The current studies show that orally administered SRT501 attenuates neuronal damage in EAE optic nerves and spinal cords. Observed neuroprotective effects on RGCs are similar to effects seen previously with intravitreal administration (18
), but in those studies no effect on EAE or spinal cord pathology occurred. SRT501 is well tolerated in the eye (18
), as well as systemically (22
). Based on the current results and its favorable safety profile, SRT501 is an important potential oral therapy to prevent permanent neurological disability in MS.
MS involves a complex autoimmune inflammatory response to components of CNS myelin (1
), and neuronal damage, including RGC loss during optic neuritis in experimental models, can occur secondary to inflammation (17
). The mechanism of neuroprotection by SRT501 in EAE, however, is not mediated by reducing inflammation, as incidence of optic nerve and spinal cord inflammation was not reduced by SRT501 treatment. SRT501 also did not alter the phenotype of inflammatory cell infiltrates in the spinal cord at the peak of the acute EAE attack. In addition, EAE scores during acute disease episodes, signs that reflect active spinal cord inflammation, were not reduced by SRT501 treatment. EAE was suppressed during disease remission, with preserved axonal density, suggesting SRT501 may be able to prevent permanent neurological dysfunction and neuronal damage in MS after acute spinal cord inflammation resolves. While treatment during the first clinical EAE episode, day 10–14 post-immunization, led to improved functional recovery during remission, this treatment course did not prevent the onset of EAE relapse at day 30. Further studies with extended treatment will be important to examine longer-term effects of SRT501.
Results suggest the mechanism of SRT501 neuroprotection in EAE involves SIRT1 activation. SRT501 activates SIRT1 in vitro (22
). Administration of the SIRT1 inhibitor sirtinol blocks SRT501-mediated RGC neuroprotection, and the fact that a second distinct SIRT1 activator, SRT1720, induced similar neuroprotective effects further suggests SIRT1 activation is a requisite mechanism for the observed neuroprotection. Precise molecular pathways driven by SIRT1 activity leading to neuroprotection require further examination.
Interestingly, while the current studies showed no suppression of EAE inflammation by SRT501, resveratrol has been shown to partially suppress EAE and modulate inflammation in two other studies (29
), although there are important differences between those studies and the current studies. Singh and colleagues (29
) used a different EAE model with a chronic disease course, and in their studies resveratrol treatment was initiated right after immunization, long before clinical EAE develops, suggesting that it may affect development of the disease model as opposed to treating active disease. In addition, mechanisms of neuronal loss in chronic EAE can differ from relapsing/remitting EAE, as neuronal loss occurs several days after immunization and prior to onset of inflammation (31
), as opposed to neuronal loss only beginning after inflammation develops in the relapsing/remitting model (17
). Thus, both the mechanism of neuronal loss and the timing of treatment are likely important factors for resveratrol neuroprotective effects. In the studies by Imler and Petro (30
), resveratrol treatment was also initiated prior to disease onset, at the time of immunization, and while continuous daily treatment did result in long-term EAE suppression through multiple relapses, even in their studies resveratrol effects were limited during the first episode of EAE. Together, these studies suggest resveratrol may modulate immune responses in EAE during the induction phase of disease, and it is possible that SRT501 may alter immune responses at other time points along the EAE disease course, but our results show that once the immune response has been induced and clinical disease developed, SRT501 no longer suppresses inflammation but does retain significant ability to prevent neuronal damage. As the timing of SRT501 treatment may play a role in its ability to prevent neuronal injury, it is important to note that neuroprotective effects were seen when treatment was initiated after onset of inflammation, but prior to optic nerve axonal loss (25
). If a similar window of time can be indentified in optic neuritis patients, then there would be a potential opportunity to initiate neuroprotective therapies.
Overall, our results demonstrate a significant neuroprotective effect of SIRT1 activators in EAE mice, reducing neurological dysfunction during EAE remission and preventing axonal damage and neuronal loss. SIRT1 activators have a potential therapeutic role in preventing permanent visual loss following optic neuritis and permanent neurological dysfunction in MS patients. SRT501 itself has shown a favorable safety profile without retinal toxicity in EAE and is also safe in humans. Therefore, our findings likely can be translated into clinical trials to assess potential neuroprotection in optic neuritis and MS patients. Because SIRT1 activation does not prevent inflammation when treatment is initiated after disease onset, SIRT1 activators have potential to work synergistically with current immunomodulatory therapies.