Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

Abstract

BackgroundTreatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo’s beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both?MethodsTo address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival.ResultsAlthough disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons.ConclusionsOur data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0976-5) contains supplementary material, which is available to authorized users.

Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy

“…In addition, there is evidence suggesting that activation of the HIF pathway may be also linked to neuroprotection and perhaps remyelination [ 15 ]. Thus, the erythropoietin (EPO) gene is HIF-dependent, and EPO is neuroprotective in different animal models of MS [ 16 , 17 ]. In addition, methylprednisolone, a widely used glucocorticoid for treating MS, protects oligodendrocytes from excitotoxicity through a HIF-1α-dependent pathway [ 18 ].…”

Prolonged astrocyte-derived erythropoietin expression attenuates neuronal damage under hypothermic conditions

“…We reported previously that EPO secreted by astrocytes is protective for several brain cell types [21][22][23]. In addition, studies involving animal models have shown that EPO in the brain contributes significantly to neuroprotection [24][25][26][27]. Based on these data, we examined the effect of hypothermia on EPO expression in cultured astrocytes.…”

A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia

“…The neuroprotective properties of erythropoietin have been investigated for a number of years, regarding, for example, stroke and Alzheimer’s disease [67], autoimmune encephalomyelitis [68], neuroprotection in pre-term infants [69], as well as other neurodegenerative and traumatic diseases with cerebral damage such as Parkinson’s disease, traumatic brain injury, and cardiac arrest [70,71]. Kristensen et al’s two studies observed both an endogenous (correlated to baseline RAS activity) and exogenous neuroprotective effect on cognitive function (endogenous) and reaction time (exogenous) [27,28].…”