Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia

Abstract

The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage.

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

“…However, inhibiting mTOR signaling pathway using rapamycin or knockdown of mTOR promotes autophagy and attenuates ischemia‐induced neuronal death 14, 15, 16, 26. Reports also demonstrate that inhibition of mTOR pathway suppresses autophagy, prevents cytochromecrelease and reduces ischemic brain damage 3, 15, 27. This discrepancy may result from different animal strains, ischemic model, the time and route of drug administration.…”

“…Although tremendous progress has been made in the study of pathophysiology on ischemic stroke, translation of basic research into clinical therapies has not successed. Currently, systemic thrombolysis with recombinant intravenous tissue plasminogen activator (rtPA) remains a frequently used therapy which can improve clinical outcome of patients with acute ischemic stroke 3, 4. However, rtPA has an increased risk of hemorrhage beyond a few hours of poststroke, and only less than 4% of stroke patients can benefit from it 5, 6.…”

Temporal changes in mammalian target of rapamycin (mTOR) and phosphorylated-mTOR expressions in the hippocampal CA1 region of rat with vascular dementia

“…It has also been suggested that improvement of mTOR activation may protect cerebral ischemic injury and enhance functional recovery [4]. Therefore, it has been generally accepted that mTOR has effective neuroprotective functions, although there is controversy regarding the effects of mTOR on ischemic injury [22526]. …”

Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia

“…Increases in autophagy following ischemia–reperfusion injury are well recognized. However, there are conflicting reports that increased autophagy following cerebral ischemia-reperfusion injury can be detrimental (Baek et al, 2014; Yang et al, 2015; Au et al, 2015; He et al, 2016; Xie et al, 2016) or neuroprotective (Carloni et al, 2012; Qi et al, 2014; Su et al, 2014; Wang et al, 2014; Jiang et al, 2015). Sex differences in autophagy both in vitro (Du et al, 2009) and in vivo following HI (Weis et al, 2014) have been reported.…”