A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis.
In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial "Excitatory Amino Acid Transporters" (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a beta-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in "Myelin Oligodendrocyte Glycoprotein" (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFgamma and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a beta-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis.
Melzer
Nico
N
Department of Neurology, University of Würzburg, Würzburg, Germany.
Meuth
Sven G
SG
Torres-Salazar
Delany
D
Bittner
Stefan
S
Zozulya
Alla L
AL
Weidenfeller
Christian
C
Kotsiari
Alexandra
A
Stangel
Martin
M
Fahlke
Christoph
C
Wiendl
Heinz
H
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D009457:Neuroglia / Q000166:cytology; D051381:Rats; D047090:beta-Lactams / Q000494:pharmacology*
D027322:Amino Acid Transport System X-AG; D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D002443:Ceftriaxone
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