Interaction between cannabinoid drugs and sodium channels in diabetes/high glucose induced oxidative stress, neuroinflammation, and neurotoxicity
Diabetes mellitus, a common metabolic disorder, exhibits neuropathic complications that can eventually lead to disabling pain (Todorovic 2015). This is attributed to hyperglycemia/high glucose resulting in neuronal hyperexcitability (Todorovic 2015). Importantly, diabetes-evoked neuronal hyperexcitability and neurotoxicity can be caused by alterations in voltage-gated sodium channel (VGSC) expression (Hong, Morrow et al. 2004), resulting in changes in the sodium currents lowering the action potential threshold (Hong, Morrow et al. 2004, Chen, Wang et al. 2018). Interestingly, cannabinoids exert antinociceptive properties. In addition, both cannabinoid receptors, CB-1 and CB-2, are highly expressed in central and peripheral nervous systems, suggesting a fundamental role in nociception (Agarwal, Pacher et al. 2007, Rahn and Hohmann 2009). Also, estrogen (E2) loses its neuroprotective effect, or worsens neuronal injury in diabetic animals (Santizo, Xu et al. 2002). Thus, the current study aims to investigate the role of VGSC in high glucose-induced neurotoxicity, and whether high glucose modulation of VGSC can be altered using cannabinoids. Also, this study will investigate sex-determined modulation of cannabinoid/VGSC interaction in high glucose elicited neurotoxicity. Noteworthy, our results may identify novel molecular targets for alleviating neuropathic pain and solve the sex-specific exacerbation of neurological dysfunction elicited by diabetes.