Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway.

Clinical and epidemiological studies indicate that diabetic cognitive impairment often occurs in diabetes mellitus patients. Matrine (Mat), an active component of Sophora flavescens Ait root extracts, has widely pharmacological activities including anti-tumor, anti-diabetes, cardioprotective and neuroprotective effects. The present study was designed to elucidate the possibly neuroprotective effects of Mat against diabetic spatial learning and memory impairment caused by high-fat diet and streptozotocin injection in mice. The results showed that Mat treatment significantly ameliorated fasting blood glucose level, impaired glucose tolerance, and lipid metabolism disorder in diabetic mice. In addition, diabetic mice exhibited spatial learning and memory impairment in the Morris water maze test, which could be attenuated by Mat treatment. Moreover, administration of Mat remarkably alleviated histological damage in diabetic hippocampus. Also, further investigations showed that Mat treatment abated endoplasmic reticulum stress induced hippocampal ultra-structure injury as evidenced by increasing the numbers of rough endoplasmic reticulum and mitochondria, as well as down-regulating endoplasmic reticulum stress related protein levels (GRP78, CHOP, ATF6 and Caspase-12). Furthermore, administration of Mat enhanced hippocampal protein expressions of PK2, PKR1 and PKR2, which decreased significantly in diabetic mice. Collectively, these findings suggested that Mat could ameliorate diabetes-induced spatial learning and memory impairment, possibly by alleviating ER stress, and partly through modulation of PK2/PKRs pathway.