POTENCIAL ROLE OF BUPRENORPHINE IN MULTIPLE SCLEROSIS REMYELINATION THERAPY

SANCHEZ ES; ROBINSON S; BIGBEE JW; SATO-BIGBEE C; ALVAREZ SE

Mendoza

Congreso; 48th Reunión Científica Anual de SAIB; 2012

Multiple Sclerosis (MS) is a complex inflammatory demyelinating disease of the Central Nervous System (CNS) characterized by chronic inflammation. FTY720 (fingolimod), a sphingosine 1-phosphate (S1P) receptor modulator, is the first oral therapy approved for the treatment of MS. FTY720 is rapidly converted in vivo to the biological active form FTY1- phosphate, which binds to and activates S1P receptors. This action inhibits egress of lymphocytes from the lymph nodes, preventing its entry into the blood and thus infiltration into the CNS. FTY720 also crosses the blood-brain barrier acting on S1P receptors in cells of the CNS. While the immunological effects of FTY720 are well established, there is controversy regarding the contribution of FTY720 on myelin repair. Regeneration of myelin sheaths (remyelination) after CNS demyelination is performed by oligodendrocyte progenitors (OPs) to restore saltatory conduction and prevent axonal loss. In MS, the insufficiency of remyelination leads to the irreversible degeneration of axons which correlates with clinical decline. Therefore, a regenerative strategy to encourage remyelination is a key research aim in MS. In our laboratory we found that FTY720 arrest the differentiation of oligodendrocytes, the myelin synthesizing cells of the CNS. We have also shown for the first time that opioid signaling plays an important role in regulating myelination. Our results indicate that buprenorfine, an opioid analogue clinically used, increase the expression of myelin basic proteins and induce the differentiation of oligodendrocytes in vivo. Moreover, buprenorphine per se induces the differentiation of primary cultured OPs. These evidences suggest that buprenorphine therapy could be considered as a complementary strategy to specifically oppose the effects of FTY720 on oligodendrocyte development, to promote remyelination and to prevent neuronal irreversible damage in patients suffering from MS.