Modulation Of Endocannabinoid 2-AG On The Electrical Activity Of Ionic Channels In Caudate Nucleus Neurons Impaird By Kainic Acid Through The CB1 Receptor

Objective To investigate whether the endocannabinoid 2-AG regulates the neuroprotective mechanism of VGCC,I_A and VGSC in the excitatory neurotoxicity of caudate nucleus neurons via CB1 receptors.Methods Primary cultured neurons of caudate nucleus in neonatal SD rat were treated with endocannabinoid 2-AG,KA,RIM and/or URB602 for 12 h on day 7 of culture;（1）Hochest staining was used to observe the effect of endocannabinoid 2-AG on excitatory neurotoxicity of caudate nucleus neurons induced by KA;（2）The effects of endocannabinoid 2-AG on the electrical activities of VGCC,I_A,and VGSC in caudate nucleus neurons of KA insult were recorded using whole-cell patch-clamp technique.Results（1）Hochest staining showed that KA-induced caudate nucleus neurons showed typical apoptotic characteristics.Endocannabinoid 2-AG could significantly reduce the number of KA-induced nuclear atrophic cells.This effect works through the CB1 receptor.（2）Whole-cell patch-clamp recordings show that KA-induced excitatory neurotoxicity enhances VGCC current density in caudate nucleus neurons and decreases the half-inactivation voltage V_1/2 of the inactivation curve,but does not affect the electrical characteristics of VGCC activation;and Derived cannabinoid 2-AG can antagonize the inactive electrical activity of VGCC damaged by KA,and it acts through the CB1 receptor.（3）KA-induced excitatory neurotoxicity inhibits the I_A density in caudate nucleus neurons,reduces the slope of the inactivation curve k value,and delays the recovery of the time constantτvalue after inactivation,but does not affect the electrical characteristics of I_Achannel activation;The endocannabinoid 2-AG can antagonize the electrical activity of I_Achannel inactivation and recovery after KA damage,and it acts through the CB1 receptor.（4）KA-induced excitatory neurotoxicity elevates VGSC current density in caudate nucleus neurons and increases the half-activation voltage V_1/2 of the activation curve,but never affects the electrical characteristics of VGSC inactivation;endogenous cannabinoid 2-AG can antagonize KA damages induced the activation kinetics of VGSC and acts through the CB1 receptor.Conclusion Endocannabinoid 2-AG exerts an anti-excitatory neurotoxicity and neuroprotective effect by regulating the electrical activity of VGCC,I_A and VGSC in the caudate nucleus through CB1 receptors.The present study will demonstrate the molecular mechanism of endocannabinoids against the impairment induced by KA in caudate nucleus and further reveal the new molecular target for the prevention and treatment of KA-induced impairment and epilepsy.