Cannabidiol alleviates hemorrhagic shock‐induced neural apoptosis in rats by inducing autophagy through activation of the PI3K/AKT pathway

Abstract

Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia‐induced brain injury. However, the protective effect of CBD against mitochondrial‐dependent apoptosis in hemorrhagic shock (HS)‐induced brain injury has not been studied. In the present study, we observed the protective effects of CBD against neural mitochondrial‐dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin‐1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro‐apoptosis ratio and NF‐κB signaling activation, and upregulation of BCL2 in the cerebral cortex. Such protective effects were reversed by 3‐Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD‐induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD’s regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1. Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS‐mediated mitochondrial‐dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.

Alteration of Akt1-Gsk3β Signaling Pathway in Trauma Hemorrhagic Shock Patients

“…The downregulation of Akt1 gene and protein expression corroborated by other injuries, such as brain, liver, and heart experimental models of THS, which largely depend on the severity of the injury (29–31), also correlated with severity of trauma injury in the present study. The immunofluorescence data showed the reduced expression and cytosolic localization of pAkt1, which was also demonstrated by previous studies on Akt1 expression (32).…”

Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription

“…Collectively, these data indicate that CBD may promote activation of the autophagy pathway, potentially at the level of upstream mTOR signaling and/or pre-autophagosome formation. This is also supported by studies in several tissues, including mesenchymal stem cells, endothelial cells, neurons, as well as in vitro and mouse models of Parkinson’s and Alzheimer’s Disease [ 62 , 63 , 64 , 65 , 66 ].…”

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…This may confirm that the regulatory effect of CBD on the proteostasis network has been demonstrated by CBD-mediated protection in the expression and oxidative modifications of proteins involved in proteasome activity and protein folding [ 24 ]. Moreover, several studies show the CBD-mediated regulation of p62 expression in both an increasing [ 69 ] and decreasing trend [ 70 ], in Sprague Dawley rats using CBD (100 mg/kg) [ 69 ] and in Sprague Dawley rats with hemorrhagic shock-induced brain injury using this phytocannabinoid (5 mg/kg) [ 70 ], respectively. This indicates not only CBD effects on the regulation of autophagy but also another way for CBD-mediated regulation of the Nrf2 pathway.…”