Shengyuan Wang, Chuanling Wang, Lihua Wang and Zhiyou Cai* Pages 791 - 799 ( 9 )
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.
Minocycline, mammalian target of rapamycin, synapse, cerebral ischemia, autophagy, behavioral deficits
Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing, Department of Neurology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing