Inhibition of mammalian target of rapamycin improves neurobehavioral deficit and modulates immune response after intracerebral hemorrhage in rat

Abstract

BackgroundMammalian target of rapamycin (mTOR), a serine/threonine kinase, regulates many processes, including cell growth and the immune response. mTOR is also dysregulated in several neurological diseases, such as traumatic brain injury (TBI), stroke, and neurodegenerative disease. However, the role of mTOR in intracerebral hemorrhage (ICH) remains unexplored. The aims of our study were to determine whether inhibiting mTOR signaling could affect the outcome after ICH and to investigate the possible underlying mechanism.MethodsA rat ICH model was induced by intracerebral injection of collagenase IV into the striatum, and mTOR activation was inhibited by administration of rapamycin. mTOR signaling activation was determined by western blotting. Neurobehavioral deficit after ICH was determined by a set of modified Neurological Severity Scores (mNSS). The levels of CD4+CD25+Foxp3+ regulatory T cells (Tregs) and cytokines were examined using flow cytometry and ELISA, respectively.ResultsOur results demonstrated thatmTOR signaling was activated 30 minutes and returned to its basal level 1 day after ICH. Increased p-mTOR, which mean that mTOR signaling was activated, was predominantly located around the hematoma. Rapamycin treatment significantly improved the neurobehavioral deficit after ICH, increased the number of Tregs, increased levels of interleukin-10 and transforming growth factor-β and reduced interferon-γ both in peripheral blood and brain.ConclusionsOur study suggests that mTOR improves ICH outcome and modulates immune response after ICH.

Modulators of microglial activation and polarization after intracerebral haemorrhage

“…Although in this Review we have emphasized the importance of M2-like microglial responses (especially in the late recovery stage of ICH), treatment strategies for ICH that focus on modulating or enhancing M2-like microglia are still limited. As discussed above, rapamycin (at a low dose of 150 μg/kg) increased levels of M2-like anti-inflammatory cytokines IL-10 and TGFβ 105 . Sinomenine is a dextrorotatory morphinan analogue extracted from herbs used in traditional Chinese medicine 195,196 , and has long been used clinically for treating rheumatoid arthritis in China 197 .…”

“…In rats with collagenase-induced ICH, phosphorylation of mTOR was markedly increased at 30 min. Treatment with rapamycin(50–500 μg/kg) led to a dose-dependent increase in brain levels of the M2 cytokines IL-10 and TGFβ, as well as in the ratio of IL-10 to IFNγ, after ICH 105 . In a separate study that used the same model 106 , rapamycin treatment reduced protein levels of TNF, IL-1β and IL-6.…”

Genetic Activation of mTORC1 Signaling Worsens Neurocognitive Outcome after Traumatic Brain Injury

“…This is consistent with recently published findings that demonstrate rapamycin treatment, which would inhibit mTORC1 activity, is beneficial in a variety of injury models. [31][32][33] However, treatment of injured animals with intracerebroventricular (i.c.v) rapamycin alone was insufficient to provide significant outcome benefits. 15 Although the reason for this lack of effect is unclear,…”

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.…”