Therapeutic potential of nasal kisspeptin-54 for reducing α-synuclein accumulation and restoring hippocampal synaptic plasticity in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

BACKGROUND/AIM: Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons and pathological aggregation of α-synuclein (α-syn), leading to significant motor and cognitive impairments. Kisspeptin-54 (KP-54), a neuropeptide primarily involved in reproductive regulation, has recently been implicated in neurorestorative processes, with emerging evidence suggesting beneficial effects on locomotor activity and cognitive function. However, its therapeutic potential in PD has not yet been fully investigated. This study aimed to evaluate the therapeutic efficacy of chronic nasal KP-54 administration in a 6-hydroxydopamine (6-OHDA) rat model of PD, focusing on motor and cognitive outcomes, hippocampal synaptic plasticity, and α-syn pathology. MATERIALS AND METHODS: Adult Sprague-Dawley rats underwent unilateral 6-OHDA injections into the medial forebrain bundle to induce dopaminergic degeneration. Beginning 3 weeks after lesion induction, animals received daily nasal KP-54 or vehicle treatment for an additional 3 weeks. Motor performance was assessed using the catalepsy, beam balance, and open field tests, whereas cognitive function was evaluated using the Y-maze and object location test. Baseline assessments were conducted on day 0 prior to lesion formation. Electrophysiological recordings obtained from the hippocampal CA1 region were used to assess synaptic plasticity. Dopaminergic neuron survival and α-syn accumulation in the substantia nigra and hippocampus were quantified by immunofluorescence analysis. RESULTS: Chronic nasal KP-54 significantly ameliorated motor and cognitive deficits induced by 6-OHDA. KP-54 restored hippocampal synaptic plasticity, enhanced the survival of tyrosine hydroxylase-positive dopaminergic neurons, and reduced α-syn accumulation in both the substantia nigra and hippocampus. CONCLUSION: The findings indicate that nasal KP-54 administration exerts neurorestorative effects in a 6-OHDA rat model of PD by preserving dopaminergic neurons, improving synaptic function, and attenuating pathological α-syn aggregation. These results position KP-54 as a promising candidate for disease-modifying therapy in Parkinson's disease.