SIRT1 activation confers neuroprotection in experimental optic neuritis.
OBJECTIVE
Axonal damage and loss of neurons correlate with permanent vision loss and neurologic disability in patients with optic neuritis and multiple sclerosis (MS). Current therapies involve immunomodulation, with limited effects on neuronal damage. The authors examined potential neuroprotective effects in optic neuritis by SRT647 and SRT501, two structurally and mechanistically distinct activators of SIRT1, an enzyme involved in cellular stress resistance and survival.


METHODS
Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, was induced by immunization with proteolipid protein peptide in SJL/J mice. Optic neuritis developed in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization. RGCs were labeled in a retrograde fashion with fluorogold by injection into superior colliculi. Optic neuritis was detected by inflammatory cell infiltration of the optic nerve.


RESULTS
Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. A single dose of SRT501 on day 11 was sufficient to limit RGC loss and to preserve axon function.


CONCLUSIONS
SIRT1 activators provide an important potential therapy to prevent the neuronal damage that leads to permanent neurologic disability in optic neuritis and MS patients. Intravitreal administration of SIRT1 activators does not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies.
Shindler
Kenneth S
KS
F.M. Kirby Center for Molecular Ophthalmology, Department of Ophthalmology, University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania 19104, USA. kenneth.shindler@uphs.upenn.edu
Ventura
Elvira
E
Rex
Tonia S
TS
Elliott
Peter
P
Rostami
Abdolmohamad
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity; D001370:Axonal Transport / Q000187:drug effects; D001369:Axons / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000633:toxicity; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D009902:Optic Neuritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000473:pathology; D011726:Pyridinium Compounds; D000077185:Resveratrol; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists* / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000494:pharmacology / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D013267:Stilbenes; C018613:nicotinamide-beta-riboside; D009536:Niacinamide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol