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Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25–35 or Aβ1–40 peptide in rats

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Abstract

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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Acknowledgements

This work was supported by research grants from National Institute of Aging (AG031687; to H.T.Z.), NARSAD Young Investigator Awards (2006, 2008; to H.T.Z.), the National Natural Science Foundation of China (No. 30672453 and No. 30973518; to J.P.X.), and Guangdong Natural Science Foundation, China (No. 7117782; to J.P.X.).

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  1. Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China

    Yu-Fang Cheng, Chuang Wang, Huan-Bing Lin, Jiang-Ping Xu & Han-Ting Zhang

  2. Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, 26506-9137, USA

    Yu-Fang Cheng, Chuang Wang, Yun-Feng Li, Ying Huang & Han-Ting Zhang

  3. Beijing Institute of Pharmacology and Toxicology, Beijing, China

    Yun-Feng Li

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  1. Yu-Fang Cheng
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Correspondence to Jiang-Ping Xu or Han-Ting Zhang.

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Yu-Fang Cheng and Chuang Wang contributed equally to this work.

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Cheng, YF., Wang, C., Lin, HB. et al. Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25–35 or Aβ1–40 peptide in rats. Psychopharmacology 212, 181–191 (2010). https://doi.org/10.1007/s00213-010-1943-3

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