted and modified from Eckert et al. [<xref ref-type="bibr" rid="b36-ad-9-4-729">36</xref>] Müller et al. (37), Eckert (38))

HEK-cells harboring the Swedish mutation in the APP gene (HEKsw) and control cells (HEKut) cells were incubated with dimebon (0.1 µM) for 6 h. (A) For the determination of mitochondrial length, organells were labeled with Mito Tracker CMXRos, fixed with PFA. Mitochondrial lengths were quantified using Image J and classified in punctuated, truncated, tubular, and elongated mitochondria. Data represent the means ± SEM with at least 100 measured mitochondria per experiment, n = 8-9, Two-way ANOVA with Bonferroni post-tests, **p<0.01, ***p<0.001. (B, C) Effects of dimebon on expression levels of fission and fusion marker. Marker proteins for fission dynamin related protein1 (Drp) and fission 1 related protein (Fis), as well as markers for mitochondrial fusion protein 1 (Mfn) and optic atrophie-1 (Opa) were measured using Western Blot analysis, after electrophoretic separation and using specific antibodies. Cellular location of the proteins in the cytosolic fraction as well as in inner (IMM) and outer (OMM) mitochondrial membranes is indicated. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, *p<0,05, **p<0,01, ***p<0,001 vs. ctl; #p<0,05, ##p<0,01 vs. HEKsw. (D) Representative Western Blots.

Figure 3.  Effects on mitochondrial membrane composition (adapted and modified from Müller et al. [<xref ref-type="bibr" rid="b37-ad-9-4-729">37</xref>], Eckert [<xref ref-type="bibr" rid="b38-ad-9-4-729">38</xref>])

Cells were incubated with 0,1 μM dimebon (Dim) for 6 h. (A) In HEK control cells (HEKut) and (B) HEK-cells harboring the Swedish mutation in the APP gene (HEKsw), marker proteins for the inner (IMM) and the outer mitochondrial membrane (OMM), were measured in total homogenates, using Western Blot analysis after electrophoretic separation and using specific antibodies against translocator proteins of the inner (TIMM50) and outer (TOMM22) mitochondrial membrane, respectively. Data were normalized to HEKut (100% in A) and HEKsw (100% in B), respectively. Data represent the means ± SEM, n = 6, Two-way ANOVA with Bonferroni post-tests, *p<0,05, ***p<0,001. (C) Representative Western Blots.

Figure 4.  Effects on mitophagy (adapted and modified from Müller et al.[<xref ref-type="bibr" rid="b37-ad-9-4-729">37</xref>], Eckert [<xref ref-type="bibr" rid="b38-ad-9-4-729">38</xref>])

(A) Control cells (HEKut) and (C) HEK-cells harboring the Swedish mutation in the APP gene (HEKsw) an were incubated with 0,1 µM dimebon (Dim) for 6 h. Autophagy marker proteins for the cytosol (LC3-I) and autophagosomal membranes (LC3-II) as well as the transcription marker peroxisome proliferation-activated receptor gamma coactivator 1-alpha (PGC), were measured using western blot analysis after electrophoretic separation and using specific antibodies in total cellular homogenates. (B & D) A low LC3-I/LC3-II ratio indicates high degree of mitophagy. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, *p<0,05, **p<0,01 vs. HEKut ctr; #p<0,05 vs. HEKsw ctl. (E) Representative Western Blots.

Figure 5.  Effects on structure and function of the mitochondrial permeability transition pore (mPTP) (adapted and modified from Müller et al. [<xref ref-type="bibr" rid="b36-ad-9-4-729">36</xref>])

(A) HEKswcells were incubated with 0,1 µM dimebon (Dim) for 6 h, mPTP marker proteins of the outer mitochondrial membranes (OMM), voltage-depended anion channel (VDAC) and peripheral benzodiazepine receptor (PBR), were examined using western blot analysis after electrophoretic separation and using specific antibodies in total homogenates. Data were normalized to HEKut (100%) and represent the means ± SEM, n = 8-9, Two-way ANOVA with Bonferroni post-tests, **p<0,01, *p<0,05, ***p<0,001 vs. HEKut ctl; #p<0,05 vs. HEKsw ctl. (B) Representative Western Blots. In HEKsw cells, dimebon dramatically restored the increased expression levels of these mPTP markers (Fig 5 A). (C) Exemplary graph of a measurement of light scattering which is equivalent to mitochondrial swelling; Ca2+: inductor of physiological extent of mitochondrial swelling; Ala: Alamethicin [3.2 mg/mL], inductor of maximal mitochondrial swelling. (D) Swelling of isolated mitochondria from female NMRI mice challenged with calcium (Ca2+, 2 mmol/mg protein) and simultaneously incubated with cyclosporin A, a known inhibitor of mitochondrial swelling (CsA, 1 µM) and dimebon (0.1 µM; statistics were calculated against calcium insult; (; n=5-8; mean ± SEM; p*<0.05; p**<0.01; p***<0.001

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