Zakharova Irina O, Bayunova Liubov V, Avrova Daria K, Tretyakova Alina D, Shpakov Alexander O, Avrova Natalia F
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez Av. 44, St. Petersburg 194223, Russia.
Curr Issues Mol Biol. 2024 Jun 27;46(7):6580-6599. doi: 10.3390/cimb46070392.
Insulin is a promising neuroprotector. To better understand the mechanism of insulin action, it was important to show its ability to diminish autophagic neuronal death in animals with brain ischemic and reperfusion injury. In forebrain ischemia and reperfusion, the number of live neurons in the hippocampal CA1 region and frontal cortex of rats decreased to a large extent. Intracerebroventricular administration of the autophagy and apoptosis inhibitors to ischemic rats significantly increased the number of live neurons and showed that the main part of neurons died from autophagy and apoptosis. Intranasal administration of 0.5 IU of insulin per rat (before ischemia and daily during reperfusion) increased the number of live neurons in the hippocampal CA1 region and frontal brain cortex. In addition, insulin significantly diminished the level of autophagic marker LC3B-II in these forebrain regions, which markedly increased during ischemia and reperfusion. Our studies demonstrated for the first time the ability of insulin to decrease autophagic neuronal death, caused by brain ischemia and reperfusion. Insulin administered intranasally activated the Akt-kinase (activating the mTORC1 complex, which inhibits autophagy) and inhibited the AMP-activated protein kinase (which activates autophagy) in the hippocampus and frontal cortex of rats with brain ischemia and reperfusion.
胰岛素是一种很有前景的神经保护剂。为了更好地理解胰岛素的作用机制，证明其在脑缺血再灌注损伤动物中减少自噬性神经元死亡的能力很重要。在前脑缺血再灌注时，大鼠海马CA1区和额叶皮质中存活神经元的数量大幅减少。向缺血大鼠脑室内注射自噬和凋亡抑制剂可显著增加存活神经元的数量，并表明神经元的主要死亡原因是自噬和凋亡。每只大鼠经鼻给予0.5 IU胰岛素（在缺血前及再灌注期间每日给药）可增加海马CA1区和额叶皮质中存活神经元的数量。此外，胰岛素显著降低了这些前脑区域中自噬标志物LC3B-II的水平，该水平在缺血和再灌注期间显著升高。我们的研究首次证明了胰岛素具有减少脑缺血再灌注引起的自噬性神经元死亡的能力。经鼻给予胰岛素可激活Akt激酶（激活抑制自噬的mTORC1复合物），并抑制脑缺血再灌注大鼠海马和额叶皮质中的AMP激活蛋白激酶（激活自噬）。
