2. Academic Validation
  3. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

  • Pharmacol Res. 2020 Oct;160:105078. doi: 10.1016/j.phrs.2020.105078.
Abid Bhat 1,  Bipul Ray 1,  Arehally Marappa Mahalakshmi 1,  Sunanda Tuladhar 1,  D N Nandakumar 2,  Malathi Srinivasan 3,  Musthafa Mohamed Essa 4,  Saravana Babu Chidambaram 5,  Gilles J Guillemin 6,  Meena Kishore Sakharkar 7
Affiliations

Affiliations

  • 1 Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India.
  • 2 Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India.
  • 3 Department of Lipid Science, CSIR - Central Food Technological Research Institute (CFTRI), CFTRI Campus, Mysuru, 570020, India.
  • 4 Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman; Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman. Electronic address: [email protected].
  • 5 Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India. Electronic address: [email protected].
  • 6 Neuroinflammation group, Faculty of Medicine and Health Sciences, Macquarie University, NSW, 2109, Australia. Electronic address: [email protected].
  • 7 College of Pharmacy and Nutrition, University of Saskatchewan, 107, Wiggins Road, Saskatoon, SK, S7N 5C9, Canada.
PMID: 32673703 DOI: 10.1016/j.phrs.2020.105078
Abstract

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.

Keywords

Central nervous system; Neurological disorders; PDE4 inhibitors; Phosphodiesterase; cAMP; cGMP.

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