Reduction in presynaptic glutamate release and the prevention of glutamate excitotoxicity by lupeol in rats

This study aimed to investigate whether lupeol, a pentacyclic triterpenoid, affects glutamate release in isolated nerve terminals (synaptosomes) from the rat cerebral cortex and whether lupeol affects the excitotoxicity induced by kainic acid (KA) in rats. In rat cerebrocortical synaptosomes, lupeol reduced glutamate release in a manner that could be blocked by extracellular Ca 2+-free medium or P/Q-type Ca 2+ channel antagonism. The synaptosomal membrane potential was not affected by lupeol treatment. Docking data also revealed that lupeol formed a hydrogen bond with amino acid residues of the P/Q-type Ca 2+ channel. In the KA-induced acute excitotoxicity model, lupeol pretreatment ameliorated cortical neurodegeneration and downregulated the expression of glutamate release-related proteins vesicular glutamate transporter 1 (VGLUT1) and phospho-synapsin I, thereby reducing the glutamate levels in the cortices of rats. Our findings suggest that lupeol may exert a neuroprotective effect by reducing glutamate excitotoxicity through the inhibition of presynaptic glutamate release. These results indicate that lupeol could be a promising candidate for the treatment of glutamatergic excitotoxicity and related neurological diseases.