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

Abstract

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

Emerging myelin repair agents in preclinical and early clinical development for the treatment of multiple sclerosis

“…CNM-Au8 are a newly generated type of clean-surfaced gold nanocrystals with an average diameter of 13 nm which display high catalytic activity in primary rat neural-glia co-cultures. This was demonstrated by an enhanced expression of the redox coenzyme nicotine adenine dinucleotide (NAD+), increased intracellular levels of adenosine triphosphate (ATP), and an elevated extracellular lactate after administration of CNM-Au8 to cell cultures [68]. Treatment of OPC in vitro resulted in upregulation of differentiation and myelination pathways and significantly enhanced differentiation toward GalC-positive oligodendrocytes.…”

Current and emerging disease‐modulatory therapies and treatment targets for multiple sclerosis

“…In contrast, a multiarm phase II trial in SPMS testing three different drugs with potential neuroprotective effects, amiloride, fluoxetine and riluzole, did not result in superior outcomes compared with placebo [162]. Ongoing studies include two trials examining the potential of nanocrystalline gold to treat remyelination failure and impaired neuronal redox state (NCT03993171, NCT03536559) [163].…”

Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

“…Nanoparticles themselves can also act as remyelinating agents. Most recently, Robinson et al [64] reported a new nanocatalytic therapeutic candidate for remyelination, consisting of a suspension of clean-surfaced, faceted nanocrystals of gold, which was found to demonstrate robust remyelinating activity in response to demyelinating agents, in both chronic cuprizone and acute lysolecithin rodent animal models. More analytically, the administrated nanoparticles induced differentiation of OPCs and enhanced activities of neurons and oligodendrocytes through enhancement of bioenergetic processes of key indicators of aerobic glycolysis.…”