Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment

Abstract

Recently, silibinin, a clinically used hepatoprotectant, has been reported to prevent memory impairment induced by amyloid beta by reducing oxidative stress and inflammation in mice brain. However, the exact mechanism of neuroprotective effect of silibinin has not been properly studied especially in context of brain energy metabolism and cholinergic functions, the essential factors undergo impairment in Alzheimer’s disease. Therefore, present study investigated the effect of silibinin on impairment in memory, brain energy metabolism and cholinergic function following intracerebral (IC) streptozotocin (STZ) administration in mice. STZ (0.5 mg/kg), administered twice at an interval of 48 hr, caused significant impairment in memory tested by Morris water maze. Increased oxidative and nitrosative stress was also observed in IC STZ injected mice brain. Further, STZ significantly decreased ATP and increased intrasynaptosomal calcium level in mice brain. STZ IC induced memory impairment is associated with increased activity and mRNA expression of acetylcholinesterase (AChE) and decreased α7 nicotinic acetylcholine receptor (α-7-nAChR) mRNA expression in mice brain. Pretreatment with silibinin (100 and 200 mg/kg, PO) attenuated STZ induced memory impairment by reducing oxidative and nitrosative stress and intrasynaptosomal calcium ion level. Further, silibinin dose dependently restored ATP level indicating improvement in brain energy metabolism. The activity and mRNA expression of AChE was restored by silibinin. Moreover, α-7-nAChR mRNA expression was significantly increased by silibinin in STZ treated mice brain. The present study clearly demonstrates the beneficial effects of silibinin in memory impairment caused by STZ and may be a potential candidate for treatment of neurodegerative diseases.