Intranasal administration of insulin to rats with forebrain ischemia and reperfusion decreases the intensity of autophagy and apoptosis in hippocampus and frontal brain cortex, possible mechanism of unsulin action

Abstract

Rat forebrain ischemia and subsequent three-day reperfusion were found to result in an increase in the levels of autophagy marker LC3B-II and glial fibrillary acidic protein (GFAP) and activation of caspase-3 in the hippocampus and frontal cortex. At the same time, intranasal administration of 0.5 IU insulin to rats with forebrain ischemia and reperfusion (before ischemia and daily during reperfusion) markedly and significantly diminished the level of LC3B-II and caspase-3 activity in the hippocampus and frontal cortex. It demonstrates the ability of insulin to inhibit the activation of autophagy and apoptosis in forebrain structures during ischemia and reperfusion. It was not possible to find out a significant decrease in the level of GFAP in these brain structures under the influence of insulin administration to animals. Intranasal administration of insulin has been found to activate the protein kinase Akt (which activates the mTORC1 complex, known to inhibit autophagy processes) and to inhibit the protein kinase AMPK (initiating autophagy processes) in the hippocampus and cerebral cortex of rats with forebrain ischemia and reperfusion. These effects of insulin apparently underly its ability to diminish the autophagic and apoptotic neuronal death. The data on the modulation by insulin, administered intranasally to rats with forebrain ischemia and reperfusion, of Akt and AMPK activities are in agreement with more detailed studies of the possible mechanism of the neuroprotective action of insulin, which we previously made in vitro on cortical neurons under oxidative stress conditions.