α-Lipoic acid improves spatial learning memory deficits induced by intracerebroventricular injection of streptozotocin via activation of JAK/STAT-GPX4 in rats / 中华内分泌代谢杂志

ABSTRACT

Objective:To observe the effect of α-lipoic acid(ALA) on the intracerebroventricular injection(icv) of streptozotocin(STZ)-induced spatial learning memory impairments in rats and the underlying molecular mechanisms.Methods:Forty-five male SD rats were assigned into 3 groups, control group, icv-STZ group and icv-STZ+ ALA group, 15 rats each. STZ was dissolved in artificial cerebrospinal fluid then injected into the lateral ventricles of the rat by using stereotaxic device. ALA was administrated by gavage after STZ injection. The spatial learning memory was examined by using Morris water maze test after 4 weeks of treatment. Immunohistochemistry was performed to detect the number of microglia and astrocytes, electron microscopy was applied to detect mitochondrial integrity, Western blotting was used to detect the protein expression levels, and the changes of lipid peroxidation and redox system were examined by kit.Results:Spatial learning memory was impaired in rats after 4 weeks of STZ injection, and ALA treatment ameliorated STZ-induced cognitive dysfunction in rats. Iron concentration, lipid peroxidation, neuroinflammation, Tau hyperphosphorylated were enhanced markedly after STZ injection, along with and the activation of MAPK and GSK-3β, which were ameliorated by ALA. Further examination revealed that STZ activated the JAK2/STAT3 pathway and transcriptionally inhibited the expression of peroxidase GPX. Inhibition of STAT3 activity can block STZ-induced downregulation of GPX4 and Tau hyperphosphorylation.Conclusion:ALA ameliorated STZ-induced spatial learning memory impairments in rats via deactivation of JAK2/STAT3 pathway, restored GPX4 protein level, resulting in chelating iron, improving mitochondrial function, balancing the redox system, ameliorating Tau hyperphosphorylation and neuroinflammation.