Neuritogenesis and neuronal differentiation promoted by 2,4‐dinitrophenol, a novel anti‐amyloidogenic compound

Abstract

Neurite outgrowth is a critical event in neuronal development, formation, and remodeling of synapses, response to injury, and regeneration. We examined the effects of 2,4-dinitrophenol (DNP), a recently described blocker of the aggregation and neurotoxicity of the beta-amyloid peptide, on neurite elongation of central neurons. Morphometric analysis of rat embryo hippocampal and cortical neuronal cultures showed that neurite outgrowth was stimulated by DNP. This effect was accompanied by increases in the neuronal levels of the microtubule-associated protein tau and of cyclic adenosine 3',5' monophosphate (cAMP). DNP also promoted cAMP accumulation, increased tau level, neurite outgrowth, and neuronal differentiation in the mouse neuroblastoma cell line N2A. We show that DNP-induced differentiation requires activation of the extracellular signal-regulated kinase (ERK). The finding that DNP promotes neuritogenesis and neuronal differentiation suggests that, in addition to its anti-amyloidogenic actions, it may be a useful lead compound in the development of novel therapeutic approaches targeting neurite dystrophy and synaptic dysfunction in neurodegenerative pathologies such as Alzheimer's disease.

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

“…Phosphorylation is followed by recruitment of other proteins, resulting in the formation of multiprotein complexes that trigger a number of different signaling pathways. For example, activation of Fyn/FAK/PI3K/MAPK/ extracellular signal-regulated kinase (ERK) pathways is associated with protective (e.g., anti-apoptotic, neuritogenic) responses under normal physiological conditions [e.g., 23,33,51,54]. Although previous studies suggest that activation of PI3K/Akt may protect against neuronal death induced by Aβ [e.g.…”

Novel neuroprotective, neuritogenic and anti-amyloidogenic properties of 2,4-dinitrophenol: The gentle face of Janus

“…We recently showed that low concentrations of DNP (20 mM) promote neurite outgrowth in cultured hippocampal and cortical neurons, and induce neuronal differentiation in a neuroblastoma cell line (37). Interestingly, we found that neurite outgrowth induced by DNP is accompanied by increased levels of tau protein and cAMP in both primary cortical and hippocampal neuronal cultures and in the N2A murine neuroblastoma cell line (37).…”

“…No changes were observed in oxygen consumption (37), mitochondrial membrane potential (measured with the potential-sensitive fluorescent dye JC-1) or ROS generation (measured by DCFDA fluorescence) of N2A cells or cortical neurons treated with up to 20 mM DNP (De Felice, unpublished observations). These observations indicate that the beneficial effects of DNP discussed above are not related to mitochondrial uncoupling.…”

“…Morphologic studies have demonstrated significant loss of synaptic connectivity in many regions of the neocortex and hippocampus and a strong correlation between decreased synaptic density and cognitive decline in AD (36). We recently showed that low concentrations of DNP (20 mM) promote neurite outgrowth in cultured hippocampal and cortical neurons, and induce neuronal differentiation in a neuroblastoma cell line (37). Interestingly, we found that neurite outgrowth induced by DNP is accompanied by increased levels of tau protein and cAMP in both primary cortical and hippocampal neuronal cultures and in the N2A murine neuroblastoma cell line (37).…”

“…Importantly, it has been shown that cAMP presentation at nerve growth cones can influence their turning behavior (42), affect guidance (43) and enable nerve cells from mature animals to extend fibers across inhibitory substrates (44). In this context, it is of interest that DNP induces an increase in cAMP levels which leads to the activation of extracellular signal regulated kinase (ERK) (37). Thus, modulation of neuronal cAMP levels by DNP could also lead to promising new strategies for neuroregeneration.…”