Current status of neuroprotective and neuroregenerative strategies in multiple sclerosis: A systematic review

Abstract

Background: Immune-mediated demyelination and consequent degeneration of oligodendrocytes and axons are hallmark features of multiple sclerosis (MS). Remyelination declines in progressive MS, causing permanent axonal loss and irreversible disabilities. Strategies aimed at enhancing remyelination are critical to attenuate disease progression.

Objective: We systematically reviewed recent advances in neuroprotective and regenerative therapies for MS, covering preclinical and clinical studies.

Methods: We searched three biomedical databases using defined keywords. Two authors independently reviewed articles for inclusion based on pre-specified criteria. The data were extracted from each study and assessed for risk of bias.

Results: Our search identified 7351 studies from 2014 to 2020, of which 221 met the defined criteria. These studies reported 262 interventions, wherein 92% were evaluated in animal models. These interventions comprised protein, RNA, lipid and cellular biologics, small molecules, inorganic compounds, and dietary and physiological interventions. Small molecules were the most highly represented strategy, followed by antibody therapies and stem cell transplantation.

Conclusion: While significant strides have been made to develop regenerative treatments for MS, the current evidence illustrates a skewed representation of the types of strategies that advance to clinical trials. Further examination is thus required to address current barriers to implementing experimental treatments in clinical settings.

Keywords: Multiple sclerosis; demyelination; neuroprotection; neuroregeneration; oligodendrocytes; remyelination; therapeutics.

Figure 1.

Neurodegenerative and inflammatory processes in an MS lesion amenable to preventive and regenerative therapies. Feasible points of intervention include: (1) immunomodulation, the predominant strategy of currently available therapeutics for MS; (2) promote the viability of OPCs and oligodendrocytes; (3) preserve the quantity and integrity of neurons and axons; (4) Protect myelin to prevent further loss; (5) reduce oxidative stress, apoptosis or cellular dysfunction of neurons and glial cells; (6) promote blood–brain barrier integrity; (7) stimulate neurotrophin and growth factor production; (8) reduce pro-inflammatory activation of glial cells; (9) promote the proliferation of OPCs and their differentiation into mature myelinating oligodendrocytes; (10) induce the migration and recruitment of OPCs and oligodendrocytes to sites of demyelination; (11) induce the formation of new myelin; and (12) target inhibitory factors associated with myelin debris and promote its clearance to support remyelination of denuded axons. CSPGs: chondroitin sulfate proteoglycans; IFNγ: interferon gamma; LINGO-1: leucine-rich repeat and immunoglobin-like domain-containing protein 1; Nogo: neurite outgrowth inhibitory protein; OPC: oligodendrocyte precursor cell; ROS: reactive oxygen species; RNS: reactive nitrogen species; TNFα: tumor necrosis factor alpha.

Figure 2.

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram.

Figure 3.

Reported preclinical models (a) and clinical trial phases (b) used to evaluate remyelinating and/or neuroprotective interventions for MS. Among the 221 included articles, a total of 250 animal model studies and 19 clinical studies were reported. Descriptions of each study type are included in Supplementary Table S4. EtBr: ethidium bromide; EAE: experimental autoimmune encephalomyelitis; LPC: lysophosphatidylcholine; MHV: murine hepatitis virus; TMEV: Theiler’s murine encephalomyelitis virus.

Figure 4.

Classification of 262 interventions evaluated for neuroprotective and regenerative effects in MS patients and preclinical models of disease. Treatments applicable to multiple classes were assigned to a single class for clarity. Assessments of the same treatment in multiple different articles were counted as separate reports, for example, fingolimod (FTY720) was separately studied in and counted as 11 reports.