Objective: To assess the role of rifabutin in restoring mitochondrial function and energy balance through modulation of the AMPK–PGC-1α signaling pathway in diabetes-related Parkinsonism.

Background: Mitochondrial damage and reduced energy are the common pathophysiology of Diabetes Mellitus and Parkinson’s Disease (PD). ATP depletion, ROS overproduction, and impaired mitochondrial biogenesis are involved in the failure of pancreatic β-cells and dopaminergic neurons. Antidiabetic drugs like GLP-1 RA have dual beneficial actions on glucose metabolism and neuroprotection through activation of AMPK-PGC-1α pathways, leading to increased mitochondrial biogenesis and function. Increasing evidence suggests that rifabutin, with its additional antimicrobial activity, also has mitochondria stabilizing actions on mitochondrial function, making it a promising new agent in addressing this pathogenetic convergence in diabetes-associated Parkinson’s disease.

Method: An experimental study was designed using a Streptozotocin (60mg/Kg) induced diabetic rat model combined with nigrostriatal stress. Rifabutin was administered orally at two doses (20mg/Kg; 40mg/Kg) for four weeks. Mitochondrial function was assessed through ATP content, mitochondrial membrane potential, and ROS levels in pancreatic and brain tissues. Expression of AMPK, PGC-1α, and mitochondrial respiratory complex proteins was measured along with behavioral motor assessments, glycemic index, CKD, and  body weight variation for 28days.

Results: Rifabutin treatment 40mg/Kg significantly restored mitochondrial membrane potential and increased ATP production in both pancreatic and nigrostriatal tissues. Activation of AMPK and upregulation of PGC-1α were observed, accompanied by reduced mitochondrial ROS generation. These effects translated into improved insulin sensitivity, preserved dopaminergic neuronal integrity, and enhanced motor performance compared to untreated diabetic controls.

Conclusion: Rifabutin activates the AMPK–PGC-1α–mitochondrial axis, linking improved glycometabolism with neuroprotection in diabetes-associated Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/repurposing-rifabutin-for-neuro-metabolic-disorders-ampk-pgc-1%ce%b1-driven-mitochondrial-protection-in-diabetes-associated-parkinsonism/