Intranasal 6-OHDA Induces TRPM3-mediated Neuroinflammation in the pVTA: A Preclinical Early-stage Parkinson's Disease Model.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by motor impairment, but early-stages are dominated by non-motor symptoms such as olfactory dysfunction, anxiety, depression, and cognitive deficits, which are poorly replicated by currently studied animal models. In animal models of PD, stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra induces dopaminergic neurodegeneration, which consequently produces motor deficits; but inadequately representing early non-motor features. Emerging evidence suggests that transient receptor potential melastatin 3 (TRPM3)-associated neuroinflammation may contribute to early PD progression and non-motor symptoms. However, its role in early-stage PD, particularly in non-invasive models, remains unclear. Therefore, this study aimed to develop a novel non-invasive early-stage PD model and investigate TRPM3-associated neuroinflammation. Early-stage PD-like symptoms were induced in rats by intranasal 6-OHDA (5 mg/nostril) for 7 consecutive days and evaluated using the buried food, odor identification, open field, and elevated plus maze tests. Tyrosine hydroxylase (TH) immunoreactivity was quantified in the olfactory bulb, ventral striatum, and posterior ventral tegmental area (pVTA). TRPM3 immunoreactivity, neuroplastic changes in the pVTA and interleukin-1β (IL-1β) in the ventral striatum and pVTA were also assessed. 6-OHDA produced behavioral deficits, reduced TH immunoreactivity, increased TRPM3, elevated IL-1β, and impaired pVTA neuroplasticity. Intraperitoneal (i.p.) treatment of TRPM3 inhibitor primidone (2.5, 5, and 10 mg/kg) significantly reversed these alterations, and standard pramipexole (3 mg/kg, i.p.) also reduced behavioral deficits. Overall, the intranasal 6-OHDA model reproduces key features of early-stage PD, including non-motor deficits, dopaminergic dysfunction, TRPM3-associated neuroinflammation, and impaired neuroplasticity, providing a simple and clinically relevant platform for therapeutic evaluation.