Delphinidin modulates neuroinflammation and behavioral deficits in a Parkinson's disease mouse model.

Neuroinflammation is deeply intertwined with dopaminergic (DA) neurodegeneration in Parkinson's disease (PD). We tested whether delphinidin, an anthocyanidin with reported inflammasome/NF-κB modulatory activity, alters neuroinflammation and nigrostriatal integrity in a progressive AAV1/2-A53T α-synuclein (hαSYN) mouse model. Once-daily intraperitoneal delphinidin for nine weeks modestly ameliorated asymmetric forepaw use, attenuated the hαSYN-induced loss of striatal TH⁺ terminal density, and was associated with modest alterations in dopamine turnover, yet did not prevent the loss of DA neurons in the substantia nigra (SN). On the immunological level, delphinidin attenuated the innate immune response by reducing the number and activity of CD11b(+) microglia in both the SN and striatum. In contrast, CD4(+)-mediated adaptive inflammation remained unchanged, while the number of CD8(+) T cells increased in the SN. Notably, approximately 48% of CD8(+) T cells in the SN of these mice were identified as CD8(+)CD122(+) regulatory T cells, known for their anti-inflammatory properties. In conclusion, delphinidin was associated with a partial attenuation of neuroinflammatory changes and a context-dependent shift towards a more anti-inflammatory CD8⁺CD122(+) T cell phenotype in the SN. However, these changes did not translate into protection of SN DA somata, revealing a dissociation between striatal terminal preservation and nigral cell body survival, and underscoring the limitations of targeting innate immunity alone under the current dosing paradigm.