DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya.
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 >100,000 people as a treatment for obesity, stimulates several adaptive cellular stress-response signaling pathways in neurons including those involving the brain-derived neurotrophic factor (BDNF), the transcription factor cyclic AMP response element-binding protein (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 neurodegenerative/neuromuscular conditions, all paradoxically at body weight-preserving doses.
Mitochon Pharmaceuticals, Inc., Radnor, PA, USA.
John G
JG
Geisler
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Krisztina
K
Marosi
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Joshua
J
Halpern
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mark.mattson@nih.gov.
Mark P
MP
Mattson
D019297:2,4-Dinitrophenol / Q000008:administration & dosage*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D004195:Disease Models, Animal; D006801:Humans; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D009473:Neuronal Plasticity; D000066829:Neuroprotection / Q000502:physiology*; D000071256:Uncoupling Protein 1 / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D000071256:Uncoupling Protein 1; D019297:2,4-Dinitrophenol
BDNF; CREB; DNP; Hormesis; Mitochondrial uncoupling; Parkinson's disease; Synaptic plasticity