Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014;17(3):362-70.
doi: 10.18433/j3s02v.

Effects of PDE4 pathway inhibition in rat experimental stroke

Fan Yang  1 , Rachita K Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, Mark Fisher
Affiliations

Effects of PDE4 pathway inhibition in rat experimental stroke

Fan Yang et al. J Pharm Pharm Sci. 2014.

Abstract

Purpose: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke.

Methods: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model.

Results: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control.

Conclusions: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Coronal sections of rat brain stained with TTC 24 hours following onset of focal cerebral ischemia using ligation model. A, B, C and D, E, F are sections from vehicle (n=18) and rolipram (n=15) treated animal, respectively. (G) Effects of rolipram treatment on infarct size using ligation model of focal cerebral ischemia. Values are means±SE; **p < 0.01.
Figure 2
Figure 2
Coronal sections of rat brain stained with TTC 24 hours following onset of embolic stroke. A, B and C, D are sections from vehicle (n=16) and rolipram (n=16) treated animal, respectively. (E) Effects of rolipram treatment on infarct size with embolic experimental stroke model. Values are means±SE; n=16*p < 0.05.
Figure 3
Figure 3
A. Measurement of PDE4D protein levels by Western blot of cerebral vascular preparation. PDE4D knockout rats (KO) showed no PDE4D expression compared to wild-type rats (WT). B. Infarct size of PDE4D knockout rat (n=6) compared to wild-type (n=6) control following embolic experimental stroke model. WT: wild-type rats; KO: homozygous knockout rats. Values are means±SE.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Della-Morte D, Guadagni F, Palmirotta R, Testa G, Caso V, Paciaroni M, Abete P, Rengo F, Ferroni P, Sacco RL, Rundek T. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments. Pharmacogenomics. 2012;13(5):595–613. - PubMed
    1. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjörnsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003;35(2):131–138. - PubMed
    1. Munshi A, Babu MS, Kaul S, Shafi G, Anila AN, Alladi S, Jyothy A. Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. J Neurol Sci. 2009;285:142–145. - PubMed
    1. Saleheen D, Bukhari S, Haider SR, Nazir A, Khanum S, Shafqat S, Anis MK, Frossard P. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke. 2005;36(10):2275–2277. - PubMed
    1. Liu X, Zhu R, Li L, Deng S, Li Q, He Z. Genetic Polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis. P. 2013 Jun 17;8(6):e66374. - PMC - PubMed

Publication types

MeSH terms

Substances