Title:Minocycline Inhibits mTOR Signaling Activation and Alleviates Behavioral Deficits in the Wistar Rats with Acute Ischemia stroke
Volume: 19
Issue: 10
Author(s): Shengyuan Wang, Chuanling Wang, Lihua Wang and Zhiyou Cai*
Affiliation:
- Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing, 400013, Chongqing,China
Keywords:
Minocycline, mammalian target of rapamycin, synapse, cerebral ischemia, autophagy, behavioral deficits.
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.
