Effects of Paeoniflorin on Neurobehavior, Oxidative Stress, Brain Insulin Signaling, and Synaptic Alterations in Intracerebroventricular Streptozotocin-Induced Cognitive Impairment in Mice

Paeoniflorin (PF) is a natural monoterpene glycoside in Paeonia lactiflora pall with anti-diabetic, antioxidant, anti-inflammatory, and neuro-protective properties. This study was designed to investigate the neuroprotective effects of PF against cognitive deficits induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in mice. STZ was injected twice intracerebroventrically (3 mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with PF (10 mg/kg per day, intraperitoneally) starting from the first dose of STZ for 21 days showed an improvement in ICV-STZ induced cognitive deficits as assessed by novel object recognition and Morris water maze (MWM) test. PF significantly attenuated STZ induced mitochondrial dysfunction manifested by dramatically elevated cytochrome c oxidase activity and ATP synthesis, and restoration of the mitochondrial membrane potential (MMP), and oxidative stress in hippocampus and in the cortex compared to control. Moreover, PF treatment also markedly increased synaptic density in the CA1 region of the hippocampus compared to control. Furthermore, PF ameliorated defective insulin signaling by up-regulating p-PI3K and p-Akt protein expression while downregulating p-IRS-1 protein expression. Taken together, the outcomes of the current study suggest the therapeutic potential of PF in the cognitive deficits induced by ICV-STZ.