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Phosphodiseterases(PDEs),a superfamily of 11 enzymes(PDE1-11) that hydrolyze cyclic nucleotides(cAMP and cGMP),mediate a variety of peripheral and central functions.PDE inhibitors can be used for treatment of various diseases,including peripheral diseases such as chronic obstructive pulmonary disease(COPD),sexual dysfunction,and heart failures,and CNS disorders such as Alzheimer′s disease,depression,schizophrenia,anxiety,alcoholism,Parkinson′s disease,Huntington’s disease,and stroke.While to date there have been no PDE inhibitors approved for clinic utility for CNS disorders,significant progresses have been made in preclinical and clinical studies in this area.More specifically,we have found that inhibition of PDE4,which specifically catalyzes the hydrolysis of cAMP,reversed memory deficits produced by hippocampal infusions of β amyloid peptide 1-42(Aβ1-42).Consistent with this,the PDE4 inhibitor rolipram also attenuated Aβ42-induced inflammatory responses,apoptosis,and deficit in cAMP/CREB signaling in the hippocampus.In addition,using mice deficient in a specific PDE4 subtype(PDE4A,4B,or 4D),we identified that PDE4A and PDE4D may be the major subtypes in these processes.We also demonstrated that PDE4 might be a novel target for treatment of alcoholism.Rolipram selectively reduced ethanol preference in mice and rats,which drink excessive ethanol.This appears to be contributed by PDE4B,which is enriched in the striatum and nucleus accumbens,the brain regions mediating alcohol dependence and abuse,although the role of PDE4A cannot be excluded.PDE10 may also be involved in ethanol drinking behavior.Finally,studies to date have demonstrated that disruption of PDE1 or PDE10 could be beneficial for cognitive dysfunction in schizophrenia.Taken together,increasing demonstrations suggest that PDEs,in particular PDE1,PDE4,and PDE10,are important targets for treatment of CNS disorders,including Alzheimer′s disease,depression,schizophrenia,and alcoholism.
Phosphodiseterases (PDEs), a superfamily of 11 enzymes (PDE1-11) that hydrolyze cyclic nucleotides (cAMP and cGMP), mediate a variety of peripheral and central functions. PDE inhibitors can be used for treatment of various diseases, including peripheral diseases such as chronic obstructive pulmonary disease (COPD), sexual dysfunction, and heart failures, and CNS disorders such as Alzheimer’s disease, depression, schizophrenia, anxiety, alcoholism, Parkinson’s disease, Huntington’s disease, and stroke. Whilst to date there have been no PDE inhibitors approved for clinic utility for CNS disorders, significant progresses have been made in preclinical and clinical studies in this area. More specifically, we have found that inhibition of PDE4, which specifically catalyzes the hydrolysis of cAMP, reversed symptoms produced by hippocampal infusions of β amyloid peptide 1-42 (Aβ 1-42). Consistent with this, the PDE4 inhibitor rolipram also attenuated Aβ42-induced inflammatory responses, apoptosis, and deficit in cAMP / CREB signaling in the hippocampus.In addition, using mice deficient in a specific PDE4 subtype (PDE4A, 4B, or 4D), we identified that PDE4A and PDE4D may be the major subtypes in these processes. which a enriched in the striatum and nucleus accumbens, the brain are mediating alcohol dependence and abuse , although the role of PDE4A can not be excluded. PDN10 may also be involved in ethanol drinking behavior. F inally, studies to date have already demonstrated that disruption of PDE1 or PDE10 could be beneficial for cognitive dysfunction in schizophrenia. Taken together, increasing demonstrations suggest that PDEs , in particular PDE1, PDE4, and PDE10, are important targets for treatment of CNS disorders, including Alzheimer’s disease, depression, schizophrenia, and alcoholism.