Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets.

Cerebral hypoxia/ischemia because of the interruption of cerebral blood flow during cardiopulmonary bypass with deep hypothermia circulation arrest (DHCA) surgery for congenital cardiac surgery is a significant clinical issue (1). Fifty percent of children with complex congenital heart disease undergoing cardiopulmonary bypass with DHCA have developmental deficits, such as disabilities in speech and attention deficit disorder by school age(2). Cerebral hypoxia /ischemia occurred during DHCA is predictable(1); thus, it is possible to minimize the brain injury induced by ischemia with pharmacologic approaches. Unfortunately, no pharmacological agent with proven clinical benefit has yet been identified. Loss of cerebral vascular autoregulation is one of the key features of cerebral hypoxia/ischemia (3-5). The loss of autoregulation to hypotension could result in a pressure passive cerebral circulation, which may decrease cerebral blood flow and further aggravate brain ischemia(6). Loss of cerebrovascular regulation to hypercapnia also contributes to the development of the pressure passive circulation and periventricular leukomalacia(6). Thus, preservation of cerebral vascular autoregulation from ischemia is very important to reduce brain injury from ischemia. We recently demonstrated that salvinorin A, an active component of Salvia divinorum and a non-opioid kappa opioid receptor (KOR) agonist, is a potent cerebral vascular dilator in normal and pathological conditions (7). It is likely that salvinorin A could protect cerebral vasculature from ischemia. Unlike other KOR agonists, salvinorin A has long been used by different ethnic groups for various purposes, including spiritual experiences and “treating” illnesses (8,9), indicating its high potential as a clinically acceptable medication. It has been demonstrated that systemic administration of KOR agonists has neuroprotective effects in animal models of cerebral ischemia (10,11). KOR agonists could activate mitogen-activated protein kinase (MAPK) (12,13). MAPK is a key intracellular signaling system, which includes extracellular signal regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 (14). It was demonstrated that prolonged and persistent activation of the ERK cascade is an important contributory mechanism of cerebral ischemic preconditioning (15-17). This pathway is also involved in many other forms of pharmacological preconditioning, such as isoflurane and sevoflurane (18,19). Thus, it is likely that salvinorin A may generate cerebral protective effects via this pathway. Based on the above evidence, we hypothesized that salvinorin A pretreatment might preserve autoregulation of pial vessels to hypotension and hypercapnia from hypoxia/ischemia via activation of MAPK.