Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017:2017:7180632.
doi: 10.1155/2017/7180632. Epub 2017 Jun 7.

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

Reas S Khan  1 , Kimberly Dine  1 , John G Geisler  2 , Kenneth S Shindler  1
Affiliations

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

Reas S Khan et al. Oxid Med Cell Longev. 2017.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
MP201 preserves RGC function. Visual function, measured by OKR responses, shows significant (∗∗p < 0.01) decreases in eyes of EAE mice (N = 10 eyes) compared to control mouse eyes (N = 10) by 6 weeks after induction of EAE. Daily oral treatment of 16 mg/kg MP201 (N = 10) from days 15 to 42 postimmunization leads to significantly (@@p < 0.01 versus EAE) improved OKR responses in EAE mice. Mice receiving 80 mg/kg MP201 daily (N = 10) show initial vision loss by week 3 that then reverses with improved OKR score in subsequent weeks.
Figure 2
Figure 2
MP201 treatment attenuates RGC loss. Neuroprotective effects of MP201 were evaluated by counting RGCs immunolabelled with Brn3a antibody in 12 standardized fields, three from each quadrant of the retina. (a) RGC loss in eyes of EAE mice (∗∗p < 0.01 versus control, N = 10 eyes) is reduced by 16 mg/kg MP201 treatment from days 15 to 42 (@@@p < 0.001 versus EAE, N = 10). 80 mg/kg MP201 also induces a significant (@p < 0.05 versus EAE, N = 10) improvement in RGC numbers. (b) Representative images show RGCs in one field of retina from each group (original magnification ×20).
Figure 3
Figure 3
MP201 treatment reduces axonal loss in optic neuritis. Neurofilament staining was used to evaluate axonal loss in sections of optic nerves isolated at day 42 postimmunization. (a) The optical density of neurofilament staining calculated from three equal-sized fields from each optic nerve shows a significant decrease (∗∗∗p < 0.001) in optic nerves (N = 10 nerves) from EAE mice compared to optic nerves (N = 10) from control mice. Treatment with 16 mg/kg (@@@p < 0.001, N = 10) or 80 mg/kg (@@p < 0.01, N = 10) MP201 induces a significant increase in neurofilament staining compared to optic nerves from PBS-treated EAE mice. (b) A series of photographs of axon staining from multiple optic nerve sections shows the normal degree of variability of neurofilament staining in optic nerves of control mice and EAE mice treated with 16 mg/kg or 80 mg/kg MP201 and shows more patchy loss of neurofilament staining in optic nerves from PBS-treated EAE mice.
Figure 4
Figure 4
MP201 treatment attenuates demyelination in optic nerves during EAE. To examine whether MP201 treatment prevents demyelination, optic nerves were isolated from mice 42 days postimmunization and were stained with LFB. (a) LFB-stained optic nerve longitudinal sections were examined by a blinded investigator, and demyelination was quantified on a 0–3 point scale. Optic nerves (N = 10 nerves) from EAE mice had a significantly (∗∗p < 0.01) higher demyelination score compared to optic nerves (N = 10) from control mice, and treatment with 16 mg/kg (@@p < 0.01 versus EAE, N = 10) or 80 mg/kg (@p < 0.05 versus EAE, N = 10) MP201 leads to a significant decrease in demyelination scores. (b) A representative image of one optic nerve from a PBS-treated EAE mouse shows less LFB (blue) staining than an optic nerve from a control mouse, as well as optic nerves of EAE mice treated with either 16 mg/kg or 80 mg/kg MP201 (original magnification ×20).
Figure 5
Figure 5
MP201 treatment does not suppress inflammation in optic nerves during EAE. To examine whether MP201 treatment prevents inflammation, optic nerves were isolated from mice 42 days postimmunization and stained with H&E to examine levels of cellular infiltration. (a) H&E-stained optic nerve longitudinal sections were examined by a blinded investigator, and inflammation was quantified on a 0–4 point scale. Optic nerves (N = 10 nerves) from EAE mice showed significantly (∗∗∗p < 0.001) higher inflammation scores compared to optic nerves (N = 10) from control mice, and treatment with 16 mg/kg (∗∗∗p < 0.001 versus control, N = 10) or 80 mg/kg (∗∗∗p < 0.001 versus control, N = 10) showed no change in inflammation score compared to EAE. (b) A representative image of one optic nerve from a PBS-, 16 mg/kg MP201-, and 80 mg/kg MP201-treated EAE mouse each show increased numbers of cells, representative of inflammatory cell infiltration, as compared to an optic nerve from a control mouse (original magnification ×20).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Beck R. W., Cleary P. A., Anderson M. M., et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The New England Journal of Medicine. 1992;326:581–588. doi: 10.1056/NEJM199202273260901. - DOI - PubMed
    1. Beck R. W., Gal R. L., Bhatti M. T. Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial. American Journal of Ophthalmology. 2004;137:77–83. - PubMed
    1. Arnold C. Evolving management of optic neuritis and multiple sclerosis. American Journal of Ophthalmology. 2005;139:1101–1108. doi: 10.1016/j.ajo.2005.01.031. - DOI - PubMed
    1. Paty D. W., Li D. K. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:662–667. doi: 10.1212/WNL.43.4.662. - DOI - PubMed
    1. Trip S. A., Schlottmann P. G., Jones S. J., et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Annals of Neurology. 2005;58:383–391. doi: 10.1002/ana.20575. - DOI - PubMed