SIRT1 Activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease

Abstract

BackgroundMultiple sclerosis (MS) is characterized by central nervous system inflammation and demyelination, and increasing evidence demonstrates significant neuronal damage also occurs and is associated with permanent functional impairment. Current MS therapies have limited ability to prevent neuronal damage, suggesting additional neuroprotective therapies are needed. Compounds that activate the NAD+-dependent SIRT1 deacetylase prevent neuronal loss in an autoimmune-mediated MS model, but the mechanism of this effect is unknown, and it is unclear whether SIRT1 activating compounds exert similar effects in demyelinating disease induced by other etiologies. We measured neuronal loss in C57BL/6 mice inoculated with a neurotropic strain of mouse hepatitis virus, MHV-A59, that induces an MS-like disease.ResultsOral treatment with the SIRT1 activating compound SRTAW04 significantly increased SIRT1 activity within optic nerves and prevented neuronal loss during optic neuritis, an inflammatory demyelinating optic nerve lesion that occurs in MS and its animal models. MHV-A59 induced neuronal loss was associated with reactive oxygen species (ROS) accumulation, and SRTAW04 treatment significantly reduced ROS levels while promoting increased expression of enzymes involved in mitochondrial function and reduction of ROS. SRTAW04 exerted similar protective effects in EAE spinal cords, with decreased demyelination.ConclusionsResults demonstrate that SIRT1 activating compounds prevent neuronal loss in viral-induced demyelinating disease similar to their effects in autoimmune-mediated disease. One mechanism of this neuroprotective effect involves increasing mitochondrial biogenesis with reduction of oxidative stress. SIRT1 activators represent a potential neuroprotective therapy for MS. Understanding common mechanisms of these effects in distinct disease models will help identify targets for more specific therapies.

Kaempferol protects cardiomyocytes against anoxia/reoxygenation injury via mitochondrial pathway mediated by SIRT1

“…Though, there is rare information involves the mechanism of Kae protecting cardiomyocytes against I/R injury. SIRT1 activation reduces oxidative stress and maintains mitochondrial function in different tissues and cells after I/R Khan et al, 2014;Khader et al, 2014). Judging from the generally cell protective function of SIRT1 in model organisms, SIRT1 may also play an important role in cardiomyocytes which is suffered from I/R injury.…”

SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review

“…In addition, the spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice suggesting protection against neurological dysfunction (Shindler et al, 2010). Similar neuro-protection by SIRT1 activators against optic neuritis induced with a neurotropic strain of mouse hepatitis virus, MHV-A59, or chronic EAE induced by immunization with MOG peptide is observed in C57/Bl6 mice (Fonseca-Kelly et al, 2012; Khan et al, 2014). SIRT1 activators are shown to significantly reduce ROS levels and increase mitochondrial metabolism (Fonseca-Kelly et al, 2012; Khan et al, 2014).…”

“…Similar neuro-protection by SIRT1 activators against optic neuritis induced with a neurotropic strain of mouse hepatitis virus, MHV-A59, or chronic EAE induced by immunization with MOG peptide is observed in C57/Bl6 mice (Fonseca-Kelly et al, 2012; Khan et al, 2014). SIRT1 activators are shown to significantly reduce ROS levels and increase mitochondrial metabolism (Fonseca-Kelly et al, 2012; Khan et al, 2014). These studies support a role for SIRT1 in EAE.…”

The role and therapeutic potential of melatonin in age‐related ocular diseases

“…Several authors have demonstrated that SIRT1 may also prevent oxidative stress‐induced TM DNA damage and retinal ganglion cell death as well as axonal degeneration . Consequently, melatonin treatment regulating SIRT1 expression/activity could be a useful strategy to prevent these effects and thus glaucoma progression (Figure ) …”

“…Several authors have demonstrated that SIRT1 may also prevent oxidative stress-induced TM DNA damage and retinal ganglion cell death as well as axonal degeneration. 163,[238][239][240] Consequently, melatonin treatment regulating SIRT1 expression/activity could be a useful strategy to prevent these effects and thus glaucoma progression (Figure 2). [113][114][115]117 Additionally, and in experimental models of optic neuritis and retinal ischemia, melatonin treatment inhibits glial reactivity and reduces the expression of hypoxia inducible factor -1α, COX-2, and TNF-α genes (Figure 2).…”