Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats.Psychopharmacology (Berl). 2010 Oct; 212(2):181-91.P
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 β-amyloid peptide (Aβ)-induced memory deficits.
OBJECTIVE
Experiments were performed to demonstrate the effect of the PDE4 inhibitor rolipram on memory impairment produced by Aβ1-40 (Aβ40) or its core fragment Aβ25-35.
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 Aβ25-35 or Aβ40 into bilateral CA1 subregions, with or without rolipram administration.
RESULTS
Aβ25-35 (10 μg/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, Aβ40 (4 μg/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, Aβ40 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.
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