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The Journal of Neuroscience, September 7, 2005, 25(36):8217-8228; doi:10.1523/JNEUROSCI.1859-05.2005

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Development/Plasticity/Repair
Neurogenesis and Neuroprotection Induced by Peripheral Immunomodulatory Treatment of Experimental Autoimmune Encephalomyelitis

Rina Aharoni,¹ Ruth Arnon,¹ and Raya Eilam²

Departments of ¹Immunology and ²Veterinary Resources, The Weizmann Institute of Science, Rehovot, 76100 Israel

Brain insults such as the autoimmune inflammatory process in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) induce a measure of neurogenesis, but its regenerative therapeutic consequence is limited, because it fails to regenerate functional neurons and compensate the damage. Here, we investigated whether peripheral immunomodulatory treatment for MS/EAE, glatiramer acetate (GA), can enhance neurogenesis and generate neuroprotection in the CNS of EAE-inflicted mice. EAE was induced by myelin oligodendrocyte glycoprotein peptide, either in yellow fluorescent protein (YFP) 2.2 transgenic mice, which selectively express YFP on their neuronal population, or in C57BL/6 mice. The in situ effect of GA was studied in various brain regions; neuroprotection and neurogeneration were evaluated and quantified by measuring the expression of different neuronal antigens and in vivo proliferation markers. The results demonstrated that in EAE-inflicted mice, neuroproliferation was initially elevated after disease appearance but subsequently declined below that of naive mice. In contrast, GA treatment in various stages of the disease led to sustained reduction in the neuronal/axonal damage typical to the neurodegenerative disease course. Moreover, three processes characteristic of neurogenesis, namely cell proliferation, migration, and differentiation, were augmented and extended by GA treatment in EAE mice compared with EAE-untreated mice and naive controls. The newborn neuroprogenitors manifested massive migration through exciting and dormant migration pathways, into injury sites in brain regions, which do not normally undergo neurogenesis, and differentiated to mature neuronal phenotype. This suggests a direct linkage between immunomodulation, neurogenesis, and an in situ therapeutic consequence in the CNS.

Key words: neurogenesis; neuroprotection; immunomodulation; multiple sclerosis; MS; experimental autoimmune encephalomyelitis; EAE; glatiramer acetate

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Received May 10, 2005; revised July 12, 2005; accepted July 12, 2005.

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