Accumulating evidences have shown that inhibition of PDE4 is beneficial for the functional recovery after cerebral ischemia; i. subtype D of PDE4 (PDE4D) is viewed as a risk factor for ischemic stroke; ii. inhibition of PDE4 enhances neurological behaviors, such as learning and memory, after stroke in rodents; iii.PDE4 inhibition increases dendritic density, synaptic plasticity and neurogenesis; iv. activation of cAMP/CREB signaling by PDE4 inhibition causes an endogenous increase of BDNF, which is a potent modulator of neuroplasticity; v. PDE4 inhibition is believed to restrict neuroinflammation during ischemic stroke.
Combined linkage/association studies have demonstrated that genes encoding phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) confer risk for stroke.
Multivariate regression analysis showed that SNP87 of PDE4D gene was associated with increased risk of unfavorable outcome after total ischemic stroke (OR = 1.47, 95%CI 1.12-1.93), as well as stroke due to large-artery atherosclerosis (OR = 1.49, 95%CI 1.04-2.11) and small-artery occlusion (OR = 1.76, 95%CI 1.05-2.96) under a recessive model.
Previous studies identified that phosphodiesterase 4D (<i>PDE4D</i>) gene polymorphism might be associated with cerebral infarction or ischemic stroke, and hemorrhagic stroke in human populations.
Studies have also noticeably highlighted that PDE4D gene/pathway can be a suitable drug target for managing stroke; however, a more comprehensive research is still required to understand the molecular and cellular intricacies this gene plays in stroke development, progression and its outcome.
Studies from the different ethnic regions of world have reported variable results on association of Apolioprotein E (APOE), Methylenetetrahydrofolate reductase (MTHFR), Endothelial Nitric Oxide Synthase (ENOS), Factor V Leiden (F5), Cytochrome P450 4F2 (CYP4F2), beta-fibrinogen and Phosphodiesterase 4D (PDE4D) gene in stroke.
The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population.
We selected and genotyped a PDE4D single nucleotide polymorphism (SNP 41, rs152312) as a candidate marker for susceptibility to ischemic stroke because SNP 41 has shown the most significant association with stroke in both a meta-analysis and the original Icelandic study of the PDE4D gene.
In conclusion, the -889 C/T and SNP83 T/C SNPs of the IL-1alpha and PDE4D genes, respectively, appear to be genetic risk factors for stroke in our study population.
It is speculated that over-expression of Pde4d and Alox5ap can motivate onset of hypertensive cerebral stroke by participating in inflammation of arterial walls.
In the present paper, we review both current issues and progress in the isolation of susceptibility genes for ischemic stroke, with particular emphasis on the PDE4D gene in the STRK1 region of 5q12.
The previously established association of a PDE4D gene haplotype with ischaemic stroke in a population from Iceland was independently confirmed in our Greek population, suggesting that PDE4D may be involved in the aetiology and pathogenesis of stroke.