Mitochondrial Uncoupler Prodrug of 2,4‐Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis

Abstract

The ability of novel mitochondrial uncoupler prodrug of 2,4-dinitrophenol (DNP), MP201, to prevent neuronal damage and preserve visual function in an experimental autoimmune encephalomyelitis (EAE) model of optic neuritis was evaluated. Optic nerve inflammation, demyelination, and axonal loss are prominent features of optic neuritis, an inflammatory optic neuropathy often associated with the central nervous system demyelinating disease multiple sclerosis. Currently, optic neuritis is frequently treated with high-dose corticosteroids, but treatment fails to prevent permanent neuronal damage and associated vision changes that occur as optic neuritis resolves, thus suggesting that additional therapies are required. MP201 administered orally, once per day, attenuated visual dysfunction, preserved retinal ganglion cells (RGCs), and reduced RGC axonal loss and demyelination in the optic nerves of EAE mice, with limited effects on inflammation. The prominent mild mitochondrial uncoupling properties of MP201, with slow elimination of DNP, may contribute to the neuroprotective effect by modulating the entire mitochondria's physiology directly. Results suggest that MP201 is a potential novel treatment for optic neuritis.

Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis

“…At the structural level, MOG-induced retinal damage is in agreement with previous data [ 7 , 24 , 50 , 51 ]. In the mouse model of EAE, inflammatory cell infiltration appears to mediate ON fiber demyelination thus leading to RGC death [ 52 ].…”

“…Current therapies used for optic neuritis include the intravenous administration of corticosteroids that, however, show limited effect in preventing damages to RGC axons [ 6 ]. In fact, although corticosteroids may reduce inflammation and stimulate acute visual recovery, up to 60% of patients fail to normalize visual function (see [ 7 ]). Additional newer candidates to improve ON function have been recently established, although their benefit and harm remain to be determined (see [ 8 ]).…”

Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo

“…In summary, the present results support continued investigation of ELM-RPE OCT thickness and R1 MRI measurements as useful approaches for monitoring the impact of mitochondrial protonophores for evaluating in vivo the rod photoreceptor mitochondrial energy ecosystem [9,46,47,52,61]. The development of new approaches for in vivo imaging of mitochondrial uncoupling response maps raises the possibility for promising future applications for evaluating mitochondrial protonophore treatment in neurodegenerative disease [46,47,52,61].…”

“…More work is needed to determine if, for example, direct intraocular injection of DNP, or alternative formulations of DNP (see below) would be useful in this regard [47,61]. Nonetheless, our primary observation that DNP elicits changes in both MRI and OCT biomarkers in the outer retina in S6 mice relative to B6 mice supports our working hypothesis [4].…”

Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neurons to promote weight-loss

“…However, the concept of mitochondrial uncouplers as therapeutics has recently regained momentum with the realization of a range of beneficial effects of mild mitochondrial uncoupling. DNP at low concentrations has been shown to improve neuronal function or to be neuroprotective in a range of animal models of disease including: epilepsy, experimental optic neuritis, Parkinson's disease, Alzheimer's disease, stroke, traumatic brain injury, and peripheral nerve injury [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] . Future therapeutic approaches targeting obesity with mitochondrial uncoupling agents will need a chronic dosing strategy that offsets any toxicity.…”