Intranasal Insulin Administration to Rats with Forebrain Ischemia and Reperfusion Injury Reduces Autophagy and Apoptosis Intensity in the Hippocampus and Frontal Cortex, a Possible Mechanism of Action

Rat forebrain ischemia followed by a 3-day reperfusion ledto an increase in the levels of the autophagic marker LC3B-II andglial fibrillary acidic protein (GFAP), as well as caspase-3 activation,in the hippocampus and frontal cortex of the rat brain. Meanwhile,intranasal administration of 0.5 IU insulin to rats with forebrainischemia/reperfusion (I/R) injury (once before ischemic exposureand once a day during 3-day reperfusion) significantly diminishedthe LC3B-II level and caspase-3 activity in the hippocampus andfrontal cortex, thus demonstrating the ability of intranasal insulinto inhibit autophagy and apoptosis activation in the forebrain structuresduring I/R. A significant intranasal insulin-mediated reductionin the GFAP level within the same brain structures failed to bedetected. Intranasal insulin administration activated Akt proteinkinase (which activates mTORC1, an autophagy inhibitor) and inhibitedAMPK protein kinase (an autophagy activator) in the hippocampusand cerebral cortex of rats with forebrain I/R injury, which islikely to underlie the ability of intranasal insulin to reduce autophagic andapoptotic neuronal death. The data on the in vivo intranasal insulin-mediatedmodulation of Akt and AMPK activities are consistent with our previousresults on the possible mechanism of insulin neuroprotection, obtainedin vitro on rat cortical neurons exposed to oxidative stress.