Highly selective non-opioid kappa opioid receptor (KOR) agonist salvinorin A protects against forebrain ischemia-induced brain injury in rats

To investigate the effect of salvinorin A (SA) on brain injury and neurologic function post-brain ischemia/reperfusion (I/R) using a rat forebrain ischemia model and further explore the effect of kappa opioid receptor (KOR) inhibition by SA on aquaporin-4 (AQP4) expression in the hippocampus, cortex and striatum in the forebrain. A forebrain ischemia model was established by colligating the bilateral common carotid arteries of SD rats for 10 min. The rats were randomized to receive dimethyl sulfoxide (DMSO), SA (1 µg/100 g body weight) or SA (onset of ischemia) plus SA antagonist nor-BIN (0.2 mg/100 g body weight. Rat brain water content was measured. Apoptotic neurons in the hippocampal CA1 region, cortex and striatum were enumerated. AQP4 in CA1, the cortex and the striatum were determined by immunoblotting assays and immunohistochemistry at 24 h post-ischemia. Neuromotor tests were performed on day 1, 2 and 5 post-ischemia. Water maze test was carried out on the 5th post-ischemia day. SA significantly attenuated I/R-induced increase in brain water content. Our immunoblotting assays and immunohistochemistry further revealed that SA effectively lessened I/R-induced upregulation of AQP4 expression in the hippocampus, cortex and striatum 24 h post-ischemia. SA also significantly reduced the percentage of dead and apoptotic neurons in these regions compared to DMSO. Moreover, SA partially reversed I/R-induced decline in rat motor function and cognition. The neuroprotective effects of SA were partially abolished by nor-BIN. SA protects against I/R-induced brain injury by attenuating brain edema formation and inhibiting neuronal death and improves neurologic recovery of rats post-I/R.