Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate

Abstract

Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g-ratios, in spinal cords of GA-injected mice compared with their PBS-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA-injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination.

The role of growth factors as a therapeutic approach to demyelinating disease

“…This conditioned medium elevates numbers of cultured oligodendrocyte progenitors. Moreover, after a lysolecithin lesion GA treatment elevates oligodendrocyte progenitors in lesions of the spinal cord coincident with increases in IGF-I, as well as BDNF (Skihar et al 2009) and GA treatment during development enhances numbers of oligodendrocyte progenitors as well as mature oligodendrocytes and myelin in a manner coincident with increases in IGF-I and BDNF (From et al 2014). …”

Ulk4 deficiency leads to hypomyelination in mice

“…Oligodendrocytes synthesize myelin, extend processes to contact multiple neighboring axons and enwrap short axonal segments (Baumann & Pham‐Dinh, ). Myelinogenesis occurs predominantly in the first three postnatal weeks in rodents (Fields ; From et al, ), and in the first 2 years in children, which coincides with the diagnostic age for many neurodevelopmental disorders. Hypomyelination is common in both neurodegenerative and neurodevelopmental disorders.…”

Remyelination in multiple sclerosis: realizing a long-standing challenge

“…[12] In the developing nervous system, GA enhanced postnatal myelinogenesis elevating the number of myelinated axons as well as the thickness of the myelin encircling them and their resulting G-ration. [13] These effects are attributed to increased OPCs proliferation and differentiation along the oligodendroglial maturation cascade. [9,13] GA induces elevation in brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), which are known to promote myelination, suggesting that its mode of action is linked to neurotrophic effects.…”

“…[13] These effects are attributed to increased OPCs proliferation and differentiation along the oligodendroglial maturation cascade. [9,13] GA induces elevation in brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), which are known to promote myelination, suggesting that its mode of action is linked to neurotrophic effects. [13,14] Another immunomodulatory treatment, fingolimod, was shown to modulate process outgrowth in immature oligodendrocytes and to enhance remyelination following lysolecithin-induced demyelination via sphingosine 1-phosphate receptors on astrocytes and oligodendrocytes.…”

“…[9,13] GA induces elevation in brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), which are known to promote myelination, suggesting that its mode of action is linked to neurotrophic effects. [13,14] Another immunomodulatory treatment, fingolimod, was shown to modulate process outgrowth in immature oligodendrocytes and to enhance remyelination following lysolecithin-induced demyelination via sphingosine 1-phosphate receptors on astrocytes and oligodendrocytes. [15] However, conflicting results regarding the remyelination potency of FTY720 have been recently reported.…”