In an LPS-induced rat model of Parkinsonism, isotopically enriched 64Zn-aspartate reduced behavioral deficits and apomorphine rotations, normalized systemic inflammatory indices and CRP, shifted circulating and peritoneal phagocytes toward anti-inflammatory phenotypes, partially restored thymus…

Provides strong preclinical evidence that an immunomodulatory, microbiota-stabilizing zinc compound can target neuroimmune–gut axis dysfunction in PD, making it a promising disease-modifying candidate for further mechanistic and translational studies.

A growing body of research indicates that systemic inflammation contributes substantially to the progression of Parkinson's disease (PD). Foundational studies propose that targeting inflammatory pathways may offer therapeutic benefits for PD and other neurodegenerative conditions. Our previous work demonstrated that a novel zinc aspartate compound enriched with the light isotope 64Zn (64Zn-asp) can counteract inflammatory and cognitive impairments triggered by intra-hippocampal Aβ1-40 in rats, and can also mitigate neuroinflammation while promoting neuronal survival in a PD model. In the present study, we investigated the impact of this isotopically modified zinc compound on systemic inflammatory responses and gut microbiota composition in a rat model of PD induced by a single stereotactic intranigral injection of lipopolysaccharide (LPS). LPS-lesioned rats exhibited impaired locomotion, heightened anxiety-like behavior, and progressive dopaminergic dysfunction. 64Zn-asp administration attenuated behavioral deficits and reduced apomorphine-induced rotations. Treatment normalized CRP levels, reversed LPS-induced increases in granulocytes and platelets, and corrected elevations in systemic inflammatory indices (including NLR, PLR, SII, and SIRI). 64Zn-asp shifted circulating and peritoneal phagocytes toward an anti-inflammatory phenotype and partially restored thymus structure and cellularity. In the gut, LPS-induced PD resulted in marked reductions in Bifidobacterium and Lactobacillus spp. and an expansion of opportunistic Enterobacteriaceae and Staphylococcus spp. 64Zn-asp largely preserved beneficial anaerobes and suppressed opportunistic taxa in both luminal and mucosa-associated compartments. These findings demonstrate that 64Zn-aspartate exerts anti-inflammatory, immunomodulatory, and microbiota-stabilizing effects, suggesting potential therapeutic value as a disease-modifying strategy targeting neuroimmune-gut axis dysfunction in PD.