Abstract: Objective To investigate the modulatory effect of 2-arachidonoylglycerol (2-AG) on voltage-gated sodium currents (VGSCs) in rat caudate nucleus (CN) neurons with kainic acid (KA)- induced injury and explore the molecular mechanism underlying the neuroprotective effect of 2-AG. Methods Primary cultures of CN neurons isolated from neonatal SD rats were treated with KA, 2-AG+KA, RIM (a CB1 receptor antagonist) +2-AG+KA, or vehicle only (as control). After 7 days in primary culture, the neurons were treated with corresponding agents for 12 h (RIM and 2-AG were added at the same time; KA was added 30 min later) before recording of current density changes, current-voltage characteristics, activation and inactivation kinetics of VGSCs (INa) using whole-cell patch clamp technique. Results In cultured CN neurons, KA significantly increased current density of VGSCs (P=0.009) as compared with vehicle treatment. KA also produced a hyperpolarizing shift in the activation curve of INa and significantly increased the absolute value of V1/2 for activation (P=0.008). Addition of 2-AG in the culture medium obviously prevented KA-induced increase of INa (P=0.009) and hyperpolarizing shift in the activation curve of INa, and significantly reduced the value of V1/2 for activation (P=0.009) in a CB1 receptor-dependent manner. 2-AG alone did not affect the density, activation or deactivation of VGSCs in rat CN neurons. Conclusion In excitotoxic events, endogenous 2-AG can offer neuroprotection by modulating VGSCs in the CN neurons through a CB1 receptor-dependent pathway

Key words: 2-arachidonoylglycerol; kainic acid; cannabinoid receptor; voltage-gated sodium channels; caudate nucleus