Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson’s Disease Models

Abstract

The exact mechanism of gut dysfunction in Parkinson's disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or without vagal disruption. A decrease in central dopamine levels induced a decrease in colonic dopamine types 1 and 2 receptor expression together with an increase in the colonic levels of dopamine and a decrease in the levels of acetylcholine, which may explain a decrease in gut motility. Central dopaminergic depletion also induced an increase in the colonic levels of inflammatory and oxidative stress markers together with activation of the pro-inflammatory arm of the local RAS. Mice with acute (1 week) or subchronic (3 weeks) gut inflammation did not show a significant increase in colonic α-synuclein and phosphorylated α-synuclein expression during this relatively short survival period. Interestingly, we observed early changes in the nigrostriatal dopaminergic homeostasis, dopaminergic neuron death, and increased levels of nigral pro-inflammatory markers and RAS pro-inflammatory activity. The present results show that a dysregulation of the neural bidirectional gut-brain interaction may explain the early gut disturbances observed in parkinsonian patients, and also the increase in vulnerability of nigral dopaminergic neurons after gut inflammation.

Acute inflammation down‐regulates alpha‐synuclein expression in enteric neurons

“…By contrast, when a more chronic administration regimen was used, we did not observe any change in the alpha-synuclein levels. Such a discrepancy might be explained by the lower levels of colonic proinflammatory cytokines that were found in this model when compared to the acute regimen (Garrido-Gil et al 2018). These observations further reinforce the possible role of proinflammatory cytokines and especially TNF-a and IL1-b in Lysates from colonic samples from day 1 to day 4 were subjected to immunoblot analysis using Syn-1, PGP 9.5 and betaactin antibodies.…”

“…Such a discrepancy might be explained by the lower levels of colonic pro‐inflammatory cytokines that were found in this model when compared to the acute regimen (Garrido‐Gil et al . ). These observations further reinforce the possible role of pro‐inflammatory cytokines and especially TNF‐α and IL1‐β in the regulation of enteric alpha‐synuclein level.…”

Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

“…In addition, brain dopamine also modulates the gut inflammation. Garrido‐Gil et al showed that central dopaminergic depletion increased the level of IL‐1β in colon. These lines of evidence may support the possibility above.…”

Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson’s Disease

“…For a long time now, it has been hypothesized that the gut may play a crucial role in the etiology of PD. The intestinal microbiome with a similar amount of bacterial cells as human cells, could be the decisive factor linking the environment and neuronal damage in the central nervous system (CNS) of PD patients [10][11][12]. According to the first theory, alpha-synuclein accumulates in the enteric nervous system and retrogradely extends to the brain stem via the vagus nerve and its nucleus dorsalis [13,14].…”