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The role of neuroinflammation, serotonin deficiency and gene expression in the pathology of L-dopa-induced dyskinesia with prolonged Levodopa treatment in a Parkinsonian rat model.

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2023

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder, which globally affects 2% of the population above 65 years old. It is characterized by motor symptoms (bradykinesia, tremor, and rigidity) and nonmotor symptoms (cognitive deficit, sleeping, and mood disorders). There is no cure for PD, however, levodopa (L-dopa) therapy is a gold-standard pharmacotherapy for managing motor symptoms. Despite its effective results, its long-term consumption causes L-dopa-induced dyskinesias (LID). The pathology of LID is not clear, however growing evidence has indicated that neuroinflammation and cognitive decline may be significant factors. This study aimed to investigate the role of dysregulated Nptx2, TH, and FosB genes in the L-dopa-induced cognitive impairment and to assess the role of serotonin deficiency and neuroinflammation in LID pathology in a Parkinsonian rat model. 72 Male Sprague-Dawley rats were divided into two equal phases (n=36 per phase), each phase had 3 groups with n=12 per group. Phase 1 had 3 groups of rats that were injected with L-dopa for 14 days (pre-LID phase) while phase 2 had rats that were injected with L-dopa for 28 days (LID phase). Animals went through behavioral assessments and were sacrificed by decapitation to obtain the hippocampus, prefrontal cortex, and striatum for neurochemical analysis (ELISA and PCR). Overall, results from this study showed that the continuation of L-dopa triggers a neuroinflammatory response, hence highly expressing proinflammatory cytokine TNF-α. We found that Nptx2, TH, and FosB genes are downregulated in the PFC with continued L-dopa therapy. This downregulation was correlated with LID-induced cognitive decline. Findings from this study suggest that expression of TNF-α and deficiency of serotonin may play a significant role in the pathology of LID and downregulation of Nptx2, FosB, and TH genes contribute to LID-induced cognitive decline.

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Masters Degree. University of KwaZulu-Natal, Durban.

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