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Class of chemical compounds From Wikipedia, the free encyclopedia
A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.[1]
The prototypical PDE4 inhibitor is rolipram. PDE4 inhibitors are known to possess procognitive (including long term memory-improving),[2] wakefulness-promoting,[3] neuroprotective,[4][5] and anti-inflammatory effects.[6] Consequently, PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), anxiety disorders, schizophrenia,[7][8] Parkinson's disease,[9] Alzheimer's disease,[10] multiple sclerosis,[11] attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.[12][13][14]
PDE4D inhibition, along with PDE4A inhibition also appears to be responsible for the antidepressant effects of PDE4 inhibitors.[14] Similarly PDE4B inhibition appears to be required for the antipsychotic effects of PDE4 inhibitors,[13] in line with this view PDE4B polymorphisms and altered gene expression in the central nervous system have been associated with schizophrenia and bipolar disorder in a postmortem study.[15] PDE4 also regulates the D1/PKA/DARPP-32 signalling cascade in the frontal cortex, which may contribute to the antipsychotic and procognitive effects of PDE4 inhibitors.[16] Whereas PDE4C is expressed primarily in the periphery and hence may be partly responsible for the peripheral effects of PDE4 inhibitors (e.g. their anti-inflammatory effects).[14] PDE4 inhibition is also known to attenuate ethanol seeking and consumption in rats,[17] hence suggesting its possible utility in the treatment of alcohol dependence. Indeed, one experiment has found that intake of a PDE4 oral medication for psoriasis has significantly reduced alcohol consumption in serious human drinkers compared with those taking the placebo.[18] A few different lines of evidence suggests the therapeutic utility in the treatment of brain tumours.[19]
The clinical development of PDE4 inhibitors has been hampered by their potent emetic effects, which appear to be related to their inhibition of PDE4D which is expressed in the area postrema.[14]
Nausea, vomiting, and related general gastrointestinal side effects are the most commonly implicated side effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections, which have been discovered from the clinical use of roflumilast.[20]
PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.[citation needed]
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