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. 2017 May;13(5):582-591.
doi: 10.1016/j.jalz.2016.08.001. Epub 2016 Sep 4.

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

John G Geisler  1 , Krisztina Marosi  2 , Joshua Halpern  2 , Mark P Mattson  3
Affiliations

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

John G Geisler et al. Alzheimers Dement. 2017 May.

Abstract

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.

Keywords: BDNF; CREB; DNP; Hormesis; Mitochondrial uncoupling; Parkinson's disease; Synaptic plasticity.

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Figures

Figure 1
Figure 1
Neuronal responses to mitochondrial uncoupling are consistent with a hormesis-based mechanism of action. As is true with many processes in biology and medicine, the dose – response curve for mitochondrial uncoupling is biphasic, with mild uncoupling eliciting beneficial adaptive responses and high levels of uncoupling causing cell damage and death. Mild uncoupling may enhance neuronal resilience by activating signaling pathways that promote synaptic plasticity, reduce oxidative damage, increase autophagy and bolster bioenergetics. Some of the proteins that may mediate the hormetic effects of mild uncoupling are brain derived neurotrophic factor (BDNF), cyclic AMP response element-binding protein (CREB), superoxide dismutase 2 (SOD2) and glucose transporter 3 (GLUT3). Excessive sustained uncoupling can trigger cell death which is mediated by pro-apoptotic proteins such as p53 and BAX.
Figure 2
Figure 2
Mechanisms by which mild mitochondrial uncoupling protects neurons against oxidative stress, excitotoxicity and the accumulation of disease-related self-aggregating proteins such as amyloid β-peptide, Tau and α-synuclein. Mild uncoupling resulting from activation of endogenous uncoupling proteins (UCP) or pharmacological agents such as 2,4-dinitrophenol (DNP) triggers an adaptive bioenergetic stress response (ABSR) involving multiple signaling pathways and organelles. The ABSR involves activation of kinases, and transcription factors such as CREB, PGC-1α and NF-kB which, in turn, induce the expression of genes encoding proteins that enhance stress resistance and neuroplasticity including: the immediate early gene products Fos and Arc; the neurotrophic factor BDNF; the antioxidant enzyme SOD2; the regulator of mitochondrial biogenesis TFAM; an inhibitor of the mTOR pathway (TSC2). CamK, calcium/calmodulin-dependent kinase; ClC7, chloride channel 7; GLUT3, glucose transporter 3; MCLN, mucolipin; TPC2, two pore channel 2; MCT2, monocarboxylic acid transporter 2; vATPase, vesicular ATPase.
Figure 3
Figure 3
Treatment of mice with low doses of the uncoupler DNP results in increased expression of BDNF in the brain and improves functional outcomes in models of epileptic seizures and Alzheimer’s disease (AD). A. Mice were administered the indicated doses of DNP or vehicle by oral gavage once daily for 14-days. BDNF mRNA levels in cortex tissue samples were measured by semi-quantitative PCR (qPCR). Values are the mean and SEM of measurements made on samples from 8 mice/group. *p<0.05, **p<0.01 compared to the value for vehicle-treated mice. B. Mice were administered the indicated doses of DNP or vehicle by oral gavage once daily for 7-days. Mice were then administered the seizure-inducing excitotoxin kainic acid by direct injection into the dorsal hippocampus [99]. Seizures were evaluated during the ensuing 4 hours using a semi-quantitative rating scale as described previously [100]. Values are the mean and SEM (6 mice/group). *p<0.01 compared to the value for vehicle-treated mice. C and D. APP/PS1 double mutant transgenic mice (an animal model of AD) were administered the indicated doses of DNP (mpk, mg/kg) or vehicle by oral gavage once daily for 4 months. Hippocampus-dependent spatial learning and memory were then evaluated in a water maze test in which the time taken to locate a submerged platform in the pool (goal latency; memory acquisition) was measured daily for 7 days of training (C). The platform was then removed from the pool and the total distance the mouse swam in the specific area where the platform had been was determined at 4, 24, 48 and 72 hours (an indicator of memory retention) (D). See ref. for methods. Values are the mean and SEM of measurements made on samples from 5 or 6 mice/group. *p<0.01, **p<0.01, ***p<0.001.
Figure 4
Figure 4
Historical timeline of studies of DNP dose-dependent clinical efficacy and toxicity, mechanisms of action, and potential applications to acute and chronic neurodegenerative conditions.
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