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Int J Biol Sci 2018; 14(12):1745-1754. doi:10.7150/ijbs.26230


Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke

Haitao Wang1, Uma Gaur2, Jiao Xiao1, Bingtian Xu1, Jiangping Xu1✉, Wenhua Zheng2✉

1. Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
2. Faculty of Health Sciences, University of Macau, Taipa, Macau, China.


Sensorimotor recovery following ischemic stroke is highly related with structural modification and functional reorganization of residual brain tissues. Manipulations, such as treatment with small molecules, have been shown to enhance the synaptic plasticity and contribute to the recovery. Activation of the cAMP/CREB pathway is one of the pivotal approaches stimulating neuroplasticity. Phosphodiesterase 4 (PDE4) is a major enzyme controlling the hydrolysis of cAMP in the brain. Accumulating evidences have shown that inhibition of PDE4 is beneficial for the functional recovery after cerebral ischemia; i. subtype D of PDE4 (PDE4D) is viewed as a risk factor for ischemic stroke; ii. inhibition of PDE4 enhances neurological behaviors, such as learning and memory, after stroke in rodents; iii.PDE4 inhibition increases dendritic density, synaptic plasticity and neurogenesis; iv. activation of cAMP/CREB signaling by PDE4 inhibition causes an endogenous increase of BDNF, which is a potent modulator of neuroplasticity; v. PDE4 inhibition is believed to restrict neuroinflammation during ischemic stroke. Cumulatively, these findings provide a link between PDE4 inhibition and neuroplasticity after cerebral ischemia. Here, we summarized the possible roles of PDE4 inhibition in the recovery of cerebral stroke with an emphasis on neuroplasticity. We also made some recommendations for future research.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
How to cite this article:
Wang H, Gaur U, Xiao J, Xu B, Xu J, Zheng W. Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke. Int J Biol Sci 2018; 14(12):1745-1754. doi:10.7150/ijbs.26230. Available from