Steroids Impact on Myelin Repair, Neurogenesis and Visual Pathway in Multiple Sclerosis: Preclinical Perspectives

Abstract

Ab s t r a c tEven though steroids have drawn significant therapeutic interests for decades, data about their benefits for neural regeneration are missing as current observational studies unfold progressive abnormalities in cerebral gray matter and cerebellum compartments, apart from demyelination lesions in white matter of the central nervous system (CNS) in multiple sclerosis (MS). This medical-scientific appraisal is based on a series of structured questions in part addressed in our investigative clinical review on the benefits and risks of glucocorticosteroids (GC), which highlights that steroids can intensify the disease progression, aside from other global side effects recognized in MS and associated optic neuritis (MS-ON). Corticosteroids treatments, whilst temporally and selectively suppress immune reactions, can interfere with the clearance of myelin debris and inhibit proliferation-migration of the myelinating cells, affecting the axonal repair and CNS functions. This review compiles and summarizes datasets extracted largely from complementary laboratory studies published in Medline, It discusses related pharmacologic and disease mechanisms and relevancies of the distinct MS disease models in rodents, with emphasis on the strengths and weaknesses of the associations of GCs use, glucocorticoid receptors sensitivity, and clinical outcomes. Based on these assessments, we conclude that steroids can suppress inflammation to the determent of neuronal remodeling in a mutually exclusive manner. Excess steroids can contribute to neuronal loss and retinal damage in optic pathology, and thus may expand cerebral atrophy and disease burden in multiple sclerosis.

Glucocorticosteroids: Risk-Benefit Appraisals in Multiple Sclerosis and MS-Associated Optic Neuritis

“…To date, no known biomarker of the immune system seems essential and sufficient to initiate degeneration in MS or visual pathways in MS-ON. Alternative hypotheses on the beneficial roles of activated immune cells in MS and ON disease models in animals in relations to the impacts of steroids treatments are reviewed elsewhere [42] . Our clinical assessments are aligned with the viewpoint that transient suppression of MS relapses through steroids use may inevitably carry additional risks, such as inability to control intracerebral replication of such viruses as Epstein-Barr virus (EBV) and JC polyomavirus (JCV) [50,51], as well as induction of pro-apoptotic elements in oligodendrocyte progenitor cells (OPCs) hence hindering myelin repair and neurogenesis [42].…”

“…The rationale of this approach relies on the deregulated immune response and inflammation as a basis of the pathophysiology of MS [63][64][65]. However, a treatment option that falls back on a continuous stimulation and release of endogenous corticosteroids might arguably bring out the worst pharmacodynamic characteristics, such as proapoptotic effects on OPCs, rather than only neuroprotective activities [42]. Furthermore, elevated levels of steroids can adversely affect myelin repair: the inhibition of immune cells in the CNS may hinder clearance of the cellular debris from injurious neurons in multiple sclerosis [42].…”

“…Moreover, low-dose steroids in combination therapies fail to slow down disability progression and cortical atrophy (Table 3). Studies on the respective disease models in rodents demonstrate that steroids treatment are lethal to axonal, ganglionic and myelinating cells, and can damage retina and visual pathway (reviewed in [42]). …”

“…Corticosteroids differentially affect oligodendrocytes and neurons in both GC-resistant and GC-responsive MS [42]. Several active trials are evaluating efficacy and safety of steroids in MS and optic neuritis, while others shifting to radical approaches to determine for instance efficacy of stem-cell transplants in MS.…”

“…Other studies indicate that high-dose steroids may worsen the brain atrophy in clinically-definite MS [73] and MS-ON [74], and as described in detail in this article. While the steroids-suppressed immune cells may lose their beneficial roles in the clearance of myelin and other cellular debris in the injury pathways and hence inhibit remyelination and neurogenesis [42], do steroids exert harmful effects only on certain CNS cell types? …”