TY - JOUR
T1 - Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease
AU - Sommer, N.
AU - Martin, R.
AU - McFarland, H. F.
AU - Quigley, L.
AU - Cannella, B.
AU - Raine, C. S.
AU - Scott, D. E.
AU - Löschmann, P. A.
AU - Racke, M. K.
N1 - Funding Information:
N.S. was supported by the Deutsche Forschungsgemeinschaft. R.M. is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft. M.K.R. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society (JF 2078-A-2) and recipient of the Young Investigator in Multiple Sclerosis Award from the American Academy of Neurology Education and Research Foundation. This work was also supported in part by USPHS grants NS 08952, NS 07098, and NS 11920; and NMSS grant RG 1001-H-8 (C.S.R.).
PY - 1997/10
Y1 - 1997/10
N2 - It was recently demonstrated that selective phosphodiesterase type 4 (PDE4) inhibition suppresses the clinical manifestations of acute experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and inhibits the production of tumor necrosis factor-α (TNF- α), a pathogenetically central cytokine. Since the most common presentation of MS in humans is a relapsing-remitting course, we investigated the therapeutic potential of PDE4 inhibition in the relapsing-remitting EAE model of the SJL mouse. Administration of rolipram, the prototypic PDE4 inhibitor, reduced the clinical signs of EAE during both the initial episode of disease and subsequent relapses. In parallel, there was marked reduction of demyelination and also less inflammation throughout the central nervous system (CNS) of rolipram-treated animals. Gene expression of proinflammatory cytokines in the CNS was reduced in most of the rolipram-treated animals. Additional experiments demonstrated that PDE4 inhibition acted principally by inhibiting the secretion of Th1 cytokines, however, the encephalitogenic potential of myelin basic protein-specific T cells was not impaired. Our findings suggest that PDE4 inhibitors are a promising cytokine-directed therapy in chronic demyelinating disease.
AB - It was recently demonstrated that selective phosphodiesterase type 4 (PDE4) inhibition suppresses the clinical manifestations of acute experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and inhibits the production of tumor necrosis factor-α (TNF- α), a pathogenetically central cytokine. Since the most common presentation of MS in humans is a relapsing-remitting course, we investigated the therapeutic potential of PDE4 inhibition in the relapsing-remitting EAE model of the SJL mouse. Administration of rolipram, the prototypic PDE4 inhibitor, reduced the clinical signs of EAE during both the initial episode of disease and subsequent relapses. In parallel, there was marked reduction of demyelination and also less inflammation throughout the central nervous system (CNS) of rolipram-treated animals. Gene expression of proinflammatory cytokines in the CNS was reduced in most of the rolipram-treated animals. Additional experiments demonstrated that PDE4 inhibition acted principally by inhibiting the secretion of Th1 cytokines, however, the encephalitogenic potential of myelin basic protein-specific T cells was not impaired. Our findings suggest that PDE4 inhibitors are a promising cytokine-directed therapy in chronic demyelinating disease.
KW - Cytokine
KW - Experimental autoimmune encephalomyelitis
KW - Multiple sclerosis
KW - Phosphodiesterase type 4
KW - Rolipram
KW - Tumor necrosis factor
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U2 - 10.1016/S0165-5728(97)00111-2
DO - 10.1016/S0165-5728(97)00111-2
M3 - Article
C2 - 9357447
AN - SCOPUS:0030660328
SN - 0165-5728
VL - 79
SP - 54
EP - 61
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
IS - 1
ER -