Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway
This animal study (n=30) investigated the role of salvinorin A (10 and 20µg/kg) in cerebral pial artery protection in a rat model of forebrain ischemia injury and found that salvinorin A treatment preserved the autoregulation of the cerebral pial artery, protected the brain tissues from ischemia injury by decreasing cell death, and hastened the recovery of their motor functions.
Authors
- Dong, H. P.
- Zhou, W.
- Ma, X. X.
Published
Abstract
Introduction
This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms.
Methods
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.
Results
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.
Discussion
Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.
Research Summary of 'Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway'
Introduction
Dong and colleagues frame the study within the clinical problem of global cerebral ischemia, which occurs in scenarios such as cardiac arrest, drowning or profound systemic hypotension and is associated with high mortality and neurological impairment. Previous work indicates that cerebral ischemia alters vascular tone and impairs vessel responsiveness, so loss of autoregulation during hypercapnia and hypotension contributes to neuronal injury. The authors note that maintaining cerebrovascular autoregulation is therefore important for preserving cerebral blood supply and metabolism, but effective pharmacological strategies are lacking. The paper tests whether salvinorin A, a selective kappa opioid receptor (KOR) agonist that crosses the blood–brain barrier and has previously been reported to dilate vessels and reduce brain injury, can preserve cerebral pial artery autoregulation after transient forebrain ischemia. The investigators also set out to explore mechanisms, focusing on the PI3K/AKT pathway and downstream nitric oxide/cGMP signalling, because PI3K/AKT can regulate nitric oxide synthase (NOS) and cGMP-mediated vasodilation. Their primary aim was to determine if salvinorin A given at reperfusion preserves pial artery responses to hypercapnia and hypotension and whether PI3K/AKT/cGMP signalling mediates these effects.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topic
- APA Citation
Dong, H., Zhou, W., Ma, X., He, Z., & Wang, Z. (2018). Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway. Brazilian Journal of Medical and Biological Research, 51(5). https://doi.org/10.1590/1414-431X20176714
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