«One Small Step for Mouse»: High CO₂ Inhalation as a New Therapeutic Strategy for Parkinson's Disease

Parkinson's disease (PD) is a ubiquitous neurodegenerative disorder for which no effective treatment strategies are available. Existing pharmacotherapy is aimed only at correcting symptoms and slowing the progression of the disease, mainly by replenishing dopamine deficiency. It is assumed that mitochondrial dysfunction plays a key role in the pathogenesis of PD. It has been suggested that activation of specific degradation of damaged mitochondria (mitophagy) may prevent cell death. An almost exclusive way to initiate mitophagy is acidification of intracellular pH. We attempted to implement transient brain acidification using two experimental therapy strategies: forced moderate physical activity and high CO₂ inhalation. The beneficial effects of CO₂ supplementation on behavioral aspects were demonstrated in a rotenone-induced PD model. Mice treated with CO₂ restored their exploratory behavior and total locomotor activity lost after rotenone administration. Additionally, this treatment enabled the removal of impaired coordination. We have illustrated this therapeutic strategy using histological studies of brain sections to confirm the survival of nigrostriatal areas. These findings suggest that high CO₂ inhalation presumably initiates mitophagy via transient brain acidification, and can treat PD-like symptoms in a rodent rotenone model of PD.