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Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats

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Abstract

Inhibition of phosphodiesterase-4 (PDE4) by rolipram, a prototypical PDE4 inhibitor, reverses memory impairment produced pharmacologically or genetically. Comparably, much less is known about the effect of rolipram on cerebral ischemia-induced memory deficits. The objective of this study was to determine the effects of rolipram on ischemia-induced memory deficit, neuronal damage, and alteration of PDE4 activity in the hippocampus. Memory was examined using Morris water-maze and step-through passive avoidance tests in rats subjected to global cerebral ischemia with or without repeated treatment with rolipram (0.3 or 1 mg/kg, i.p.); neuronal damage in the hippocampus and PDE4 activity in hippocampal tissues were determined using Nissl staining and HPLC, respectively. In the water-maze test, cerebral ischemia significantly increased the escape latency to reach the platform during acquisition training and decreased the exploration time in the target quadrant in the probe trial test; these were blocked by rolipram in a dose-dependent manner. Rolipram also reduced the distracted platform searches induced by cerebral ischemia. In the passive avoidance test, ischemia decreased the 24-h latency to the dark compartment, which was also blocked by rolipram treatment. In addition, Nissl staining revealed ischemia-induced neuron loss in hippocampal CA1; this was blocked by rolipram. Further, cerebral ischemia led to increases in activity of PDE, primarily PDE4, in the hippocampus, which also was antagonized by rolipram. These results suggest that rolipram prevents cerebral ischemia-induced memory deficits via inhibition of increased PDE4 activity and attenuation of hippocampal, neuronal damages induced by ischemia. PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia.

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Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (No. 30672453 to JPX), the Guangdong Natural Science Foundation, China (No. 7117782 to JPX), and US National Institute of Aging (AG031687 to HTZ).

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The authors do not have financial interests to disclose.

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Authors and Affiliations

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

    Ling-Xia Li, Yu-Fang Cheng, Huan-Bing Lin, Chuang Wang & Jiang-Ping Xu

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

    Chuang Wang & Han-Ting Zhang

  3. Department of Physiology & Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, 26506-9137, USA

    Chuang Wang & Han-Ting Zhang

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  1. Ling-Xia Li
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Correspondence to Jiang-Ping Xu or Han-Ting Zhang.

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Li, LX., Cheng, YF., Lin, HB. et al. Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. Metab Brain Dis 26, 37–47 (2011). https://doi.org/10.1007/s11011-011-9235-0

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