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Aging and disease    2016, Vol. 7 Issue (4) : 336-449     DOI: 10.14336/AD.2016.0117
Original Article |
Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model
Cai Pingtao1, Ye Jingjing1, Zhu Jingjing1, Liu Dan1, Chen Daqing2, Wei Xiaojie3, Johnson Noah R.4, Wang Zhouguang1, Zhang Hongyu1, Cao Guodong4, Xiao Jian1,*, Ye Junming5,*, Lin Li1,*
1School of Pharmaceutical Sciences, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
2Emergency Department, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
3Department of Neurosurgery, Cixi People’s Hospital, Wenzhou Medical University, Ningbo, Zhejiang, 315300, China
4Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
5Department of Anesthesia, the First Affiliated Hospital, Gannan Medical College, Ganzhou, 341000, China
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Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress.

Keywords Parkinson's disease      ER stress      bFGF      6-OHDA     
Corresponding Authors: Xiao Jian,Ye Junming,Lin Li   
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These authors had equal contribution and are designated as co-first authors.

Issue Date: 01 August 2016
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Cai Pingtao
Ye Jingjing
Zhu Jingjing
Liu Dan
Chen Daqing
Wei Xiaojie
Johnson Noah R.
Wang Zhouguang
Zhang Hongyu
Cao Guodong
Xiao Jian
Ye Junming
Lin Li
Cite this article:   
Cai Pingtao,Ye Jingjing,Zhu Jingjing, et al. Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model[J]. Aging and disease, 2016, 7(4): 336-449.
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Figure 1.  Effects of bFGF infusions on amphetamine-induced rotation and neurotransmitter levels in the striatum of PD model rats. (A) Effects of bFGF administration on the apomorphine (APO)-induced ipsilateral rotations measured at 1, 2 and 3 weeks after lesion. **P < 0.01 versus sham group, # P < 0.05 and ## P < 0.01 versus PD group. (B), (C), (D) The levels of monoamine neurotransmitters in the striatum detected by HPLC-ED at 3 weeks post-lesion. **P < 0.01 versus sham group, #P < 0.05 and ##P < 0.01 versus PD group. Values are presented as the mean ± SD (n = 10).
Figure 2.  Effects of bFGF on TH levels and ER stress-related proteins at 3 weeks post-lesion in PD rats. (A) Immunohistochemistry of TH-positive cells in the right and left nigra. (B) TH levels analyzed by Western blot. **P < 0.01 versus sham group, ##P < 0.01 versus PD group. (C) Immunohistochemical analysis of GRP78, CHOP and caspase-12 in the left nigra. (D) GRP78, CHOP and caspase-12 levels analyzed by Western blot. (E) Erk1/2 and Akt analyzed by Western blot. **P < 0.01 versus sham group, #P < 0.05 and ##P < 0.01 versus PD group (n = 6).
Figure 3.  Effects of bFGF on 6-OHDA-induced apoptosis in primary hippocampal neurons. (A) Primary hippocampal neurons were treated with different concentrations of 6-OHDA for 24 h, and then cell viability was assessed by MTT assay. (B) Primary hippocampal neurons were treated with 6-OHDA (150 µM) and different concentrations of bFGF for 24 h, and then cell viability was assessed by MTT assay. (C) Primary hippocampal neurons were treated with 6-OHDA (150 µM) and bFGF (20 ng/ml) for 24 h, and then cells were stained with annexin V-FITC/propidium iodide and detected by flow cytometry; the lower right panel indicates the apoptotic cells. (D) Levels of cell apoptosis. *P < 0.05 versus control group, **P < 0.01, ***P< 0.001, #P < 0.05 versus 6-OHDA group (n = 3).
Figure 4.  Effect of bFGF on 6-OHDA-induced ER stress and Erk/Akt phosphorylation in primary hippocampal neurons. (A) Primary hippocampal neurons were treated with 6-OHDA (150 µM) and bFGF (20 ng/ml) for 24 h. Cells were then collected, and ATF6,GRP78, XBP-1, caspase12, CHOP were analyzed by Western blot. (B) Optical density analysis of ER stress-related proteins. (C) p-Erk1/2, Erk1/2, p-Akt and Akt were analyzed by Western blot. (D) Optical density analysis of p-Erk/Erk and p-Akt/Akt. *P < 0.05 and **P < 0.01 versus control group, #P < 0.05 versus 6-OHDA group (n = 3).
Figure 5.  Inhibition of PI3K/Akt and Erk1/2 pathways partially attenuates the reduction of the ER stress by bFGF in primary hippocampal neurons. (A) Primary hippocampal neurons were treated with or without the specific inhibitors LY294002 (20 μM) and U0126 (20 μM). Cell lysates were then analyzed by Western blotting for the expression of p-Akt, Akt, p-Erk, Erk, GRP78, XBP-1, ATF6, cleaved-caspase-12, and TH. Bar diagrams of (B) p-Akt/Akt and p-Erk/Erk; (C) GRP78, XBP-1, and ATF6; (D) cleaved caspase-12 and CHOP; and (E) TH from three Western blot analyses. *P < 0.05 versus control group, #P < 0.05 versus 6-OHDA group (n = 3).
Figure 6.  Inhibition of PI3K/Akt and Erk1/2 pathways partially impairs the protective effects of bFGF in 6-OHDA-induced primary hippocampal neurons. (A) Primary hippocampal neurons were collected and stained with annexin V-FITC/PI and detected by flow cytometry; the lower right panel indicates apoptotic cells. (B) Cell apoptosis levels from three separate experiments. ***P < 0.001 versus control group, #P < 0.05 versus 6-OHDA group (n = 3).
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