Abstract
This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.
Highlights
Global cerebral ischemia, usually seen in clinical conditions such as cardiac arrest, drowning, or systemic hypotension during surgery [1], is associated with high mortality rates [2]
Salvinorin A preserved cerebral pial artery autoregulation after cerebral cortex ischemia All animals were monitored with blood gas and temperature and no significant difference was found on the baseline value
We investigated the role of salvinorin A in cerebral pial artery protection in a rat model of forebrain ischemia injury
Summary
Usually seen in clinical conditions such as cardiac arrest, drowning, or systemic hypotension during surgery [1], is associated with high mortality rates [2]. Neuronal death and behavioral dysfunction caused by brain injury-induced ischemia are common in patients with stroke. Studies have shown that ischemia could change the vascular tension and reduce response of vessels, thereby leading to disruption of the blood flow around the ischemic area [3,4]. The accompanying hypercapnia and hypotension could result in the dysfunction of the vessel and final cell injury in the brain. Autoregulation of blood vessels is considered to play a critical role in the neuronal protection after ischemia during the hypercapnia and hypotension condition [5,6]. It is necessary to maintain the autoregulation function of the blood vessel to preserve the normal blood supply and cell metabolism. Until now, no effective therapeutic drug or strategy is available
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