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Folia Neuropathologica
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3/2022
vol. 60
 
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Original paper

Mitochonic acid 5 ameliorates the motor deficits in the MPTP-induced mouse Parkinson’s disease model by AMPK-mediated autophagy

Juan Wan
1, 2
,
Yijiang Gao
1, 2
,
Jian Tan
1, 2
,
Shanqing Yi
1, 2
,
Kailiang Huang
3
,
Yao Liu
1, 2
,
Dong Chang
1, 2
,
Jiali Xie
1, 2
,
Shuangxi Chen
1, 2, 4
,
Heng Wu
1, 2

1.
The First Affiliated Hospital, Department of Neurology, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
2.
Clinical Research Center for Immune-Related Encephalopathy in Hunan Province, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
3.
Department of Emergency, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, PR China
4.
Health Center of Yumushan Town, Zhengxiang District, Hengyang, Hunan, PR China
Folia Neuropathol 2022; 60 (3): 329-337
Online publish date: 2022/10/11
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- Mitochonic.pdf  [0.15 MB]
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Introduction


Parkinson’s disease (PD), a common neurodegenerative disease in aging people, affects more than 4 million population around the world [4]. In this aging disorder, the degeneration of dopaminergic neurons was observed in substantia nigra pars compacta (SNpc), and resultant depletion of dopamine was detected in the striatum, accompanied by both motor and non-motor symptoms [13,14]. Current drug therapies for PD provide only symptomatic treatment and do not prevent the progressive loss of dopaminergic neurons in PD patients and concomitant decline [1]. It has been suggested that excessive generation of reactive oxygen species (ROS), oxidative stress, neuroinflammation, and mitochondrial dysfunction may account for the loss of dopaminergic neurons and neuronal apoptosis [30,36,52]. In this setting, to find an agent that can reduce the oxidative stress and inhibit neuroinflammation may be beneficial for the treatment of PD.
Mitochonic acid 5 (MA-5), an analogue of indole3-acetic acid with its key roles in reducing neuroinflammation and preserving microglial function via synthesizing the indispensable neurotransmitters [38], is originally isolated from the plant [44], which primarily benefited from mitochondrial function mitochondrial function via reducing mitochondrial oxidative stress and accelerating mitochondrial energy metabolism [29]. MA-5 has been tested for treatment in patients with mitochondrial disease, cardiac myocyte damage and renal tubular injury [56]. MA-5 increases cellular ATP and protects mitochondrial patients’ fibroblasts from cell death [44]. MA-5 also upregulates cardiac and renal respiration in the mitochondrial disease model [34]. Moreover, accumulating evidence indicates that MA-5 can attenuate the neuroinflammation and the apoptosis via activating the mitophagy [22,26,46].
Yet, since multiple mechanisms come into exert in PD, we then searched for other targets involved in MA-5 that can ameliorate PD. One of targets is autophagy, a pathway related to the degradation of organelles and protein [32], which is associated with the pathology of PD [5]. Autophagic dysfunction has been identified in various PD animal models and samples obtained from PD patients [28]. Accumulated evidence reveals that autophagy exerts critical roles in neuroprotection [15,55], for instance, the autophagic pathway can protect the survival of dopaminergic neurons via removing the synuclein in SNpc in PD models [2]. AMP-activated protein kinase (AMPK)/mTOR signalling, playing an essential role in neuronal survival and cell death [50,53], is associated with the regulation of autophagy in PD [12]. It has been demonstrated that activation of AMPK ameliorates the phenotypes of PD in Drosophila genetic models [35]. In addition, the induction AMPK-mediated autophagy by a multiple of drugs, including resveratrol and metformin, has recently been demonstrated to accelerate the functional recovery after spinal cord injury (SCI) [54,55].
Given the key neuroprotective roles of MA-5 under diseased conditions, we were interested in the effect of MA-5 on PD, hence, hypothesizing that MA-5 may exert a neuroprotective role in PD by fostering neuroinflammation via activating AMPK-mediated autophagy. In the present study, we reported a neuroprotective role of MA-5 against MPTP-induced neurotoxicity via activating AMPK-mediated autophagy, proposing that MA-5 is a novel candidate for the therapeutic strategy of PD.

Material and methods

Animals and groups


The 4-week-old male C57BL/6 mice with the body weight of 18 g were purchased from Hunan SJA Laboratory Animal CO., LTD and maintained (4/cage) in an air-conditioned room (22 ±1°C) with a 12 h light/12 h dark cycle and water and food ad libitum. All experimental protocols performed on animals were approved by the Laboratory Animal Ethics Committee of the First Affiliated Hospital, University of South China (Permit No. 20201226003).
C57BL/6 mice received i.p. injections of MPTP (30 mg/kg) in a volume of 10 ml/kg of body weight once daily for 7 days [43] and were randomly divided into 4 groups (n = 10/group): 1) MPTP + phosphate buffered saline (PBS) group treated with PBS; 2) MPTP + MA-5 group treated with MA-5; 3) MPTP + MA-5 + Compund C group treated with MA-5 and Compound C; and 4) MPTP + MA-5 + CSA group treated with MA-5 and CSA. The mice in the CTRL group were treated daily with 0.1 ml saline.

Open field test


The open field experiment is an efficient assay for evaluating the overall expression of motor deficits in mouse models of PD [41]. In this experiment, the open field consisted of a plaza box (50 × 50 cm), and a fence (40 cm tall). Mice were placed individually in the middle of the box and allowed to adapt to the new environment for a few minutes. Then, their behaviour was recorded on video for approximately 5 min. The box was cleaned with 70% alcohol and dried between each experiment to remove odour trails. The movement of the each mouse within 5 min was observed, and the total distance of movement was calculated. After performing the behavioural test, the mice were sacrificed.

Tissue preparation


Tissue preparation was performed according to the previous publications [6,8,9,49]. For western blot analysis, mice were sacrificed after anaesthesia by isoflurane. Briefly, the SN tissues (n = 3/group) were dissected and washed with 0.9% of ice-cold saline, and then, dissolved in 100 µl RIPA buffer with 1% PMSF and homogenised. The supernatants were collected after centrifugation at 14,000 g and 4°C for 15 min, and stored at –80°C for further analysis.

Western blot analysis


Western blot analysis was performed according to the previous publications [7,10,11,21,27,51]. The tissue lysates mixed with a sample loading buffer were heated at 95°C for 15 min. Protein samples were subjected to 10% SDS-PAGE and electroblotted onto polyvinylidene difluoride (PVDF) membranes. After being incubated in 5% bovine serum albumin (BSA) diluted in Tris-HCl saline buffer supplemented with 0.1% Tween-20 (TBST, pH 7.4) for 1 h to block non-specific protein binding sites, membranes were incubated overnight at 4°C with one of the following antibodies: rabbit anti-AMPK antibody (1 : 1,000; ab133448, Abcam), rabbit anti-LC3A/B antibody (1 : 1,000; ab128025, Abcam), rabbit anti-P62 antibody (1 : 1,000; ab91526, Abcam), mouse antiparkin antibody (1 : 1,000; ab77924, Abcam), rabbit anti-PTEN-inducible kinase 1 (PINK1) antibody (1 : 1,000; ab216144, Abcam), rabbit anti-b-actin (1 : 2,000; ab8227, Abcam). Then the membrane was washed with 0.1% TBST 3 times for 5 min each at RT, horseradish peroxidase-conjugated goat anti-mouse (1 : 10,000; ab6789, Abcam) or goat anti-rabbit secondary antibodies (1 : 10,000; ab97051, Abcam) diluted in TBST were incubated at RT for 1.5 h. Next, membranes were washed in 0.1% TBST 3 times for 5 min each at RT. The immunoreactive bands were visualized by an enhanced chemiluminescence (ECL) kit (170-5061, Bio-Rad Laboratories). The signal intensities were quantified by ImageJ 5.0 software.

Statistics


All statistical analyses were performed using GraphPad Prism 6 software. Data were expressed as mean ±SD and one-way ANOVA was performed followed by a post-hoc Bonferroni test. P < 0.05 was considered statistically significant.

Results

MA-5 up-regulates the phosphorylation of AMPK and promotes the autophagy in SN of MPTP-treated mice


To determine the effect of MA-5 on the AMPK phosphorylation and the mitophagy in SN of MPTP-treated mice, western blot was carried out to detect the p-AMPK level and LC3-I, LC3-II, P62, parkin, and PINK levels.
We observed that, in comparison to the CTRL group, the phosphorylation level of AMPK was down-regulated in the MPTP-treated group, but after the treatment of MA-5, the phosphorylation level of AMPK was up-regulated (Fig. 1A, B).
We also observed that, in comparison to the CTRL group, the ratio of LC3-II to LC3-I was decreased in the MPTP-treated group, but after the treatment of MA-5, the ratio of LC3-II to LC3-I was increased (Fig. 1C, D). The P62 level was down-regulated in response to the treatment of MPTP, but up-regulated in response to the treatment of MA-5 (Fig. 1C, E). In comparison to the CTRL group, the levels of parkin and PINK were decreased in the MPTP-treated group, but after the treatment of MA-5, the levels of parkin and PINK were increased (Fig. 1C, F, G).

MA-5 ameliorates the impaired motor function in MPTP-treated mice via activating the AMPK-mediated autophagy


To determine the effect of MA-5 on the recovery of the motor function in MPTP-treated mice, an Open Field Test was carried out and the total distance and average speed were calculated.
We observed that, in comparison to the CTRL group, the total distance and average speed were decreased in the MPTP-treated group, but after the treatment of MA-5, the total distance and average speed were increased, whereas, after inhibiting the AMPK and autophagy, MA-5 did not increase the total distance and average speed (Fig. 2A, B).

MA-5 up-regulates the expression of TH in SN of MPTP-treated mice via activating the AMPK-mediated autophagy


To determine the effect of MA-5 on the TH expression in SN of MPTP-treated mice, western blot was carried out to detect the TH level.
We observed that, in comparison to the CTRL group, the level of TH was down-regulated in the MPTP-treated group, but after the treatment of MA-5, the level of TH was up-regulated, whereas, after inhibiting the AMPK and autophagy, MA-5 did not increase the TH level (Fig. 3A, B).

MA-5 suppresses the inflammation in SN of MPTP-treated mice via activating the AMPK-mediated autophagy


To determine the effect of MA-5 on the inflammation in SN of MPTP-treated mice, western blot was carried out to detect the interleukin (IL)-1b, IL-6 and tumour necrosis factor a (TNF-a) levels.
We observed that, in comparison to the CTRL group, the levels of IL-1b, IL-6 and TNF-a were up-regulated in the MPTP-treated group, but after the treatment of MA-5, the levels of IL-1b, IL-6 and TNF-a were downregulated, whereas, after inhibiting the AMPK and autophagy, MA-5 did not decrease the levels of IL-1b, IL-6 and TNF-a (Fig. 4A-C).

Discussion


In the previous studies, we demonstrated that MA-5 can exert beneficial effects on mitochondrial homeostasis and increase microglial apoptosis by regulating mitophagy via Bnip3 through the MAPK-ERK-Yap signalling pathway [26] and promote the survival of microglial cells via Mitofusin 2-related mitophagy in response to lipopolysaccharide-induced inflammation [46]. In this study, we revealed that MA-5 can ameliorate the impaired motor function under MPTP-induced neurotoxicity via activating AMPK-mediated autophagy.
The dysfunctional autophagy has been well-known in relation to PD [31]. AMPK, acting as an energy sensor in response to stress conditions, including oxidative stress and nutrition deprivation, serves as an important modulator in the development of autophagy [25]. LC3 and P62 proteins are wide acknowledged to performed to monitor the autophagic flux [37]. The LC3-II/LC3-I, an indicator of autophagy status [42], is significantly up-regulated in PD [20]. P62, a proteolytic substrate in autophagy, is down-regulated with the increase of autophagy [40], and is down-regulated in PD [48]. To date, the most well-known mitophagy pathway, has been mediated by PINK1 and Parkin, representing a crucial amplifying mechanism that renders mitophagy more efficient [18]. In the present study, we observed that MA-5 can promote the phosphorylation of AMPK and the autophagy in mice induced by MPTP.
As we all know, neurological function rehabilitation is beneficial for protecting against further worsening under the pathological condition of PD patients [45]. Assessment of the neurological function is widely carried out to determine the therapeutic effect of strategies. Multiple studies have reported that behavioural tests can be performed to evaluate the motor dysfunction in the MPTP-induced PD mouse model [39]. Locomotor dysfunction serves as a wide-acknowledged clinical symptom of PD [23]. In our previous study, we observed that dietary tryptophan can ameliorate the impaired motor function in PD [47], in the current study, we revealed that MA-5 can promote the recovery of the motor function in mice induced by MPTP via activating the AMPK-mediated autophagy.
The main origin of PD and its related impaired motor function is the degeneration of dopaminergic neurons [19]. The lack of TH, a specific marker of dopaminergic neurons, is thought to contribute to the progression of PD [24]. TH, a rate-limiting enzyme during biosynthesis of L-dihydroxyphenylalanine (L-DOPA), is closely associated with the motor function [24]. In the current study, we revealed that MA-5 can up-regulate the TH level in SN of mice induced by MPTP via activating the AMPK-mediated autophagy.
Concentrations of IL-1b and IL-6 in SNpc and blood are significantly higher in PD than age-matched subjects without any neurological disease [33]. Subsequently, it has been shown that the secretion of IL-1b, IL-6, and TNF-a is significantly enhanced in peripheral blood mononuclear cells of PD patients compared with age-matched controls [3]. Previous studies have also indicated that the survival of dopaminergic neurons could be protected via inhibiting the microglia-related neuroinflammatory responses [16,17]. In the present study, we observed that MA-5 can inhibit the expression levels of IL-1b, IL-6 and TNF-a in mice induced by MPTP via AMPK-mediated mitophagy via activating the AMPK-mediated autophagy.
In conclusion, MA-5 can exert a beneficial effect on PD, at least in part, via the AMPK-mediated autophagy, laying the foundation for providing invaluable therapeutic strategies for the treatment of PD.
Although the results seem promising, our study still exhibited some limitations. Further studies are no doubt needed to be performed to detect the survival rate of dopaminergic neurons using histochemical staining. All in all, MA-5 may be a novel candidate for the treatment of PD.

Acknowledgments


This research was funded by the Hunan Provincial Natural Science Foundation of China (grant nos. 2021JJ30624, 2021JJ70114), Scientific research project of Hunan Health Committee (grant nos. 20201911, 20201963), and Hunan Science and Technology Innovation Key Project (Grant no. 2020SK1013).

Disclosure


The authors report no conflict of interest.
1. Athauda D, Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol 2015; 11: 25-40.
2. Bellomo G, Paciotti S, Gatticchi L, Parnetti L. The vicious cycle between a-synuclein aggregation and autophagic-lysosomal dysfunction. Mov Disord 2020; 35: 34-44.
3. Bessler H, Djaldetti R, Salman H, Bergman M, Djaldetti M. IL-1beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed Pharmacother 1999; 53: 141-145.
4. Cao X, Cao L, Ding L, Bian JS. A new hope for a devastating disease: hydrogen sulfide in Parkinson’s disease. Mol Neurobiol 2018; 55: 3789-3799.
5. Cerri S, Blandini F. Role of autophagy in Parkinson’s disease. Curr Med Chem 2019; 26: 3702-3718.
6. Chen S, He B, Zhou G, Xu Y, Wu L, Xie Y, Li Y, Huang J, Wu H, Xiao Z. Berberine enhances L1 expression and axonal remyelination in rats after brachial plexus root avulsion. Brain Behav 2020; 10: e01792.
7. Chen S, Hou Y, Zhao Z, Luo Y, Lv S, Wang Q, Li J, He L, Zhou L, Wu W. Neuregulin-1 accelerates functional motor recovery by improving motoneuron survival after brachial plexus root avulsion in mice. Neuroscience 2019; 404: 510-518.
8. Chen S, Jiang Q, Huang P, Hu C, Shen H, Schachner M, Zhao W. The L1 cell adhesion molecule affects protein kinase D1 activity in the cerebral cortex in a mouse model of Alzheimer’s disease. Brain Res Bull 2020; 162: 141-150.
9. Chen S, Wu L, He B, Zhou G, Xu Y, Zhu G, Xie J, Yao L, Huang J, Wu H, Xiao Z. Artemisinin facilitates motor function recovery by enhancing motoneuronal survival and axonal remyelination in rats following brachial plexus root avulsion. ACS Chem Neurosci 2021; 12: 3148-3156.
10. Chen SX, He JH, Mi YJ, Shen HF, Schachner M, Zhao WJ. A mimetic peptide of a2,6-sialyllactose promotes neuritogenesis. Neural Regen Res 2020; 15: 1058-1065.
11. Chen SX, Hu CL, Liao YH, Zhao WJ. L1 modulates PKD1 phosphorylation in cerebellar granule neurons. Neurosci Lett 2015; 584: 331-336.
12. Curry DW, Stutz B, Andrews ZB, Elsworth JD. Targeting AMPK Signaling as a neuroprotective strategy in Parkinson’s disease. J Parkinsons Dis 2018; 8: 161-181.
13. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003; 39: 889-909.
14. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006; 5: 525-535.
15. Fang B, Li XQ, Bao NR, Tan WF, Chen FS, Pi XL, Zhang Y, Ma H. Role of autophagy in the bimodal stage after spinal cord ischemia reperfusion injury in rats. Neuroscience 2016; 328: 107-116.
16. Furuyashiki T. Roles of dopamine and inflammation-related molecules in behavioral alterations caused by repeated stress. J Pharmacol Sci 2012; 120: 63-69.
17. Gao HM, Liu B, Zhang W, Hong JS. Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 2003; 24: 395-401.
18. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12: 119-131.
19. Giguère N, Burke Nanni S, Trudeau LE. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front Neurol 2018; 9: 455.
20. Han B, Wang L, Fu F, Wang Z, Zhang L, Qi GJ, Wang T. Hydroxysafflor yellow A promotes a-synuclein clearance via regulating autophagy in rotenone-induced Parkinson’s disease mice. Folia Neuropathol 2018; 56: 133-140.
21. He D, Chen S, Xiao Z, Wu H, Zhou G, Xu C, Chang Y, Li Y, Wang G, Xie M. Bisdemethoxycurcumin exerts a cell-protective effect via JAK2/STAT3 signaling in a rotenone-induced Parkinson’s disease model in vitro. Folia Histochem Cytobiol 2020; 58: 127-134.
22. Huang D, Liu M, Jiang Y. Mitochonic acid-5 attenuates TNF-a-mediated neuronal inflammation via activating Parkin-related mitophagy and augmenting the AMPK-Sirt3 pathways. J Cell Physiol 2019; 234: 22172-22182.
23. Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK, Griffith SG, Grundman M, Soto J, Ostrowitzki S, Boess FG, Martin-Facklam M, Quinn JF, Isaacson SH, Omidvar O, Ellenbogen A, Kinney GG. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-a-synuclein monoclonal antibody, in patients with parkinson disease: a randomized clinical trial. JAMA Neurol 2018; 75: 1206-1214.
24. Johnson ME, Salvatore MF, Maiolo SA, Bobrovskaya L. Tyrosine hydroxylase as a sentinel for central and peripheral tissue responses in Parkinson’s progression: Evidence from clinical studies and neurotoxin models. Prog Neurobiol 2018; 165-167: 1-25.
25. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132-141.
26. Lei Q, Tan J, Yi S, Wu N, Wang Y, Wu H. Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFa-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett 2018; 23: 14.
27. Li J, Chen S, Zhao Z, Luo Y, Hou Y, Li H, He L, Zhou L, Wu W. Effect of VEGF on inflammatory regulation, neural survival, and functional improvement in rats following a complete spinal cord transection. Front Cell Neurosci 2017; 11: 381.
28. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ. The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2: a009357.
29. Matsuhashi T, Sato T, Kanno SI, Suzuki T, Matsuo A, Oba Y, Kikusato M, Ogasawara E, Kudo T, Suzuki K, Ohara O, Shimbo H, Nanto F, Yamaguchi H, Saigusa D, Mukaiyama Y, Watabe A, Kikuchi K, Shima H, Mishima E, Akiyama Y, Oikawa Y, Hsin-Jung HO, Akiyama Y, Suzuki C, Uematsu M, Ogata M, Kumagai N, Toyomizu M, Hozawa A, Mano N, Owada Y, Aiba S, Yanagisawa T, Tomioka Y, Kure S, Ito S, Nakada K, Hayashi KI, Osaka H, Abe T. Mitochonic acid 5 (MA-5) facilitates ATP synthase oligomerization and cell survival in various mitochondrial diseases. EBioMedicine 2017; 20: 27-38.
30. Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000; 1: 120-129.
31. Meng T, Lin S, Zhuang H, Huang H, He Z, Hu Y, Gong Q, Feng D. Recent progress in the role of autophagy in neurological diseases. Cell Stress 2019; 3: 141-161.
32. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Füllgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 2017; 93: 1015-1034.
33. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 1994; 180: 147-150.
34. Nakada K, Inoue K, Ono T, Isobe K, Ogura A, Goto YI, Nonaka I, Hayashi JI. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 2001; 7: 934-940.
35. Ng CH, Basil AH, Hang L, Tan R, Goh KL, O’Neill S, Zhang X, Yu F, Lim KL. Genetic or pharmacological activation of the Drosophila PGC-1a ortholog spargel rescues the disease phenotypes of genetic models of Parkinson’s disease. Neurobiol Aging 2017; 55: 33-37.
36. Onyango IG. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Neurochem Res 2008; 33: 589-597.
37. Pugsley HR. Assessing autophagic flux by measuring LC3, p62, and LAMP1 co-localization using multispectral imaging flow cytometry. J Vis Exp 2017; 125: 55637.
38. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Keni-son JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kébir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016; 22: 586-597.
39. Shi X, Chen YH, Liu H, Qu HD. Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson’s disease in mice. Mol Med Rep 2016; 14: 2397-2404.
40. Shin WH, Park JH, Chung KC. The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson’s disease. BMB Rep 2020; 53: 56-63.
41. Song Q, Peng S, Zhu X. Baicalein protects against MPP(+)/MPTP-induced neurotoxicity by ameliorating oxidative stress in SH-SY5Y cells and mouse model of Parkinson’s disease. Neurotoxicology 2021; 87: 188-194.
42. Sun B, Ou H, Ren F, Huan Y, Zhong T, Gao M, Cai H. Propofol inhibited autophagy through Ca(2+)/CaMKKb/AMPK/mTOR pathway in OGD/R-induced neuron injury. Mol Med 2018; 24: 58.
43. Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, Cui C, Shen YQ. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-a signaling pathway. Brain Behav Immun 2018; 70: 48-60.
44. Suzuki T, Yamaguchi H, Kikusato M, Hashizume O, Nagatoishi S, Matsuo A, Sato T, Kudo T, Matsuhashi T, Murayama K, Ohba Y, Watanabe S, Kanno SI, Minaki D, Saigusa D, Shinbo H, Mori N, Yuri A, Yokoro M, Mishima E, Shima H, Akiyama Y, Takeuchi Y, Kikuchi K, Toyohara T, Suzuki C, Ichimura T, Anzai JI, Kohzuki M, Mano N, Kure S, Yanagisawa T, Tomioka Y, Toyomizu M, Tsumoto K, Nakada K, Bonventre JV, Ito S, Osaka H, Hayashi KI, Abe T. Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage. J Am Soc Nephrol 2016; 27: 1925-1932.
45. Takeuchi T, Arii Y. Use of sports in the rehabilitation of Parkinson’s disease. Brain Nerve 2019; 71: 125-133.
46. Tan J, Chen SX, Lei QY, Yi SQ, Wu N, Wang YL, Xiao ZJ, Wu H. Mitochonic acid 5 regulates mitofusin 2 to protect microglia. Neural Regen Res 2021; 16: 1813-1820.
47. Wang Y, Chen S, Tan J, Gao Y, Yan H, Liu Y, Yi S, Xiao Z, Wu H. Tryptophan in the diet ameliorates motor deficits in a rotenone-induced rat Parkinson’s disease model via activating the aromatic hydrocarbon receptor pathway. Brain Behav 2021; 11: e2226.
48. Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS Neurosci Ther 2019; 25: 859-875.
49. Xu J, Hu C, Chen S, Shen H, Jiang Q, Huang P, Zhao W. Neuregulin-1 protects mouse cerebellum against oxidative stress and neuroinflammation. Brain Res 2017; 1670: 32-43.
50. Yan Q, Han C, Wang G, Waddington JL, Zheng L, Zhen X. Activation of AMPK/mTORC1-mediated autophagy by metformin reverses clk1 deficiency-sensitized dopaminergic neuronal death. Mol Pharmacol 2017; 92: 640-652.
51. Yi S, Chen S, Xiang J, Tan J, Huang K, Zhang H, Wang Y, Wu H. Genistein exerts a cell-protective effect via Nrf2/HO-1//PI3K signaling in Ab25-35-induced Alzheimer’s disease models in vitro. Folia Histochem Cytobiol 2021; 59: 49-56.
52. Youn JK, Kim DW, Kim ST, Park SY, Yeo EJ, Choi YJ, Lee HR, Kim DS, Cho SW, Han KH, Park J, Eum WS, Hwang HS, Choi SY. PEP-1-HO-1 prevents MPTP-induced degeneration of dopaminergic neurons in a Parkinson’s disease mouse model. BMB Rep 2014; 47: 569-574.
53. Zhang C, Li C, Chen S, Li Z, Ma L, Jia X, Wang K, Bao J, Liang Y, Chen M, Li P, Su H, Lee SMY, Liu K, Wan JB, He C. Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways. Sci Rep 2017; 7: 41082.
54. Zhang D, Xuan J, Zheng BB, Zhou YL, Lin Y, Wu YS, Zhou YF, Huang YX, Wang Q, Shen LY, Mao C, Wu Y, Wang XY, Tian NF, Xu HZ, Zhang XL. Metformin improves functional recovery after spinal cord injury via autophagy flux stimulation. Mol Neurobiol 2017; 54: 3327-3341.
55. Zhao H, Chen S, Gao K, Zhou Z, Wang C, Shen Z, Guo Y, Li Z, Wan Z, Liu C, Mei X. Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience 2017; 348: 241-251.
56. Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J, Chen Y. Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. Sci Rep 2015; 5: 12898.
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