A Novel Rat Model for Inflammatory Gut–Brain Interactions in Parkinson's Disease

Abstract

Gut inflammation is a salient prodromal feature of Parkinson's disease (PD) implicated in pathologic processes leading to nigrostriatal dopaminergic degeneration. However, existing rodent models of PD are suboptimal for investigating the interaction between gut inflammation and neuropathology. This study aimed to develop a rat model of PD in which gut inflammation exacerbated PD symptoms induced by a parkinsonian lesion. This was achieved by combining the 6-hydroxydopamine (6-OHDA) rat model for PD and the dextran sodium sulfate (DSS) rat model for colitis. The model was characterised using behavioural tests, including reaching, step, gait, open-field and cylinder tests, plus stereological quantification of substantia nigra (SN) DA neurodegeneration, and histological analysis of SN microglial activation and distal colon morphology. The combination of 6-OHDA and DSS resulted in greater stool softening and bleeding, shorter colons and greater distal colon histological damage, when compared with the 6-OHDA model. Additionally, 6-OHDA and DSS rats displayed similar DA neurodegeneration, yet less SN microglial activation, when compared to 6-OHDA rats that did not receive DSS. Finally, DSS + 6-OHDA rats exhibited impaired forelimb motor function compared with 6-OHDA rats, with decreased performance in reaching and step tests. In conclusion, DSS administration exacerbated forelimb motor dysfunction in 6-OHDA rats. Behavioural changes in DSS + 6-OHDA rats were associated with lower levels of microglial activation and similar levels of dopamine depletion compared with 6-OHDA-only rats. These results support that the DSS + 6-OHDA rat model is a promising PD animal model to investigate deleterious gut–brain interactions in PD.