Hydroxytyrosol Attenuates Hippocampal Inflammation and Damage in an Experimental Model ofParkinson’s Disease: The Critical Role of the JNK–c-Jun–AP-1 Signaling Pathway in Neuroprotection

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Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra, resulting in motor and non-motor symptoms. Inflammation caused by microglia in the hippocampus and overactivation of the JNK–c-Jun–AP-1 signaling pathway are key mechanisms involved in cognitive deficits associated with PD. This study examined the anti-inflammatory, neuroprotective, and antioxidant properties of hydroxytyrosol (HT) in a rat model of Parkinson's disease caused by reserpine (RES). Male Wistar rats were divided into five groups: control, vehicle + saline (VR + NS), RES + NS, HT + VR, and RES + HT. Behavioral assessments, including catalepsy, rotarod, beam walking, Y-maze, and passive avoidance tests, were conducted to evaluate motor and cognitive functions. Additionally, oxidative stress biomarkers, pro-inflammatory cytokines, acetylcholinesterase (AChE) activity, gene expression of the JNK/c-Jun/AP-1 pathway, and the density of dark neurons in the hippocampus were measured. HT administration significantly enhanced motor and cognitive performance, lowered oxidative stress markers, regulated cytokine levels, inhibited JNK–c-Jun–AP-1 activation, and reduced hippocampal dark neuron density. These findings highlight HT's neuroprotective potential against RES-induced neuronal injury, suggesting its promise as an additional therapeutic approach to mitigate inflammation and preserve cognitive function in PD.

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