title: Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system.
abstract: Phosphodiesterase-4 (PDE-4) inhibitors promote memory by blocking the degradation of cAMP. Existing evidence also shows that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response element-binding protein. In this regard, PDE-4 inhibitors have also been shown to reverse pharmacologically and genetically induced memory impairment in animal models. In the present study, the authors examined the effect of both rolipram and roflumilast (PDE-4 inhibitors) on the impairment of learning and memory observed in hypertensive rats. Deoxycorticosterone acetate (DOCA) salt hypertensive model was used to induce learning and memory deficits. The mRNA expression of different PDE-4 subtypes along with the protein levels of pCREB and BDNF in the hippocampus was quantified. Systolic blood pressure was significantly increased in DOCA salt hypertensive rats when compared to sham operated rats. This effect was reversed by clonidine, an α2 receptor agonist, while PDE-4 inhibitors did not. PDE-4 inhibitors significantly improved the time-induced memory deficits in object recognition task (ORT). In DOCA salt hypertensive rats, the gene expression of PDE-4B and PDE-4D was significantly increased. Furthermore, both pCREB and BDNF showed decreased levels of expression in hypertensive rats in comparison to sham operated rats. Repeated administration of PDE-4 inhibitors significantly decreased both PDE-4B and PDE-4D with an increase in the expression of pCREB and BDNF in hypersensitive rats. Also, rolipram, roflumilast and roflumilast N-oxide showed a linear increase in the plasma and brain concentrations after ORT. Our present findings suggested that PDE-4 inhibitors ameliorate hypertension-induced learning impairment via cAMP/CREB signaling that regulates BDNF expression downstream in the rat hippocampus.
authors.affiliation: Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India.
authors.forename: S Sugin Lal
authors.initials: SS
authors.lastname: Jabaris
authors.affiliation: Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India.
authors.forename: Haridass
authors.initials: H
authors.lastname: Sumathy
authors.affiliation: Department of Nephrology, Sri Ramachandra University, Chennai 600116, Tamil Nadu, India; Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Girish
authors.affiliation: Foundation for Neglected Disease Research, Sri Krishnadevaraya Research Centre, Bangalore 562 157, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India.
authors.forename: Mani
authors.initials: M
authors.lastname: Sugumar
authors.affiliation: Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India. Electronic address: ceftpublications@gmail.com.
authors.forename: Chidambaram
authors.initials: C
authors.lastname: Saravana Babu
authors.affiliation: Centre for Toxicology and Developmental Research (CEFT), Sri Ramachandra University (SRU), Chennai 600116, Tamil Nadu, India.
authors.forename: Sadagopan
authors.initials: S
authors.lastname: Thanikachalam
authors.affiliation: Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Thanikachalam
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003521:Cyclopropanes / Q000494:pharmacology; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000631:Aminopyridines; D000959:Antihypertensive Agents; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D003521:Cyclopropanes; D018697:Nootropic Agents; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D064791:Desoxycorticosterone Acetate; D000242:Cyclic AMP; C517734:roflumilast N-oxide; D020889:Rolipram; D003000:Clonidine
keywords: BDNF; Cognition; Hypertension; Roflumilast; Rolipram; pCREB