Rutina previne neurotoxicidade e alterações comportamentais em modelo animal de degeneração dopaminérgica induzido por aminocromo

Abstract

Aminochrome is a compound produced in dopaminergic neurons during neuromelanin formation, with the potential to induce oxidative stress, alpha-synuclein accumulation, and neuroinflammation, resembling the pathophysiology of Parkinson’s disease (PD). Despite advances in understanding the disease’s pathophysiological mechanisms, PD remains incurable, as the gold-standard treatment, L-DOPA, is unable to halt or mitigate the neurodegenerative process. Rutin, a flavonoid with well-documented anti-inflammatory, antioxidant, and neurogenic properties, has been recognized in the literature. Thus, this study aims to investigate the behavioral and neuroprotective effects of rutin in an in vivo PD model induced by aminochrome. To this end, male Wistar rats (270–330 g) (CEUA-ICS, Protocol No. 3006070223) were divided into four groups: control (CTR), 10 mg/kg rutin (RUT), 6 nmol aminochrome (AMI), and aminochrome + rutin (AMI + RUT). The rats underwent stereotaxic surgery for aminochrome injection into the striatum. Animals in the RUT and AMI + RUT groups received daily oral doses of rutin for 21 days. All animals were subjected to behavioral tests on the 14th day. Midbrain and striatal samples were collected on the 22nd day and fixed with 4% paraformaldehyde for immunohistochemistry (TH and SOX-10) and immunofluorescence (GFAP, S100B, IBA-1, and TH). The open-field test revealed a reduction in the total frequency of rearing and grooming in the AMI group compared to the CTR group. The elevated plus-maze test showed that AMI group animals navigated the apparatus less and exhibited fewer entries into the open arms compared to the CTR group. Immunohistochemical quantification of TH+ cells confirmed reduced cell viability induced by aminochrome at the level of the third cranial nerve pair in the substantia nigra pars compacta (SNpc). Furthermore, the AMI group displayed an increase in IBA1+ cells and microglia-neuron interactions compared to the CTR group. Colocalized expression of GFAP+ and S100B+ was also higher in the AMI group compared to the CTR and AMI + RUT groups. Quantification of SOX10+ cells showed no significant changes. Collectively, these findings demonstrate that striatal aminochrome injection induces pronounced degeneration in the medial SNpc, accompanied by glial reactivity, neuroinflammation, and anxiogenic behavioral changes. These effects were prevented by enteral rutin treatment. The behavioral consequences of unilateral aminochrome lesions in the striatum had not been well described previously; thus, this study contributes to the characterization of a novel PD model and elucidates the therapeutic potential of rutin in the disease.