Hexahydrocurcumin Attenuates Neuronal Injury and Modulates Synaptic Plasticity in Chronic Cerebral Hypoperfusion in Rats.

Dementia is the most common age-related problem due predominantly to Alzheimer's disease (AD) and vascular dementia (VaD). It has been shown that these contributors are associated with a high amount of oxidative stress that leads to changes in neurological function and cognitive impairment. The aim of study was to explore the mechanism by which hexahydrocurcumin (HHC) attenuates oxidative stress, amyloidogenesis, phosphorylated Tau (pTau) expression, neuron synaptic function, and cognitive impairment and also the potential mechanisms involved in induced permanent occlusion of bilateral common carotid arteries occlusion (BCCAO) or 2-vessel occlusion (2VO) in rats. After surgery, rats were treated with HHC (40 mg/kg) or piracetam (600 mg/kg) by oral gavage daily for 4 weeks. The results showed that HHC or piracetam attenuated oxidative stress by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) activity, and alleviated expression of synaptic proteins (pre- and post-synaptic proteins) mediated by the Wingless/Integrated (Wnt)/β-catenin signaling pathway. Moreover, HHC or piracetam also improved synaptic plasticity via the brain-derived neurotrophic factor (BDNF)/Tyrosine receptor kinase B (TrkB)/cAMP responsive element binding protein (CREB) signaling pathway. In addition, HHC reduced amyloid beta (Aβ) production and pTau expression and improved memory impairment as evidenced by the Morris water maze. In conclusion, HHC exerted remarkable improvement in cognitive function in the 2VO rats possibly via the attenuation of oxidative stress, improvement in synaptic function, attenuation of amyloidogenesis, pTau, and neuronal injury, thereby improving cognitive performance.