INVESTIGATING THE NEUROPROTECTIVE MECHANISMS OF CANNABINOIDS THROUGH ENDOPLASMIC RETICULUM STRESS MODULATION

Abstract

The aggregation of misfolded proteins in the endoplasmic reticulum (ER) is a pathological trait shared by many neurodegenerative disorders. This aggregation leads to the persistent activation of the unfolded protein response (UPR) and ultimately apoptosis due to ER stress. Cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been reported to be neuroprotective in in vitro and in vivo models of neurodegeneration through their antioxidant and anti-inflammatory properties. However, little is known about the role of these cannabinoids in the context of ER stress. STHdhQ7/Q7 cells were treated with the ER stress inducer thapsigargin (TG) and cannabinoids in three different experimental paradigms to investigate the effect of 2.5 µM THC and 1 µM CBD monotreatment and cotreatment on ER stress-induced cell death. The mouse striatal neurons survived significantly more when THC or CBD was given before TG exposure. To further investigate this experimental paradigm, the gene and protein expression of UPR proteins was measured to determine the effect of cannabinoid pre-treatment on cell survival through ER stress modulation. A significant increase in the gene expression of the ER chaperone GRP78 and the ER-resident neurotrophic factor MANF in pre-treated samples suggest that with THC or CBD pre-treatment, the protein folding capacity of the cell is improved. Additionally, a decrease in the ER-mediated apoptotic markers such as BIM and caspase 12 with THC or CBD pre-treatment provides further evidence that cannabinoid pre-treatments are neuroprotective through ER stress modulation. These data suggest that prior cannabinoid monotherapy prepares the cell for future insults to the ER. Understanding the role of ER stress in the neuroprotective properties of THC and CBD provides insight into the therapeutic potential of cannabinoids and the role of ER dysfunction in various neurodegenerative disorders.