HE3286 Reduces Axonal Loss and Preserves Retinal Ganglion Cell Function in Experimental Optic Neuritis

Khan, Reas S.; Dine, Kimberly; Luna, Esteban; Ahlem, Clarence N.; Shindler, Kenneth S.

doi:10.1167/iovs.14-14672

Cited by 29 publications

(50 citation statements)

References 37 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neurofilament staining was used to quantify axon density in PBS- and MP201-treated EAE mice as in prior studies [11, 38]. Significant ( p < 0.001) reduction in axonal staining occurred in optic nerves from PBS-treated EAE mice as compared to optic nerves from control mice (Figure 3()), similar to prior studies [11, 38].…”

Section: Resultssupporting

confidence: 77%

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

Khan

Dine

Geisler³

et al. 2017

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 77%

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

Khan

Dine

Geisler³

et al. 2017

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

show abstract

“…Earlier studies of DHEA treatment in EAE showed that it exerted anti‐inflammatory effects, particularly in circulating leukocytes, resulting in diminished severity of EAE (Du et al, ). In another study, treatment of EAE with a synthetic derivative (HE3286) of a natural steroid, β‐AET, improved aspects of optic neuritis (Khan, Dine, Luna, Ahlem, & Shindler, ). In the present study, treatment with DHEA‐S was implemented because it is a downstream product of CYP17A1, is more stable than DHEA, and is detectable in human blood.…”

Section: Discussionmentioning

confidence: 99%

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Boghozian

McKenzie

Saito

et al. 2017

Glia

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Neurosteroids are reported to exert anti-inflammatory effects in several neurological disorders. We investigated the expression and actions of the neurosteroid, dehydroepiandrosterone (DHEA), and its more stable 3β-sulphated ester, DHEA-S, in MS and associated experimental models. CNS tissues from patients with MS and animals with experimental autoimmune encephalomyelitis (EAE) displayed reduced DHEA concentrations, accompanied by diminished expression of the DHEA-synthesizing enzyme CYP17A1 in oligodendrocytes (ODCs), in association with increased expression of inflammatory genes including interferon (IFN)-γ and interleukin (IL)-1β. CYP17A1 was expressed variably in different human neural cell types but IFN-γ exposure selectively reduced CYP17A1 detection in ODCs. DHEA-S treatment reduced IL-1β and -6 release from activated human myeloid cells with minimal effect on lymphocyte viability. Animals with EAE receiving DHEA-S treatment showed reduced Il1b and Ifng transcript levels in spinal cord compared to vehicle-treated animals with EAE. DHEA-S treatment also preserved myelin basic protein immunoreactivity and reduced axonal loss in animals with EAE, relative to vehicle-treated EAE animals. Neurobehavioral deficits were reduced in DHEA-S-treated EAE animals compared with vehicle-treated animals with EAE. Thus, CYP17A1 expression in ODCs and its product DHEA were downregulated in the CNS during inflammatory demyelination while DHEA-S provision suppressed neuroinflammation, demyelination, and axonal injury that was evident as improved neurobehavioral performance. These findings indicate that DHEA production is an immunoregulatory pathway within the CNS and its restoration represents a novel treatment approach for neuroinflammatory diseases.

show abstract

“…[16][17][18][19] Furthermore, the ability to model AON in rodents means that genetically engineered iovs.arvojournals.org j ISSN: 1552-5783 mouse strains can be used to provide further insights into neurodegeneration in MS. 11,19,20 However, because of the potential complication of the rd8 mutation arising in such strains, an assessment is necessary. In particular, because many genetically modified mouse lines have been derived using a C57BL/6N background 21 and studies of AON have already been performed on some of these lines, 11 or even on C57BL6 mice of an undefined substrain identity, 20,22,23,24 such an assessment would allow readers to know whether one can have confidence in data obtained from such studies.…”

mentioning

confidence: 99%

Murine Autoimmune Optic Neuritis Is Not Phenotypically Altered by the Retinal Degeneration 8 Mutation

Stojic

Fairless

Beck

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

HE3286 Reduces Axonal Loss and Preserves Retinal Ganglion Cell Function in Experimental Optic Neuritis

Abstract: HE3286 suppresses inflammation, reduces demyelination and axonal loss, and promotes RGC survival during experimental optic neuritis. Importantly, HE3286 treatment also preserves some RGC function. Results suggest that HE3286 is a potential novel treatment for optic neuritis.

Cited by 29 publications

References 37 publications

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

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

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Murine Autoimmune Optic Neuritis Is Not Phenotypically Altered by the Retinal Degeneration 8 Mutation

Contact Info

Product

Resources

About