DNP: Low Dose DNP as Medicine

In relation to peds DNP is usually associated with being extremely powerful with terrible risk/reward ratio. In march 2019 a paper was published by Mitochon Pharmaceuticals that shares some extremely disruptive ideas about DNP I would like to plagiarize summarize.

At the heart of the paper is the question “Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction?” the therapy is based off the premise that “It is possible to wake up redundant cellular compensatory mechanisms by modulating the mitochondria’s physiology towards survival of the cell, slowing aging, and the potential to prophylactically treat patients to entirely prevent the myriad of age-related illnesses."

Based on the mass of old human and more recent animal data the FDA has granted an open Investigational New Drug status to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Exciting times, we will soon see if DNP it truly as promising as the authors believe.

Evidence supporting the therapeutic effects of DNP

The early immediate effects of DNP lower the mitochondrial membrane potential, which abolishes reactive oxygen species (ROS) production and subsequently closes the transporter involved in calcium influx. This is responsible for the acute effects of DNP. The downstream effects cause increased cAMP leading to a cascade resulting in the increase of BDNF causing long term changes.

Reactive Oxygen: DNP directly reduces ROS production, it also lowers NADH which further reduces ROS production and has significant health and anti-aging benefits.

Calcium Overload

Occurs after TBI, stroke, drug overdose and as part of many chronic diseases, leading to cell death. In studies DNP reduced levels of ROSs and Ca2+ and resulted in increased survival of the injured areas.DNP may induce autophagy“Since DNP lowers the membrane potential, there is a theory that it might selectively push those already marginally functioning mitochondria into autophagy to shift the global mitochondrial population towards better functioning high ATP producers and lower ROS producers.”

ATP levels

At low doses glucose consumption was unaffected indicating that cells adapt to chronic respiratory uncoupling allowing continuous and efficient mitochondrial ATP production without the need to increase glucose consumption. So collectively, it is possible that the net outcome is a higher ATP pool through more efficient mitochondrial functioning under chronic DNP treatment, than could previously be generated without the uncoupler.

Neuroprotection

The same previously mentioned mechanisms have a powerful neuroprotective effect though changing ROS production, Ca2+ handling, autophagy, induction of BDNF and cellular remodeling. Very low doses of DNP equivalent to ~0.5mg protect short term memory and increases lifespan in Alzheimer’s model. DNP provided significant behavioral protection preserving grip-strength and motor skill coordination in animal model of parkinson's. Large doses of DNP are not neuroprotective.

Diabetes, Metabolic Syndrome and Fatty Liver Diseases

DNP prevented hepatic fat accumulation from high fat diet, DNP treated animals showed lower fasting plasma glucose, triglyceride, and insulin concentrations

Healthy way to use DNP (maybe)

The authors make the statement that “perhaps it is time for a paradigm shift from the lofty goals of weight loss, to a wellness program. Merging the 1930s data that suggested long chronic treatment can lower the glucose levels in obese individuals, with the idea that very low doses over long periods of time can have a striking effect on many endpoints, could be such a paradigm shift.” they suggest 2-22mg of DNP/day with the optimal dose likely being dependant on purpose ( neuroprotection is strongest at lowest doses equivalent to 2mg or less DNP per day.) This dose is 20-200x smaller than the doses used for weight loss, greatly expanding the drugs therapeutic window and minimizing side effects. I eagerly await the results of the human trials.

https://www.reddit.com/r/PEDsR/comments/boddt1/low_dose_dnp_as_medicine/