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CNS & Neurological Disorders - Drug Targets

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ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

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Research Article

Minocycline Inhibits mTOR Signaling Activation and Alleviates Behavioral Deficits in the Wistar Rats with Acute Ischemia stroke

Author(s): Shengyuan Wang, Chuanling Wang, Lihua Wang and Zhiyou Cai*

Volume 19, Issue 10, 2020

Page: [791 - 799] Pages: 9

DOI: 10.2174/1871527319999200831153748

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Abstract

Background: Mammalian target of rapamycin (mTOR) has been evidenced as a multimodal therapy in the pathophysiological process of Acute Ischemic Stroke (AIS). However, the pathway that minocycline targets mTOR signaling is not fully defined in the AIS pathogenesis. This study aims at the roles of minocycline on the mTOR signaling in the AIS process and further discovers the underlying mechanisms of minocycline involved in the following change of mTOR signaling-autophagy.

Methods: Cerebral ischemia/reperfusion (CIR) rat animal models were established with the transient suture occlusion into the middle cerebral artery. Minocycline (50mg/kg) was given by intragastric administration. The Morris water maze was used to test the cognitive function of animals. Immunohistochemistry and immunofluorescence were introduced for testing the levels of synaptophysin and PSD-95. Western blot was conducted for investigating the levels of mTOR, p-mTOR (Ser2448), p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366), p-eIF4B (Ser406), LC3, p62, synaptophysin and PSD-95.

Results: Minocycline prevents the cognitive decline of the MCAO stroke rats. Minocycline limits the expression of p-mTOR (Ser2448) and the downstream targets of mTOR [p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366) and p-eIF4B (Ser406)] (P<0.01), while minocycline has no influence on mTOR. LC3-II abundance and the LC3-II/I ratio were upregulated in the hippocampus of the MCAO stroke rats by the minocycline therapy (P<0.01). p62 was downregulated in the hippocampus from the MCAO stroke rats administrated with minocycline therapy(P<0.01). The levels of SYP and PSD-95 were upregulated in the brain of the MCAO stroke rats administrated with minocycline therapy.

Conclusion: Minocycline prevents cognitive deficits via inhibiting mTOR signaling and enhancing the autophagy process, and promoting the expression of pre- and postsynaptic proteins (synaptophysin and PSD-95) in the brain of the MCAO stroke rats. The potential neuroprotective role of minocycline in the process of cerebral ischemia may be related to mitigating ischemia-induced synapse injury via inhibiting the activation of mTOR signaling.

Keywords: Minocycline, mammalian target of rapamycin, synapse, cerebral ischemia, autophagy, behavioral deficits.

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[1]
Furie KL, Jayaraman MV. Guidelines for the early management of patients with acute ischemic stroke. Stroke 2018; 49(3): 509-10.
[http://dx.doi.org/10.1161/STROKEAHA.118.020176] [PMID: 29367335]
[2]
Powers WJ, Rabinstein AA, Ackerson T, et al. American Heart Association Stroke Council. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2018; 49(3): e46-e110.
[http://dx.doi.org/10.1161/STR.0000000000000158] [PMID: 29367334]
[3]
Gong Z, Pan J, Li X, Wang H, He L, Peng Y. Hydroxysafflor yellow a reprograms tlr9 signalling pathway in ischaemic cortex after cerebral ischaemia and reperfusion. CNS Neurol Disord Drug Targets 2018; 17(5): 370-82.
[http://dx.doi.org/10.2174/1871527317666180502110205] [PMID: 29732997]
[4]
Wang S, Ma F, Huang L, et al. Dl-3-n-Butylphthalide (NBP): a promising therapeutic agent for ischemic stroke. CNS Neurol Disord Drug Targets 2018; 17(5): 338-47.
[http://dx.doi.org/10.2174/1871527317666180612125843] [PMID: 29895257]
[5]
Beard DJ, Hadley G, Thurley N, Howells DW, Sutherland BA, Buchan AM. The effect of rapamycin treatment on cerebral ischemia: A systematic review and meta-analysis of animal model studies. Int J Stroke 2019; 14(2): 137-45.
[http://dx.doi.org/10.1177/1747493018816503] [PMID: 30489210]
[6]
Hadley G, Beard DJ, Couch Y, et al. Rapamycin in ischemic stroke: Old drug, new tricks? J Cereb Blood Flow Metab 2019; 39(1): 20-35.
[http://dx.doi.org/10.1177/0271678X18807309] [PMID: 30334673]
[7]
Fagan SC, Cronic LE, Hess DC. Minocycline development for acute ischemic stroke. Transl Stroke Res 2011; 2(2): 202-8.
[http://dx.doi.org/10.1007/s12975-011-0072-6] [PMID: 21909339]
[8]
Cai Z, Zhao Y, Yao S, Bin Zhao B. Increases in β-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-κB pathway activation. Pharmacol Rep 2011; 63(2): 381-91.
[http://dx.doi.org/10.1016/S1734-1140(11)70504-7] [PMID: 21602593]
[9]
Cai Z, Yan Y, Wang Y. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder. Clin Interv Aging 2013; 8: 1089-95.
[http://dx.doi.org/10.2147/CIA.S46536] [PMID: 23983461]
[10]
Zhang E, Zhao X, Zhang L, et al. Minocycline promotes cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy to prevent sepsis-induced cardiac dysfunction by Akt/mTOR signaling. Apoptosis 2019; 24(3-4): 369-81.
[http://dx.doi.org/10.1007/s10495-019-01521-3] [PMID: 30756206]
[11]
Ren Z, Wang X, Xu M, Frank JA, Luo J. Minocycline attenuates ethanol-induced cell death and microglial activation in the developing spinal cord. Alcohol 2019; 79: 25-35.
[http://dx.doi.org/10.1016/j.alcohol.2018.12.002] [PMID: 30529756]
[12]
Ahmed A, Wang LL, Abdelmaksoud S, Aboelgheit A, Saeed S, Zhang CL. Minocycline modulates microglia polarization in ischemia-reperfusion model of retinal degeneration and induces neuroprotection. Sci Rep 2017; 7(1): 14065.
[http://dx.doi.org/10.1038/s41598-017-14450-5] [PMID: 29070819]
[13]
Ataie-Kachoie P, Pourgholami MH, Bahrami-B F, Badar S, Morris DL. Minocycline attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies. Am J Cancer Res 2015; 5(2): 575-88.
[PMID: 25973298]
[14]
Cai ZY, Yan Y, Sun SQ, et al. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull 2008; 24(5): 305-13.
[http://dx.doi.org/10.1007/s12264-008-0324-y] [PMID: 18839024]
[15]
Cai Z, Wang C, Chen Y, He W. An antioxidant role by minocycline via enhancing the activation of LKB1/AMPK signaling in the process of cerebral ischemia injury. Curr Mol Med 2018; 18(3): 142-51.
[http://dx.doi.org/10.2174/1566524018666180907161504] [PMID: 30198433]
[16]
Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model. Neurosci Bull 2010; 26(1): 28-36.
[http://dx.doi.org/10.1007/s12264-010-0818-2] [PMID: 20101270]
[17]
Kawamura S, Li Y, Shirasawa M, Yasui N, Fukasawa H. Reversible middle cerebral artery occlusion in rats using an intraluminal thread technique. Surg Neurol 1994; 41(5): 368-73.
[http://dx.doi.org/10.1016/0090-3019(94)90029-9] [PMID: 8009410]
[18]
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20(1): 84-91.
[http://dx.doi.org/10.1161/01.STR.20.1.84] [PMID: 2643202]
[19]
Zhao Y, Xiao M, He W, Cai Z. Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits. Neuropsychiatr Dis Treat 2015; 11: 507-16.
[PMID: 25750531]
[20]
Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1(2): 848-58.
[http://dx.doi.org/10.1038/nprot.2006.116] [PMID: 17406317]
[21]
Yamada D, Kawabe K, Tosa I, et al. Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system. Commun Biol 2019; 2: 346.
[http://dx.doi.org/10.1038/s42003-019-0582-4] [PMID: 31552299]
[22]
Doan H, Parsons A, Devkumar S, Selvarajah J, Miralles F, Carroll VA. HIF-mediated Suppression of DEPTOR Confers Resistance to mTOR Kinase Inhibition in Renal Cancer iScience 2019; 21: 509-20.
[23]
Fouqué A, Delalande O, Jean M, et al. Correction to a novel covalent mTOR inhibitor, DHM25, shows in vivo antitumor activity against triple-negative breast cancer cells. J Med Chem 2019; 62(20): 9339-40.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01578] [PMID: 31603322]
[24]
Martín-Flores N, Fernández-Santiago R, Antonelli F, et al. MTOR pathway-based discovery of genetic susceptibility to L-DOPA-induced dyskinesia in parkinson’s disease patients. Mol Neurobiol 2019; 56(3): 2092-100.
[http://dx.doi.org/10.1007/s12035-018-1219-1] [PMID: 29992529]
[25]
Athauda D, Gulyani S, Karnati HK, et al. Utility of neuronal-derived exosomes to examine molecular mechanisms that affect motor function in patients with parkinson disease: a secondary analysis of the exenatide-PD trial. JAMA Neurol 2019; 76(4): 420-9.
[http://dx.doi.org/10.1001/jamaneurol.2018.4304] [PMID: 30640362]
[26]
Heras-Sandoval D, Pérez-Rojas JM, Pedraza-Chaverri J. Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases. Cell Signal 2020; 65: 109442.
[http://dx.doi.org/10.1016/j.cellsig.2019.109442] [PMID: 31639492]
[27]
Gudasheva TA, Povarnina PY, Volkova AA, Kruglov SV, Antipova TA, Seredenin SB. A nerve growth factor dipeptide mimetic stimulates neurogenesis and synaptogenesis in the hippocampus and striatum of adult rats with focal cerebral ischemia. Acta Naturae 2019; 11(3): 31-7.
[http://dx.doi.org/10.32607/20758251-2019-11-3-31-37] [PMID: 31720014]
[28]
Wang CJ, Wu Y, Zhang Q, Yu KW, Wang YY. An enriched environment promotes synaptic plasticity and cognitive recovery after permanent middle cerebral artery occlusion in mice. Neural Regen Res 2019; 14(3): 462-9.
[http://dx.doi.org/10.4103/1673-5374.245470] [PMID: 30539814]
[29]
Birdsall V, Waites CL. Autophagy at the synapse. Neurosci Lett 2019; 697: 24-8.
[http://dx.doi.org/10.1016/j.neulet.2018.05.033] [PMID: 29802916]
[30]
Bhukel A, Beuschel CB, Maglione M, et al. Autophagy within the mushroom body protects from synapse aging in a non-cell autonomous manner. Nat Commun 2019; 10(1): 1318.
[http://dx.doi.org/10.1038/s41467-019-09262-2] [PMID: 30899013]
[31]
Liang Y, Sigrist S. Autophagy and proteostasis in the control of synapse aging and disease. Curr Opin Neurobiol 2018; 48: 113-21.
[http://dx.doi.org/10.1016/j.conb.2017.12.006] [PMID: 29274917]
[32]
Luo Y, Zhou B, Liu F, Ai R, Wen M, Tong X. Enhanced autophagy activates p38/MEF2C pathway to regulate the expression of synapse-associated proteins and improve the symptoms of autistic rats. Xibao Yu Fenzi Mianyixue Zazhi 2019; 35(3): 236-42. [Enhanced autophagy activates p38/MEF2C pathway to regulate the expression of synapse-associated proteins and improve the symptoms of autistic rats].
[PMID: 31030717]
[33]
Fontes-Júnior EA, Maia CS, Fernandes LM, et al. Chronic alcohol intoxication and cortical ischemia: study of their comorbidity and the protective effects of minocycline. Oxid Med Cell Longev 2016; 2016: 1341453.
[http://dx.doi.org/10.1155/2016/1341453] [PMID: 27418952]
[34]
Cao R, Li L, Ying Z, et al. A small molecule protects mitochondrial integrity by inhibiting mTOR activity. Proc Natl Acad Sci USA 2019; 116(46): 23332-8.
[http://dx.doi.org/10.1073/pnas.1911246116] [PMID: 31653761]
[35]
Wang J, Wang A, He H, et al. Trametenolic acid B protects against cerebral ischemia and reperfusion injury through modulation of microRNA-10a and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother 2019; 112: 108692.
[http://dx.doi.org/10.1016/j.biopha.2019.108692] [PMID: 30798122]
[36]
Medeiros MRB, de Mello Alves Rodrigues AC, Alves MR, et al. Bibliometrics of CNS & Neurological Disorders - Drug Targets: an international evolution along time. CNS Neurol Disord Drug Targets 2019; 18(3): 239-44.
[http://dx.doi.org/10.2174/1871527318666181227123924] [PMID: 30588889]

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