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

Nimmagadda, Vamshi K.C.; Makar, Tapas K.; Chandrasekaran, Krish; Sagi, Avinash Rao; Ray, Jayanta; Russell, James W.; Bever, Christopher T.

doi:10.1016/j.jneuroim.2016.07.007

Cited by 38 publications

(21 citation statements)

References 76 publications

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“…Intriguingly, this NAD + deficiency increases amongst MS subgroups with increasing severity of the disease 27 . NAD + has been proposed to be a potential therapeutic target for MS treatment [27][28][29] .…”

Section: Discussionmentioning

confidence: 99%

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Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

Robinson

Zhang²,

Titus

et al. 2020

Sci Rep

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Development of pharmacotherapies that promote remyelination is a high priority for multiple sclerosis (MS), due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of myelin differentiation markers. Additional in vitro data demonstrated that these gold nanocrystals act via a novel energy metabolism pathway involving the enhancement of key indicators of aerobic glycolysis. in response to gold nanocrystals, co-cultured central nervous system cells exhibited elevated levels of the redox coenzyme nicotine adenine dinucleotide (nAD+), elevated total intracellular Atp levels, and elevated extracellular lactate levels, along with upregulation of myelin-synthesis related genes, collectively resulting in functional myelin generation. Based on these preclinical studies, clean-surfaced, faceted gold nanocrystals represent a novel remyelinating therapeutic for multiple sclerosis. Myelination is a complex process by which axons are wrapped with oligodendrocyte (OL) membranes containing specialized proteins and lipids, facilitating axonal electrical conduction and providing essential trophic support to neurons 1. During active myelination, OLs synthesize on the order of 100,000 proteins per minute 2 and several thousand new lipid molecules per second 3 , reflecting the significant energetic investment needed for biomass generation, and making this cell type among the most energetically demanding of the body. Dysregulated energy metabolism impacting OLs has been postulated to play a central role in MS disease progression 4,5. Limited remyelination occurs in multiple sclerosis (MS) lesions despite the presence of OPCs in or around lesion sites. These OPCs fail to remyelinate and exhibit markers of metabolic stress 6. Similarly, cultured human OLs, placed under metabolic stress using low glucose media, retract their cellular processes and exhibit significantly reduced glycolytic activity, favouring cell survival at the expense of myelin stability 7,8. Under favourable growth conditions, human OPCs and OLs preferentially utilize aerobic glycolysis over oxidative phosphorylation for energy generation, resulting in an enhanced capacity to differentiate and myelinate axons 7. Aerobic glycolysis results in production of pyruvate, acetyl coenzyme A, and NADPH, the requisite precursors of myelin

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Section: Discussionmentioning

confidence: 99%

“…OPCs present in MS lesions are thought to be unable to remyelinate because they have undergone cellular stresses that have led to their bioenergetic failure (3). CNM-Au8 may catalytically compensate for intracellular energy loss, stimulating OPC differentiation and accelerating myelination 28,29 .…”

Section: Discussionmentioning

confidence: 99%

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

Robinson

Zhang²,

Titus

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Intriguingly, this NAD+ deficiency increases amongst MS subgroups with increasing severity of the disease (28). NAD+ has been proposed to be a potential therapeutic target for MS treatment (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, these therapies work by blocking inhibitory signaling pathways, or by stimulating positive signaling pathways, of OPC differentiation (38)(39)(40). Unlike these signaling therapies, CNM-Au8 catalytically compensates for energy loss, stimulating OPC differentiation and accelerating myelination in a unique mode of action that likely falls downstream of many stimulatory signaling pathways (29,30). Moreover, bioenergetic failure is a noted pathophysiologic mechanism common to many age-related neurodegenerative diseases (33).…”

Section: Discussionmentioning

confidence: 99%

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

Robinson

Zhang²,

Titus

et al. 2019

Preprint

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One Sentence Summary: Nanocatalytic activity of clean-surfaced, faceted gold nanocrystals results in robust remyelinating activity in demyelination animal models of multiple sclerosis. Abstract:Development of pharmacotherapies that promote remyelination are a high priority for multiple sclerosis (MS) due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. Furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of key myelin differentiation markers.Additional in vitro data demonstrated that these gold nanocrystals act via a novel energy metabolism pathway involving the enhancement of key indicators of aerobic glycolysis. In response to gold nanocrystals, co-cultured central nervous system cells exhibited elevated levels of the redox coenzyme nicotine adenine dinucleotide (NAD+), elevated total ATP levels, elevated extracellular lactate levels, and upregulation of myelin-synthesis related genes, collectively resulting in functional myelin generation. Based on these preclinical studies, cleansurfaced, faceted gold nanocrystals represent a novel remyelinating therapeutic for multiple sclerosis.

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“…The sirtuin family is a family of highly conserved NAD + dependent deacetylases, Sirt1 is the most widely studied sirtuin protein at present and a popular drug design target ( 8 ). Sirt1 is able to interact with a variety of signal transduction proteins, induce the deacetylation of histone lysine residues and transcription factors, and regulate neuroprotection, cell senescence, apoptosis, lipid metabolism, insulin secretion, inflammation, oxidative stress response and angiogenesis ( 9 , 10 ). Due to the effect of Sirt1 on biomedical regulation and in order to effectively apply Sirt1 in the treatment of diabetes, cardiovascular disease, metabolic syndrome and aging-associated diseases; several Sirt1 agonists have been identified and studied ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

A novel dressing seeded with embryonic artery CD133+ cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers

Cheng

Chen

et al. 2018

Exp Ther Med

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Refractory ischemic ulcers that occur in patients with diabetes present a major clinical challenge. Embryonic artery cluster of differentiation 133+ cells (EACCs) may promote the healing of diabetic ulcers; however, the high glucose environment in the diabetic ulcers decreases the survival rate of transplanted EACCs and inhibit their biological function. Furthermore, microcirculation in diabetic ischemic ulcers is impaired, which inhibits the beneficial effect of EACCs. In the current study, the Sirt1 agonist SRT1720 was selected as a therapeutic drug and loaded into a dressing composed of PLGA, collagen and silk (PCSS) formed using electrospinning technology. EACCs were seeded onto the PCSS dressing and this was used to treat diabetic ulcers. The results indicated that SRT1720 promotes the proliferation of EACCs, enhances the secretion of vascular endothelial growth factor A, interluekin 8 and basic fibroblast growth factor, and inhibits the secretion of tumor necrosis factor α. Furthermore, SRT1720 promoted the paracrine function of EACCs and promoted the proliferation and migration of human umbilical vein endothelial cells. PCSS induced the steady release of SRT1720 over a 15-day period and PCSS seeded with EACCs (PCSS-EACCs) were transplanted into the diabetic ischemic ulcers of mice with diabetes. The results of these experiments indicated that angiogenesis and the healing of diabetic ischemic ulcers was significantly improved following the transplantation of PCSS-EACCs. Therefore, PCSS-EACCs may be a novel and effective treatment for diabetic ischemic ulcers.

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

Cited by 38 publications

References 76 publications

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis

A novel dressing seeded with embryonic artery CD133+ cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers

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