Pharmacological Postconditioning by Protocatechuic Acid Attenuates Brain Injury in Ischemia–Reperfusion (I/R) Mice Model: Implications of Nuclear Factor Erythroid-2-Related Factor Pathway

Ischemia-reperfusion (I/R) injury often follows cardiovascular aberrations that predispose the patient to be neurological and cognitive abnormalities. Pharmacological postconditioning (pPoCo) aims to mitigate I/R origin cerebral infarction and neurobehavioral impairment. Protocatechuic acid (PCA) is a natural polyphenol possessing anti-oxidant and anti-inflammatory activities. This study investigated the effects of PCA pPoCo using a global I/R mice prototype. Mice were injected PCA (50 and 100 mg/kg) immediately after bilateral common carotid artery occlusion (17 min) followed by 24 h reperfusion. Trigonelline (10 mg/kg) was administered separately before I/R surgery to assess the role of the Nrf2 pathway in PCA and I/R treated mice. Results displayed neurological deficits 24 h post-reperfusion, and I/R triggered sensorimotor and memory deficits that were attenuated by PCA. PCA pPoCo increased antioxidants and Nrf2 expression in the brain against I/R injury. In I/R mice, PCA pPoCo attenuated lipid peroxidation, inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6), and myeloperoxidase activity. Histopathology revealed a decrease in total infarct area (TTC staining) and cortical neuron density by I/R surgery that was attenuated by PCA. Trigonelline antagonized beneficial effects of PCA pPoCo and attenuated Nrf2 pathway in I/R mice model. PCA pPoCo dose-dependently improves neurobehavioral functions against global I/R injury via the Nrf2 mechanism.