Exercise Mimetic Irisin's Potential in Parkinson's Treatment

Fighting Inflammation is Crucial in Parkinson’s

Parkinson’s disease, a neurodegenerative disorder, is characterized by the presence of Lewy bodies and the loss of dopaminergic neurons [1]. Recent studies have established a correlation between the degeneration of dopaminergic neurons and neuroinflammation, marked by increased microglial activity and elevated inflammatory compounds in the brain [2]. A significant factor exacerbating this process is the accumulation of α-synuclein in the hippocampus, which drives neuroinflammation and accelerates neuronal deterioration [3]. Consequently, treatments that mitigate neuroinflammation may offer some efficacy in alleviating Parkinson’s symptoms.

Previously, research has demonstrated that exercise can naturally diminish inflammation, including in cerebral tissue, suggesting its potential as a therapy for Parkinson’s disease symptoms [4]. For instance, injecting plasma derived from exercising rodents into those exhibiting Parkinson’s symptoms has shown promising results in remission [5].

However, previous investigations failed to fully elucidate the underlying biochemical mechanisms. The current study centers on irisin, an exercise-induced compound noted for its anti-inflammatory properties [6]. Therefore, the researchers aimed to bridge the knowledge gap concerning the interactions among irisin, inflammation, and Parkinson’s disease.

Exercise Affects More Than Just Inflammation

The initial experiment involved administering MPTP, a neurotoxin known to induce Parkinson’s-like symptoms, to mice. This treatment led to significant Parkinson's pathology and hindered neurogenesis in the hippocampus. Furthermore, MPTP-treated mice exhibited poorer performance on the Morris water maze test, a common test for cognitive ability.

Remarkably, the introduction of a regular exercise regimen—specifically 10 weeks of treadmill running—resulted in a notable restoration of neurogenesis and improved performance on the water maze, relative to their non-exercised counterparts (Table 1).

Furthermore, exercise contributed to a reduction in apoptosis within the hippocampus. MPTP treatment raised markers for cellular death, which were effectively normalized through the exercise program. Inflammatory markers such as TNF-α, NFκB, and IL-1β showed similar improvements, indicating a comprehensive reduction in neuroinflammation (Table 2).

A Closer Look at Irisin

To delve deeper into the role of irisin, the researchers initiated a series of experiments utilizing cultured microglia exposed to α-synuclein. As predicted, these microglia exhibited heightened inflammatory activity; however, this effect was mitigated by the application of MCC950, a known NLRP3 inhibitor. Notably, irisin also demonstrated a similar capacity to diminish NLRP3 expression and its inflammatory consequences.

In a subsequent phase, rats engaged in a 4-week treadmill regimen had their serum analyzed. When microglia were treated with both α-synuclein and the serum from exercising rats, a significant decrease in NLRP3 and inflammatory markers was observed alongside an elevation in irisin levels, compared to controls exposed solely to α-synuclein. Further verification through NLRP3 agonists and irisin inhibitors (cRGDyk) reinforced that these positive outcomes stemmed from irisin's employment of NLRP3 suppression.

Crucially, direct administration of irisin into the mice recreated many of the exercise-induced benefits, confirming its therapeutic potential. Inflammatory markers and markers of apoptosis were reduced, while neurogenesis was enhanced; mice also displayed improvements on cognitive tests (Table 3).

Conclusion

These promising findings offer hope for individuals afflicted with Parkinson’s disease. Since Parkinson's severely impairs motor functions, traditional exercise may not always be feasible as a treatment. The identification of an exercise mimetic, such as irisin, could play a pivotal role in the development of future therapies. However, it is crucial to emphasize that these results were derived from animal models; therefore, human clinical trials are necessary to establish whether irisin exhibits similar benefits in humans.

In summation, the ongoing exploration of irisin and its mechanisms may pave the way for innovative treatments that cater to individuals unable to engage in physical exercise.

Literature Cited

[1] Zaman, V., et al. (2021). Cellular and molecular pathophysiology in the progression of Parkinson’s disease. Metabolic brain disease, 36, 815-827.

[2] Han, Q. Q., & Le, W. (2023). NLRP3 inflammasome-mediated neuroinflammation and related mitochondrial impairment in Parkinson’s disease. Neuroscience Bulletin, 39(5), 832-844.

[3] Kouli, A., et al. (2020). Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta neuropathologica communications, 8, 1-19.

[4] Wang, R., et al. (2023). Association of glial activation and α-synuclein pathology in Parkinson’s disease. Neuroscience bulletin, 39(3), 479-490.

[5] De Miguel, Z., et al. (2021). Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature, 600(7889), 494-499.

[6] Zhao, R. (2022). Irisin at the crossroads of inter-organ communications: Challenge and implications. Frontiers in Endocrinology, 13, 989135.

[7] Khot, M., et al. (2022). NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson’s disease. European Journal of Pharmacology, 934, 175300.