TY - JOUR
T1 - Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders
AU - Bhat, Abid
AU - Ray, Bipul
AU - Mahalakshmi, Arehally Marappa
AU - Tuladhar, Sunanda
AU - Nandakumar, D. N.
AU - Srinivasan, Malathi
AU - Essa, Musthafa Mohamed
AU - Chidambaram, Saravana Babu
AU - Guillemin, Gilles J.
AU - Sakharkar, Meena Kishore
N1 - Funding Information:
Mr Abid Bhat acknowledges the Indian Council of Medical Research , Govt of India, New Delhi, for financial assistance as Senior Research Fellowship. PProf Guillemin is supported by the National Health and Medical Research Council, Australian Research Council and Macquarie University, Sydney, Australia. Dr. Essa MM highly acknowledge the support from Sultan Qaboos University, Oman (IG/AGR/FOOD/17/02).This manuscript is professionally edited by Red Fern Communication, Australia.
Copyright © 2020 Elsevier Ltd. All rights reserved.
PY - 2020/1
Y1 - 2020/1
N2 - Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases−chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.
AB - Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases−chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.
KW - Central nervous system
KW - Neurological disorders
KW - PDE4 inhibitors
KW - Phosphodiesterase
KW - cAMP
KW - cGMP
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UR - https://www.mendeley.com/catalogue/1b3d9b83-f2b2-3f42-8372-bba55325002d/
U2 - 10.1016/j.phrs.2020.105078
DO - 10.1016/j.phrs.2020.105078
M3 - Article
C2 - 32673703
AN - SCOPUS:85088392483
SN - 1043-6618
VL - 160
SP - 105078
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 105078
ER -
