Neuroinflammation plays a prominent role in the pathophysiology of several
neurodegenerative disorders, including
Multiple Sclerosis. Reactive microglial cells are always found in areas of active
demyelination as well as in normal-appearing white matter. Microglia contribute to initiating and maintaining
brain inflammation, and once activated release pro-inflammatory mediators potentially cytotoxic, like
nitric oxide (NO). It is now evident that the mTOR signaling pathway regulates different functions in the innate immune system, contributing to macrophage activation. More recently, mTOR has been found to enhance the survival of EOC2 microglia during
oxygen-
glucose deprivation and increase
NO synthase 2 (NOS2) expression during
hypoxia in BV2 microglial cell line, thus suggesting an involvement in microglial pro-inflammatory activation. In the present study, we detected mTOR activation in response to two different stimuli, namely LPS and a mixture of
cytokines, in primary cultures of rat cortical microglia. Moreover,
mTOR inhibitors reduced NOS activity and NOS2 expression induced by
cytokines, but not those induced by LPS. The mTOR inhibitor
RAD001, in combination with
cytokines, also reduced microglial proliferation and the intracellular levels of
cyclooxygenase. Under basal conditions mTOR inhibition significantly reduced microglial viability. Interestingly,
mTOR inhibitors did not display any relevant effect on astrocyte NOS2 activity or cell viability. In conclusion, mTOR selectively controls microglial activation in response to pro-inflammatory
cytokines and appears to play a crucial role in microglial viability; thus these drugs may be a useful pharmacological tool to reduce
neuroinflammation.