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Int J Neuropsychopharmacol. 2012 Jul;15(6):749-66. doi: 10.1017/S1461145711000836. Epub 2011 Jun 9.

The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats.

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1
Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.

Abstract

β-amyloid (Aβ) peptides play an important role in cognition deficits, neuroinflammation, and apoptosis observed in Alzheimer's disease (AD). Activation of cyclic AMP (cAMP) signalling enhances memory and inhibits inflammatory and apoptotic responses. However, it is not known whether inhibition of phosphodiesterase-4 (PDE4), a critical controller of intracellular cAMP concentrations, affects AD-associated neuroinflammatory and apoptotic responses and whether these responses contribute to deficits of memory mediated by cAMP signalling. We addressed these issues using memory tests and neurochemical measures. Specifically, rats microinfused with aggregated Aβ25-35 (10 μg/side) into bilateral CA1 subregions displayed deficits in learning ability and memory, as evidenced by decreases in escape latency during acquisition trials and exploratory activities in the probe trial in the water-maze task and 24-h retention in the passive avoidance test. These effects were reversed by rolipram (0.1, 0.25 and 0.5 mg/kg.d i.p.), a prototypic PDE4 inhibitor, in a dose-dependent manner. Interestingly, Aβ25-35-treated rats also displayed decreases in expression of phosphorylated cAMP response-element binding protein (pCREB) and Bcl-2, but increases in expression of NF-κB p65 and Bax in the hippocampus; these effects were also reversed by rolipram in a dose-dependent manner. Similar neurochemical results were observed by replacing Aβ25-35 with Aβ1-42, a full-length amyloid peptide that quickly forms toxic oligomers. These results suggest that PDE4 inhibitors such as rolipram may reverse Aβ-induced memory deficits at least in part via the attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signalling. PDE4 could be a target for treatment of memory loss associated with AD.

PMID:
21733236
DOI:
10.1017/S1461145711000836
[Indexed for MEDLINE]
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