Piracetam attenuates oxidative stress and inflammation-induced neuronal cell death in rats with vascular dementia potentially via the activation of the AMPK/SIRT-1/Nrf-2 signaling pathway

Abstract

Chronic cerebral hypoperfusion (CCH) is the second leading cause of dementia and a major contributor to vascular dementia (VaD). Among the mechanisms underlying CCH-induced cognitive decline, programmed cell death plays a pivotal role. Lytic forms of programmed cell death, including necroptosis and pyroptosis, have recently been identified as consequences of chronic inflammation. However, their precise involvement in VaD remains unclear. It has been demonstrated that piracetam has neuroprotective and cognitive-enhancing properties, potentially through anti-inflammatory and antioxidant mechanisms. Nevertheless, its effects in the context of VaD have not yet been fully investigated. This study aimed to investigate the therapeutic potential of piracetam and elucidate any underlying mechanisms. Male Wistar rats underwent bilateral common carotid artery occlusion to induce CCH. Following this procedure, the rats received either piracetam (600 mg/kg) or resveratrol (20 mg/kg) daily for 28 days. Before euthanasia, cognitive performance was assessed using the Morris water maze test. Then biochemical analyses, including Western blotting and immunohistochemistry, were performed to assess markers of oxidative stress, neuroinflammation, pyroptosis, and necroptosis. Our findings demonstrated that piracetam reduced oxidative stress, suppressed neuroinflammatory responses, enhanced superoxide dismutase activity, and provided protection against pyroptotic and necroptotic cell death. Mechanistic studies showed that piracetam activated AMP-activated protein kinase (AMPK), which in turn upregulated sirtuin 1 (SIRT-1) and nuclear factor erythroid 2–related factor 2 (Nrf-2), leading to improved cognitive performance. In conclusion, piracetam ameliorates cognitive impairment in CCH-induced VaD by modulating oxidative damage, neuroinflammation, and inflammatory cell death, potentially through activation of the AMPK/SIRT-1/Nrf-2 signaling pathway.