Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB–Bcl-2 pathway after subarachnoid hemorrhage in rats

Abstract

Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether Cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague Dawley rats (n=123) were subjected to SAH by endovascular perforation. Rats received vehicle or JWH133 at 1 hour after SAH. Neurological deficits and brain water content were evaluated at 24 hours after SAH. Western blot was performed to quantify phosphorylated CREB (pCREB), Bcl-2, and cleaved caspase-3 levels. Neuronal cell death was evaluated with terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling staining. Additionally, CREB siRNA was administered to manipulate the proposed pathway. JWH133 (1.0 mg/kg) improved neurological deficits and reduced brain water content in left hemisphere 24 hours after SAH. JWH133 significantly increased activated CREB (pCREB) and Bcl-2 levels and significantly decreased cleaved caspase-3 levels in left hemisphere 24 hours after SAH. CREB siRNA reversed the effects of treatment. TUNEL positive neurons in the cortex were reduced with JWH133 treatment. Thus, CB2R stimulation attenuated EBI after SAH possibly through activation of pCREB-Bcl-2 pathway.

Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

“…The present results indicated that loganin up-regulated p-Akt level under SMN-deficient conditions. Moreover, activation of Akt/GSK-3CREB pathway regulates several critical factors related to neuronal survival, such as BDNF and Bcl-2 [48,49]. The present results indicated that loganin activated Akt, induced phosphorylation of GSK-3at Serine 9, and further activated CREB.…”

Endocannabinoids in cerebrovascular regulation

“…A similar interaction between TNF-␣ and endocannabinoids or synthetic CB2 agonists could potentially attenuate delayed cerebrovascular constriction and consequent brain ischemia after SAH, since TNF-␣ has been reported recently to play a significant pathogenic role in this process by enhancing the myogenic tone in cerebral arteries, resulting in the development of vasospasm (256). In accordance with these observations and the putative role of cytokines in the development of cerebrovascular dysfunction, CB2 stimulation was recently shown to attenuate the early brain injury following SAH (75,76).…”

“…Endocannabinoids themselves, as well as pharmacological interventions on their receptors, have been shown to interfere with the development and progression of certain CNS disorders, such as subarachnoid hemorrhage (SAH) (75,76), traumatic brain injury (TBI) (147,212), and ischemic stroke (164). On the other hand, cerebrovascular dysfunction is a common feature in these disorders, raising the possibility that the cerebrovascular actions of cannabinoids play a significant role in their pathogenesis or resolution.…”

Ethyl pyruvate alleviates early brain injury following subarachnoid hemorrhage in rats

“…The pathophysiological mechanisms of early brain injury are complicated. Disruption of the blood-brain barrier (BBB), microglia activation, and apoptosis play a pivotal role in the pathogenesis of early brain injury after SAH [12,22,27].…”