Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential

Abstract

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the substantia nigra of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.

Keywords: Allosteric modulation; Neurodegeneration; PDE4; PDE4 inhibitors; Parkinson’s disease; cAMP.

Fig. 1

Different isoforms of PDE4; long, short, super-short, and dead-short in humans. ERK: Extracellular signal-regulated kinase, LR1 and 2: Linker regions 1 and 2, PKA: Protein kinase A, TD: Targeting domains, UCR1 and 2: Upstream conserved regions 1 and 2

Fig. 2

Ribbon presentation of the secondary structure of the catalytic unit of PDE4B2B (PDB ID, 1f0j) with residues 152–489. Cyan: 1st subdomain; magenta: 2nd subdomain, green: 3rd subdomain, dark grey: Zn, and yellow: Mg

Fig. 3

Ribbon presentation of the catalytic unit of monomeric PDE4D2 (PDB ID, 1q9m). Rolipram: blue sticks, divalent metals: red balls

Fig. 4

Signaling cascades (illustration of cAMP/CREB/BDNF, MAPKs, Epac/Akt, and NF-κB) involving PDE4 isoenzyme in PD and the potential of PDE4 inhibitors. AC: Adenyl cyclase, Akt: Protein kinase B, AMP: Adenosine monophosphate, ATP: Adenosine triphosphate, Bax: Bcl2 associated X, Bcl2: B-cell lymphoma 2, BDNF: Brain-derived neurotrophic factor, B-raf: Serine/threonine-protein kinase B-raf, cAMP: Cyclic adenosine monophosphate, CRE: cAMP response element, CREB: cAMP response element-binding protein, Epac: Exchange factor directly activated by cAMP, ERK 1/2: Extracellular signal-regulated kinase 1/2, GDNF: Glial cell-derived neurotrophic factor, GDP: Guanosine diphosphate, GPCR: G protein-coupled receptor, GSK-3: Glycogen synthase kinase 3, GTP: Guanosine triphosphate, IL: Interleukins, IFN-γ: Interferon gamma, JNK: c-Jun N-terminal kinase, MEK: Mitogen-activated protein kinase kinase, MMP: Mitochondrial membrane potential, NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells, P38MAPK: p38 mitogen-activated protein kinase, PDE4: Phosphodiesterase-4, PKA: Protein kinase A, PI3K: Phosphatidylinositol 3-kinase, Rap: Member of the Ras superfamily of GTP-binding protein, ROS: Reactive oxygen species

Fig. 5

Illustration of cAMP/AMPK/SIRT1 pathway and the potential of PDE4 inhibition in α-synuclein degradation. AMP: Adenosine monophosphate, AMPK: AMP-activated protein kinase, cAMP: Cyclic adenosine monophosphate, CTSD: Cathepsin D, LAMP1: Lysosomal-associated membrane protein 1, NADH: Nicotinamide adenine dinucleotide hydrogen, NAMPT: Niacinamide phosphoribosyltransferase, PDE4: Phosphodiesterase-4, PKA: Protein kinase A, SIRT1: Sirtuin1

Fig. 6

Illustration of signaling cascades involving PDE4 in DARPP-32 phosphorylation and the potential of PDE4 inhibitors. AC: Adenyl cyclase, AMP: Adenosine monophosphate, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, cAMP: Cyclic adenosine monophosphate, CDK5: Cyclin-dependent kinase 5, CK1 and 2: Casein Kinase 1 and 2, D1R and D2R: Dopamine receptor 1 and 2, DARPP-32: Dopamine and cAMP-regulated phosphoprotein 32 kDa, NMDA: N-methyl-D-aspartate receptor, PDE4: Phosphodiesterase-4, PKA: Protein kinase A, PP1/2A/2C: Protein phosphatase-1/2A/2C, SER97/130: Serine 97/130, Thr34/75: Threonine 34/75

Fig. 7

Illustration of activation of PKA/UPS and α-synuclein degradation by PDE4 inhibition. AMP: Adenosine monophosphate, cAMP: Cyclic adenosine monophosphate, E1/2/3: Ubiquitin-activating enzyme/ubiquitin-conjugating enzyme/ubiquitin ligase, PDE4: Phosphodiesterase-4, PKA: Protein kinase A, Rpn6/PSMD11: 26S proteasome non-ATPase regulatory subunit 11, 19S: regulatory unit of 26S proteasome, 20S: The catalytic core of 26S proteasome

Fig. 8

The chemical structures of PDE4 inhibitors investigated in PD. Rolipram is 4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one, Ro-201724 is 4-[(3-butoxy-4-methoxyphenyl)methyl]imidazolidin-2-one, XT-A is 1,3-dicyclopropylmethyl-8-aminoxanthine, SDZ MNS 949 is 1-[3,5-bis(2-methoxyethoxy)phenyl]-6,7-dimethoxy-3-methylisoquinoline, NQ-A is 1-(3-carbomethoxyphenyl)-3-benzyl-quinazoline-2,4-dione, resveratrol is 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol, ibudilast is 2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, FCPR16 is N-(2-Chlorophenyl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide, arylbenzylamine derivative 11r is N-(Pyridin-3-yl)-3-(3-fluorophenyl)-4-methoxybenzylamine, arylbenzylamine derivative 11 s is N-(Pyridin-3-yl)-3-(3-methoxyphenyl)-4-methoxybenzylamine, roflupram is 1-[4-(difluoromethoxy)-3-(oxolan-3-yloxy)phenyl]-3-methylbutan-1-one, and 4e derivative of α-mangostin is 7-((5-Hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-oxo-2H,6H-pyrano[3,2-b]xanthen-9-yl)oxy)heptanoic Acid