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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

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.

Authors+Show Affiliations

Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20640406

Citation

Cheng, Yu-Fang, et al. "Inhibition of Phosphodiesterase-4 Reverses Memory Deficits Produced By Aβ25-35 or Aβ1-40 Peptide in Rats." Psychopharmacology, vol. 212, no. 2, 2010, pp. 181-91.
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 (Berl). 2010;212(2):181-91.
Cheng, Y. F., Wang, C., Lin, H. B., Li, Y. F., Huang, Y., Xu, J. P., & Zhang, H. T. (2010). Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats. Psychopharmacology, 212(2), 181-91. https://doi.org/10.1007/s00213-010-1943-3
Cheng YF, et al. Inhibition of Phosphodiesterase-4 Reverses Memory Deficits Produced By Aβ25-35 or Aβ1-40 Peptide in Rats. Psychopharmacology (Berl). 2010;212(2):181-91. PubMed PMID: 20640406.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats. AU - Cheng,Yu-Fang, AU - Wang,Chuang, AU - Lin,Huan-Bing, AU - Li,Yun-Feng, AU - Huang,Ying, AU - Xu,Jiang-Ping, AU - Zhang,Han-Ting, Y1 - 2010/07/17/ PY - 2010/05/27/received PY - 2010/06/25/accepted PY - 2010/7/20/entrez PY - 2010/7/20/pubmed PY - 2010/12/21/medline SP - 181 EP - 91 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 212 IS - 2 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/20640406/Inhibition_of_phosphodiesterase_4_reverses_memory_deficits_produced_by_Aβ25_35_or_Aβ1_40_peptide_in_rats_ DB - PRIME DP - Unbound Medicine ER -