Neuroprotective actions of 2,4-dinitrophenol: Friend or foe?

Abstract

2,4-dinitrophenol (DNP) has long been known to be toxic at high concentrations, an effect related to uncoupling of mitochondrial oxidative phosphorylation. Five years ago, however, we reported that low concentrations of DNP protect neurons against the toxicity of the amyloid-β peptide. Since then, a number of other studies have provided evidence of beneficial actions of DNP (at low concentrations), including neuroprotection against different types of insult, blockade of amyloid aggregation, stimulation of neurite outgrowth and neuronal differentiation, and even extension of lifespan in certain organisms. Some of these effects appear due to mild mitochondrial uncoupling and prevention of oxidative stress, whereas other actions are related to activation of additional intracellular signaling pathways. This study discusses the evidence supporting beneficial neuroprotective actions of DNP. DNP and other compounds with similar biological activities may be of interest in the development of novel therapeutic approaches for neurodegenerative diseases and other neurological disorders.

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

“…Consequently, inhibition of the MPT is a promising target in neuroprotection 3 . On the other hand, depolarization of mitochondria is widely used a predictor of toxicity 72 but depolarization connected with uncoupling of the respiratory chain or stimulation of electron flux can also be cytoprotective 73 . Due to its redox-cycling capability, MB can restore the electron flux in the respiratory chain in the presence of inhibitors of complex-I 74 .…”

Targeting mitochondrial Ca2+ uptake for the treatment of amyotrophic lateral sclerosis

“…However, the toxicity of high‐dose usage of DNP was shortly confirmed and the compound never obtained FDA approval as a therapeutic drug (Colman, 2007; Grundlingh et al., 2011). Over the last decade, accumulating evidence indicates that low‐dose DNP is neuroprotective (De Felice & Ferreira, 2006; De Felice et al., 2001; Ferreira & Felice, 2007; Geisler, 2019; Lee et al., 2017; Wasilewska‐Sampaio et al., 2005) and improves treatment outcomes for traumatic brain injury (Pandya et al., 2007). Mechanistically, apart from its traditional role as a proton ionophore to reduce ΔΨ m and inhibit mitochondrial Ca 2+ influx, low‐dose DNP suppresses the mammalian target of rapamycin (mTOR) pathway and stimulates the cAMP‐response element‐binding (CREB) protein–BDNF cascade, which is essential for synaptic plasticity, adaptive stress responses and cognitive function (Fernanda et al., 2007; Kandel et al., 2014; Liu et al., 2015).…”