Targeting neuroinflammation in Parkinson's disease
- Publication Type:
- Thesis
- Issue Date:
- 2022
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Parkinson’s disease (PD) is a chronic neurodegenerative disease characterised by the progressive loss of midbrain dopaminergic neurons. No one knows how or why dopamine neurons are lost but several studies confirm the presence of neuroinflammation as a critical pathological component of the disease. As such, disease-modifying strategies that can reduce/halt neuroinflammation are likely to ameliorate PD progression and reduce severity.
Considerable evidence suggests that blockade of the dopamine D3 receptor (D3R) is neuroprotective and reduces inflammation in animal models of PD. However, to date there are no selective D3R antagonists in the market. Recently, computational analyses have demonstrated that buspirone, an FDA-approved anxiolytic drug with serotonin 1A (Htr1a) agonist activity, also functions as a potent D3R antagonist. Therefore, we aimed to test in cellular and animal models of PD if buspirone’s D3R antagonism exerts anti-inflammatory and, therefore, neuroprotective activities.
In vitro, CRISPR-Cas9 gene deletion of the D3R and/or buspirone treatment in BV2 microglial cells attenuated microglial polarisation after LPS challenge. To determine if this result translated in vivo, we generated a rotenone mouse model of PD. Systemic administration of rotenone replicated several pathogenic and behavioural features of PD, including significant locomotor and exploratory impairments, dopaminergic degeneration, widespread alterations of mitochondrial function, increased oxidative stress, glial activation and heightened expression of inflammatory mediators in the midbrain and several extra-nigral CNS sites.
Accordingly, we used this model to assess the ability of buspirone to mitigate rotenone-induced toxicity. Buspirone prevented rotenone-induced behavioural deficits and mitigated dopaminergic degeneration. Drug treatment also prevented astrocyte and microglial activation, which was paralleled by a global downregulation of pro-inflammatory markers and the upregulation of anti-inflammatory markers and neurotrophic factors in several brain regions.
Interestingly, throughout our studies we also report disruptions in the expression levels of the neuroprotective and immune modulatory peptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) following rotenone intoxication, which were rescued by buspirone. This prompted us to test whether these neuropeptides elicited anti-inflammatory activities against rotenone toxicity in BV2 microglia. Both peptides reliably suppressed microglial activation, suggesting an indirect involvement in the anti-inflammatory machinery triggered by buspirone.
In conclusion, our findings indicate that buspirone mitigates rotenone-induced neurotoxicity and inflammation via the activation of multiple protective and anti-inflammatory pathways, perhaps including PACAP and VIP neuropeptides. Altogether, these findings support the notion that targeting the D3R, PACAP or VIP may be a promising therapeutic strategy to reduce inflammation in PD.
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