DNP Mitochondrial Uncoupling and Neuroprotection: A Little Dab’ll Do Ya

摘要

Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic challenges such as caloric restriction and exercise, and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to over 100,000 people as a treatment for obesity, stimulates several adaptive cellular stress response signaling pathways in neurons including those involving the neurotrophic factor BDNF, the transcription factor CREB, and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer’s and Parkinson’s diseases, epilepsy and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious neurodegenerativeeuromuscular conditions, all paradoxically at body weight-preserving doses.