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PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

AuthorsMestre, Leyre ; Redondo, Miriam ; Carrillo-Salinas, F. J.; Morales-García, José A. ; Alonso-Gil, Sandra ; Pérez Castillo, Ana ; Gil, Carmen ; Martínez, Ana ; Guaza, Carmen
KeywordsPhosphodiesterase-7 Inhibitors
Multiple sclerosis
TMEV model
Issue Date14-Jul-2015
PublisherJohn Wiley & Sons
CitationBritish Journal of Pharmacology 172(17): 4277–4290 (2015)
Abstract[Background and Purpose]: cyclic Adenosine monophosphate (cAMP) plays an important role in the transduction of signaling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP specific phosphodiesterases (PDEs) such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study we evaluated the therapeutic potential of the selective PDE7 inhibitor, named TC3.6 in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. [Experimental Approach]: TMEV-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 analyzed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model is used to test the efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the presymptomatic phase and once the disease was established. [Key Results]: Treatment with TC3.6 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 proinflammatory mediators such as COX-2 and the cytokines, IL-1β, TNFα, IFNγ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration. [Conclusion]: These findings support the interest of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS raising the possibility to develop regulatory preclinical studies to reach the clinic.
Description44p.-7 fig.-1 tab.
Publisher version (URL)http://dx.doi.org/ 10.1111/bph.13192
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