Related Industry Reports:
- World Neurodegenerative Diseases Market 2009-2024
- The World Alzheimer's Disease Market (Incidence, Treatments, Key Companies, Pipeline and Trends)
- UpdatesPlus Nicotinic Receptors - Current Research and Development - February 2009
- UpdatesPlus-Nicotinic Receptors (February 2008)
- Pipeline Report - Neuronal alpha 7 nicotinic receptors: Candidates for the treatment of Alzheimers disease and Schizophrenia
Inhibition of phosphodiesterase-4 reverses memory deficits produced by Abeta25-35 or Abeta1-40 peptide in rats.
Psychopharmacology 2010 Jul 17; In press
Cheng Y YF, Wang C, Lin H HB, Li Y YF, Huang Y, Xu J JP, Zhang H HT
Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
RATIONALE: Cyclic AMP signaling plays an important role in memory loss associated with Alzheimer's disease (AD). However, little is known about whether inhibition of phosphodiesterase-4 (PDE4), which increases intracellular cAMP, reverses beta-amyloid peptide (Abeta)-induced memory deficits. OBJECTIVE: Experiments were performed to demonstrate the effect of the PDE4 inhibitor rolipram on memory impairment produced by Abeta1-40 (Abeta40) or its core fragment Abeta25-35. METHODS: We tested memory using Morris water-maze and passive avoidance tasks and examined expression of phosphorylated cAMP response-element binding protein (pCREB) in the hippocampus in rats treated with Abeta25-35 or Abeta40 into bilateral CA1 subregions, with or without rolipram administration. RESULTS: Abeta25-35 (10 mug/side) increased escape latency during acquisition training and decreased swimming time and distance in the target quadrant in the water-maze probe trial; it also decreased 24-h retention in the passive avoidance paradigm. All these were reversed by chronic administration of rolipram (0.5 mg/kg). Similarly, Abeta40 (4 mug/side) produced memory impairment, as demonstrated by decreased retention in passive avoidance; this was also reversed by repeated treatment with rolipram. In addition, rolipram blocked extinction of memory during the 32-day testing period in the passive avoidance test. Further, Abeta40 decreased pCREB expression in the hippocampus, which was also reversed by rolipram; the changes in pCREB were highly correlated with those in memory. CONCLUSIONS: These results suggest that the PDE4 inhibitor rolipram reverses cognitive deficits associated with AD most likely via increased cAMP/CREB signaling in the hippocampus; PDE4 could be a target for drugs that improve cognition in AD.