Pharmacotherapeutic potential of phosphodiesterase inhibitors in experimental paradigms of Huntington s disease

Abstract

Huntington s disease (HD) is an inherited neurodegenerative disorder characterized by cognitive decline, motor dysfunction and psychiatric disturbances. It is caused by more than 36 CAG triple repeat expansion and involves the mutation of HTT gene that is translated into polyglutamine (polyQ) sequences in the huntingtin (htt) protein. In this study, neuroprotective effects and mechanisms of PDE 3, PDE 4 and PDE 5 inhibitors namely cilostazol, roflumilast and zaprinast respectively were explored in Quinilonic acid (QA) induced HD model. Cyclic nucleotides (cAMP and cGMP) are intracellular second messengers that play an important role in signaling in a variety of physiological processes. PDE upregulate cAMP/cGMP levels and this resumes the activation of several survival signals which are blocked during HD. cAMP stimulates CREB/BDNF pathways and replenishes the neuronal growth factors, furthermore, PI3K/Akt is a downstream activator of CREB that enhances BDNF expression. In behavioral parameters maximum percent change was observed with roflumilast in locomotion and motor coordination than cilostazol and zaprinast. In biochemicals and neuroinflammatory parameters maximum percent change was observed with roflumilast (PDE 4 inhibitor) with respect to LPO, nitrite catalase, SOD, GSH and proinflammatory cytokines (NF-and#954;B, TNF-and#945;, IL-6) when compared to cilostazol (PDE-3 inhibitor) and zaprinast (PDE-5 inhibitor) indicating that PDE 4 inhibition provides better anti-oxidant and anti-inflammatory effect. Roflumilast and cilostazol showed their effects by activating cAMP/PKA/CREB pathway. Zaprinast showed its neuroprotective effect through PI3K/AKT/BDNF pathway. As a result, in the future, these drugs could be examined further to determine clinical relevance and possible effective therapeutic efficacy in the treatment of HD. newline