Carlo Perricone MD, Elias Toubi MD, Guido Valesini MD and Yehuda Shoenfeld MD FRCP (Hon.) MaACR
Marcella Di Gangi MD, Giorgio Amato MD, Giovanni Converso MD, Alessia Benenati MD, Concetta Leonetti MD, Elisabetta Borella MD, Andrea Doria MD and Rosario Foti MD
Rina Aharoni PhD and Ruth Arnon PhD
A fundamental challenge for multiple sclerosis (MS) therapy is to promote repair and remyelination beyond their limited spontaneous extent. Glatiramer acetate (GA, Copaxone®), an approved treatment for MS, has been shown to induce immunomodulation as well as neuroprotection in the inflamed central nervous system (CNS) in MS and in its model, experimental autoimmune encephalomyelitis (EAE). Using electron microscopy, immunohistochemistry, and advanced magnetic resonance imaging, we have demonstrated diminished myelin damage in GA-treated mice, in both relapsing-remitting and chronic EAE, even when treatment was applied late after the disease exacerbation, suggesting repair. Furthermore, quantitative analysis indicated significant elevation in remyelinated axons in GA-treated compared to untreated EAE mice. To further prove that GA can promote myelination, we studied its effect in the developing naïve CNS, when injected postnatally. Immunohistochemical and ultrastructural analyses revealed significant increase in the number of myelinated axons, the thickness of the myelin encircling them, and the resulting g-ratios in the spinal cords of GA-injected mice compared to their phosphate-buffered saline-injected littermates. A prominent elevation in the amount of progenitor oligodendrocytes and their proliferation, as well as in mature oligodendrocytes, implied that the effect of GA is linked to the differentiation along the oligodendroglial cascade. Furthermore, a functional advantage in rotating rod test was exhibited by GA-injected mice over their littermates. These cumulative findings indicate that GA treatment affects myelination under inflammatory as well as non-inflammatory conditions, supporting the notion that the repair process in the CNS can be up-regulated by therapy.
Cecilia Nalli MD and Angela Tincani MD
Paola Triggianese MD, Maria D. Guarino MD, Eleonora Ballanti MD, Maria S. Chimenti MD PhD and Roberto Perricone MD
Yael Bar-On MD, Varda Shalev MD, Dahlia Weitzman PhD, Gabriel Chodick PhD and Howard Amital MD MHA
Tomer Bashi MD, Miri Blank PhD and Yehuda Shoenfeld MD FRCP
Zahava Vadasz MD PhD and Doron Rimar MD
Zahava Vadasz MD and Elias Toubi MD
María-Teresa Arango MSc, Shaye Kivity MD, Joab Chapman MD PhD and Yehuda Shoenfeld MD FRCP
Alessandra Melegari MD and Chiara Bonaguri MD
Piercarlo Sarzi-Puttini MD and Fabiola Atzeni MD PhD
Marzia Dolcino PhD, Antonio Puccetti MD PhD, Andrea Ottria MD, Alessandro Barbieri PhD, Giuseppe Patuzzo MD PhD and Claudio Lunardi MD