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PDE 7 inhibitor TC 3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis
Author(s) -
Mestre L,
Redondo M,
CarrilloSalinas F J,
MoralesGarcía J A,
AlonsoGil S,
PérezCastillo A,
Gil C,
Martínez A,
Guaza C
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13192
Subject(s) - multiple sclerosis , medicine , neuroprotection , experimental autoimmune encephalomyelitis , disease , microglia , pathological , immunology , demyelinating disease , pharmacology , neuroscience , inflammation , biology
Background and Purpose cAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP ‐specific PDEs such as PDE 7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis ( MS ). In the present study, we evaluated the therapeutic potential of the selective PDE 7 inhibitor, TC 3.6, in a model of primary progressive multiple sclerosis ( PPMS ), a rare and severe variant of MS . Experimental Approach T heiler's murine encephalomyelitis virus‐induced demyelinated disease ( TMEV ‐ IDD ) is one of the models used to validate the therapeutic efficacy of new drugs in MS . As recent studies have analysed the effect of PDE 7 inhibitors in the EAE model of MS , here the TMEV ‐ IDD model was used to test their efficacy in a progressive variant of MS . Mice were subjected to two protocols of TC 3.6 administration: on the pre‐symptomatic phase and once the disease was established. Key Results Treatment with TC 3.6 ameliorated the disease course and improved motor deficits of infected mice. This was associated with down‐regulation of microglial activation and reduced cellular infiltrates. Decreased expression of pro‐inflammatory mediators such as COX ‐2 and the cytokines, IL ‐1β, TNF ‐α, IFN ‐γ and IL ‐6 in the spinal cord of TMEV ‐infected mice was also observed after TC 3.6 administration. Conclusion These findings support the importance of PDE 7 inhibitors, and specifically TC 3.6, as a novel class of agents with therapeutic potential for PPMS . Preclinical studies are needed to determine whether their effects translate into durable clinical benefits.