Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis
Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known treatment to preve...
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2025-01-01
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| author | Nuala O’Neill Reas S. Khan Suad Abd Alhadi Kimberly E. Dine John G. Geisler Brahim Chaqour Ahmara G. Ross Kenneth S. Shindler |
| author_facet | Nuala O’Neill Reas S. Khan Suad Abd Alhadi Kimberly E. Dine John G. Geisler Brahim Chaqour Ahmara G. Ross Kenneth S. Shindler |
| author_sort | Nuala O’Neill |
| collection | DOAJ |
| description | Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known treatment to prevent this loss. Prior studies showed that MP201, a prodrug of 2,4-dinitrophenol (DNP) administered in the experimental autoimmune encephalitis (EAE) mouse model of MS attenuated optic neuritis with preserved vision, increased retinal ganglion cell (RGC) survival, decreased axon loss, and reduced demyelination. Oral administration of MP201, which converts to active form DNP after entry in the portal vein, decreases mitochondrial-derived reactive oxygen species (ROS) and restores calcium homeostasis, which are both implicated in many neurodegenerative diseases. Due to the established therapeutic benefits of prodrug MP201 in EAE mice, we hypothesized that administration of DNP itself may also have significant potential for therapeutic effects. Here, effects of varying doses of DNP treatment in EAE mice were assessed by the extent of spinal cord paralysis, optokinetic response (OKR), RGC survival, and optic nerve demyelination and inflammation. Results show that daily oral doses of 5-10 mg/kg DNP initiated after onset of EAE can significantly reduce spinal cord paralysis, a marker of the EAE MS-like disease, by day 42 after disease induction. DNP treatment significantly reduces RGC loss induced by optic neuritis in EAE mice; however, effects of DNP do not significantly improve visual function, or optic nerve demyelination and inflammation. Current studies show DNP treatment promotes increased RGC survival, but continued inflammation and demyelination likely reduce visual function, suggesting future studies examining combination therapy of DNP with anti-inflammatory agents may be warranted. |
| format | Article |
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| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
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| series | Biomolecules |
| spelling | doaj-art-2f7e6263c9694841a93fe8d3c2c0976b2025-08-20T02:44:59ZengMDPI AGBiomolecules2218-273X2025-01-0115218910.3390/biom15020189Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple SclerosisNuala O’Neill0Reas S. Khan1Suad Abd Alhadi2Kimberly E. Dine3John G. Geisler4Brahim Chaqour5Ahmara G. Ross6Kenneth S. Shindler7Department of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USAMitochon Pharmaceuticals, Inc., 970 Cross Lane, Blue Bell, PA 19087, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Ophthalmology, Scheie Eye Institute, FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USAOptic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known treatment to prevent this loss. Prior studies showed that MP201, a prodrug of 2,4-dinitrophenol (DNP) administered in the experimental autoimmune encephalitis (EAE) mouse model of MS attenuated optic neuritis with preserved vision, increased retinal ganglion cell (RGC) survival, decreased axon loss, and reduced demyelination. Oral administration of MP201, which converts to active form DNP after entry in the portal vein, decreases mitochondrial-derived reactive oxygen species (ROS) and restores calcium homeostasis, which are both implicated in many neurodegenerative diseases. Due to the established therapeutic benefits of prodrug MP201 in EAE mice, we hypothesized that administration of DNP itself may also have significant potential for therapeutic effects. Here, effects of varying doses of DNP treatment in EAE mice were assessed by the extent of spinal cord paralysis, optokinetic response (OKR), RGC survival, and optic nerve demyelination and inflammation. Results show that daily oral doses of 5-10 mg/kg DNP initiated after onset of EAE can significantly reduce spinal cord paralysis, a marker of the EAE MS-like disease, by day 42 after disease induction. DNP treatment significantly reduces RGC loss induced by optic neuritis in EAE mice; however, effects of DNP do not significantly improve visual function, or optic nerve demyelination and inflammation. Current studies show DNP treatment promotes increased RGC survival, but continued inflammation and demyelination likely reduce visual function, suggesting future studies examining combination therapy of DNP with anti-inflammatory agents may be warranted.https://www.mdpi.com/2218-273X/15/2/189EAEoptic neuritisRGC neuroprotectiondinitrophenolmitochondrial uncoupling agent |
| spellingShingle | Nuala O’Neill Reas S. Khan Suad Abd Alhadi Kimberly E. Dine John G. Geisler Brahim Chaqour Ahmara G. Ross Kenneth S. Shindler Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Biomolecules EAE optic neuritis RGC neuroprotection dinitrophenol mitochondrial uncoupling agent |
| title | Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis |
| title_full | Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis |
| title_fullStr | Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis |
| title_full_unstemmed | Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis |
| title_short | Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis |
| title_sort | mitochondrial uncoupler 2 4 dinitrophenol reduces spinal cord paralysis and retinal ganglion cell loss in the experimental autoimmune encephalomyelitis model of multiple sclerosis |
| topic | EAE optic neuritis RGC neuroprotection dinitrophenol mitochondrial uncoupling agent |
| url | https://www.mdpi.com/2218-273X/15/2/189 |
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