Experimenting on rodents, researchers have found a pathway through which exercise could fight Parkinson’s disease and a molecule that might recapitulate this effect.
Fighting inflammation is crucial in Parkinson’s
Parkinson’s disease is characterized by Lewy bodies and the loss of dopaminergic neurons [1]. Recent work has found that this degeneration is related to neuroinflammation: the increase of microglial activity and inflammatory compounds within the brain [2]. The accumulated α-synuclein in the hippocampus has been found to be a key driver of this inflammation, and reducing neuroinflammation slows the rate of deterioriation [3], suggesting that treatments that suppress this process may be at least somewhat effective in treating the symptoms of Parkinson’s.
Previous work has found that exercise naturally reduces inflammation, including in the brain, and that it may be effective against Parkinson’s disease symptoms [4]. Deriving plasma from exercising rodents, and injecting it into rodents suffering from Parkinson’s symptoms, has also been previously found to have beneficial effects [5].
However, as these researchers note, that previous work did not fully elucidate the biochemical mechanisms involved. They specifically focus on irisin, an exercise-related compound that has been found to have benefits against neuroinflammation [6]. However, the connections between irisin, inflammation, and Parkinson’s have never been fully explored; these researchers, therefore, sought to close that gap.
Exercise affects more than just inflammation
The first experiment involved treating mice with MPTP, a compound that causes Parkinson’s-like symptoms. As expected, this caused both an increase in Parkinson’s pathology and a decrease in the hippocampus’ ability to create new neurons (neurogenesis). Similarly, the MPTP-treated mice performed worse on the Morris water maze test.
However, exercise seemed to partially ameliorate most of these effects. Following 10 weeks of regularly running on treadmills, neurogenesis was largely restored, and performance on the Morris water maze test was improved compared to unexercised MPTP-treated mice. Most interestingly, and most encouragingly, exercise was found to decrease α-synuclein itself: one of the core pathologies of Parkinson’s disease.
In these mice, exercise also decreased cellular death by apoptosis in the hippocampus. MPTP treatment causes an increase in a marker of apoptosis and a decrease in a marker of anti-apoptosis; both of these markers were brought closer to their normal levels by the exercise program. Key, well-known markers of inflammation, including TNF-α, NFκB, and IL-1β, were affected in the same way. NLRP3, an inflammatory protein that increases in Parkinson’s disease, leading to neuroinflammation and mitochondrial dysfunction [7], was also decreased by exercise, while irisin was increased.
A closer look at irisin
The researchers began their irisin experiments in cellular culture. First, they took microglia and cultured them in the presence of α-synuclein. As expected, these cells began to show signs of inflammatory activity, which could be largely reduced by exposing them to MCC950, a compound that suppresses NLRP3. Crucially, irisin was found to accomplish similar results, reducing NLRP3 expression and its downstream effects.
The researchers then subjected rats to four weeks of treadmill running and harvested their serum. When microglia were exposed to both α-synuclein and runner serum, they had reduced NLRP3 and inflammatory markers along with an increase in irisin, as compared to microglia exposed to α-synuclein alone. Further work involving NLRP3 agonists and the irisin blocker cRGDyk confirmed that these beneficial effects were indeed related to irisin’s suppression of NLRP3. Similarly, administering cRGDyk to mice prevented exercise from having beneficial effects.
Most importantly, administering irisin directly to mice recapitulated many of the benefits of exercise. Inflammatory and apoptosis markers were reduced, and signs of neurogenesis were increased. Performance on the Morris water maze test was better as well. Overall, irisin was found to recapitulate many of the benefits of exercise.
These encouraging findings provide hope to people suffering from Parkinson’s disease. Given its significantly deleterious effects on motor function, this particular disease often precludes exercise as a treatment. Therefore, an exercise mimetic, which irisin appears to be, may be a key part of future treatments. However, these findings were in model mice, not people, and a clinical trial would have to be conducted to determine if irisin works in human beings as it does in these rodents.
Literature
[1] Zaman, V., Shields, D. C., Shams, R., Drasites, K. P., Matzelle, D., Haque, A., & Banik, N. L. (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., Camacho, M., Allinson, K., & Williams-Gray, C. H. (2020). Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta neuropathologica communications, 8, 1-19.
[4] Wang, R., Ren, H., Kaznacheyeva, E., Lu, X., & Wang, G. (2023). Association of glial activation and α-synuclein pathology in Parkinson’s disease. Neuroscience bulletin, 39(3), 479-490.
[5] De Miguel, Z., Khoury, N., Betley, M. J., Lehallier, B., Willoughby, D., Olsson, N., … & Wyss-Coray, T. (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., Sood, A., Tryphena, K. P., Khan, S., Srivastava, S., Singh, S. B., & Khatri, D. K. (2022). NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson’s disease. European Journal of Pharmacology, 934, 175300.
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