Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. (October 2020)

• Record Type: Journal Article
• Authors: Bhat, Abid; Ray, Bipul; Mahalakshmi, Arehally Marappa; Tuladhar, Sunanda; Nandakumar, DN; Srinivasan, Malathi; Essa, Musthafa Mohamed; Chidambaram, Saravana Babu; Guillemin, Gilles J.; Sakharkar, Meena Kishore
• Is Part Of: Pharmacological research. Volume 160(2020)
• Publication Date: 2020-10
• Subjects: AD alzheimer's disease -- AIDS acquired immunodeficiency syndrome -- AMP adenosine monophosphate -- AMPK 5′ AMP-activated protein kinase -- AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor -- APP amyloid precursor protein -- ATP adenosine triphosphate -- AB amyloid-β -- BDNF brain-derived neurotrophic factor -- CA1 cornu ammonis-1 -- cAMP cyclic adenosine monophosphate -- CAR conditioned avoidance response -- CBP CREB-binding protein -- cGMP cyclic guanosine monophosphate -- CNS central nervous system -- COPD chronic obstruction pulmonary disease -- CREB cAMP-response element binding protein -- DA dopamine -- DISC1 disrupted in schizophrenia 1 -- DNA Deoxyribonucleic acid -- EAE experimental autoimmune encephalomyelitis -- EGF epidermal growth factor -- ERK extracellular signal-regulated kinase -- fALS Familial Amyotrophic Lateral Sclerosis -- FDA Food and Drug Administration -- fMRI functional magnetic resonance imaging -- GABA gamma aminobutyric acid -- GBM glioblastoma -- GluR1 glutamate receptor1 -- H2O2 hydrogen peroxide -- HD huntington's disease -- Htt huntingtin -- IBs inclusion bodies -- IFN-γ interferon gamma -- IL-1 β Interleukin-1beta -- IL-12 interleukin-12 -- IL-23 interleukin-23 -- IL-6 interleukin-6 -- JNK c-Jun N-terminal kinase -- LPS lipopolysaccharides -- LTP long term plasticity -- MAPK mitogen-activated protein kinase -- MDM2 Mouse double minute 2 homolog -- MPP+ 1-methyl-4-phenylpyridinium -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- MS multiple sclerosis -- NA noradrenaline -- NFT neurofibrillary tangles -- Nf-Κb nuclear factor kappa-light-chain-enhancer of activated B cells -- NGF nerve growth factor -- NMDAR N-methyl-d-aspartate-type glutamate receptors -- NO nitric oxide -- NOS nitric oxide synthase -- NT-3 neurotrophin-3 -- NT-4 neurotrophin-4 -- PC12 pheochromocytoma cells -- PD parkinson's disease -- PDE phosphodiesterase -- PDE4 phosphodiesterase 4 -- PDE4I phosphodiesterase 4 inhibitor -- PKA protein kinase A -- PKG protein kinase G -- PSD-95 postsynaptic density protein 95 -- RSK2 ribosomal S6 kinase 2 -- SAH subarachnoid hemorrhage -- sALS sporadic amyotrophic lateral sclerosis -- sGC soluble guanylyl cyclase -- SH-SY5Y human neuroblastoma -- SNpc substantia nigra pars compacta -- SSRI selective serotonin reuptake inhibitor -- TBI traumatic brain injury -- TH tyrosine hydroxylase -- TNFα tumor necrosis factor alpha -- UCR upstream conserved region -- VD vascular dementia; Phosphodiesterase -- cAMP -- cGMP -- Neurological disorders -- PDE4 inhibitors -- Central nervous system; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105078
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.