ro13-9904 and Multiple-Sclerosis

We present a case of acute neuroborreliosis in the setting of long-term treatment with natalizumab. A 33-year-old man was diagnosed with relapsing-remitting multiple sclerosis (MS) in 1999. Following failure of various immunomodulatory treatments including interferon and immunoglobulin, he was treated with mitoxantrone from May 2000 to August 2004. Due to persistently high disease activity, he was also treated with cyclophosphamide (December 2005-April 2006) and then azathioprine (April-June 2006), which were both discontinued due to adverse effects. After the patient scored 6.5 on the Expanded Disability Status Scale and had 2 relapses in 2006, we initiated natalizumab therapy (300 mg monthly, starting September 2006). The patient improved significantly in ambulation and the relapse rate slowed as well.

Topics: Adult; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Ceftriaxone; Humans; Immunologic Factors; Interferon-beta; Lyme Neuroborreliosis; Male; Multiple Sclerosis; Natalizumab

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.

Topics: Amino Acid Transport System X-AG; Animals; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Inflammation; Mice; Mice, Inbred C57BL; Models, Biological; Multiple Sclerosis; Neuroglia; Rats

Topics: Anti-Bacterial Agents; Antigens, Bacterial; Blotting, Western; Borrelia burgdorferi; Ceftriaxone; Diagnosis, Differential; Exanthema; Female; Humans; Lyme Disease; Metronidazole; Middle Aged; Multiple Sclerosis; Treatment Outcome; Trigeminal Neuralgia