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Cordycepin, an adenosine analog, has been reported to improve cognitive function, but which seems to be inconsistent with the reports showing that cordycepin inhibited long-term potentiation (LTP). Behavioral-LTP is usually used to study long-term synaptic plasticity induced by learning tasks in freely moving animals. In order to investigate simultaneously the effects of cordycepin on LTP and behavior in rats, we applied the model of behavioral-LTP induced by Y-maze learning task through recording population spikes in hippocampal CA1 region. Golgi staining and Sholl analysis were employed to assess the morphological structure of dendrites in pyramidal cells of hippocampal CA1 area, and western blotting was used to examine the level of adenosine A1 receptors and A2A receptors (A2AR). We found that cordycepin significantly improved behavioral-LTP magnitude, accompanied by increases in the total length of dendrites, the number of intersections and spine density but did not affect Y-maze learning task. Furthermore, cordycepin obviously reduced A2AR level without altering adenosine A1 receptors level; and the agonist of A2AR (CGS 21680) rather than antagonist (SCH 58261) could reverse the potentiation of behavioral-LTP induced by cordycepin. These results suggested that cordycepin improved behavioral-LTP and morphological structure of dendrite in hippocampal CA1 but did not contribute to the improvement of learning and memory. And cordycepin improved behavioral-LTP may be through reducing the level of A2AR in hippocampus. Collectively, the effects of cordycepin on cognitive function and LTP were complex and involved multiple mechanisms.

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Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.

Background and aims: Cordycepin has been proved to have neuroprotection and to improve learning and memory in cerebral ischemia. However, the potential mechanisms are unclear so far. Plasticy of synaptic structure and synaptic function are considered as the neural mechanisms of learning and memory. Therefore, we investigated the effects of cordycepin on dendritic morphology and synaptic function in cerebral ischemic models. Experimental Approach: The impact of cordycepin was studied using oxygen glucose deprivation (OGD) and global cerebral ischemia (GCI) models. Synaptic transmission and behavioral long-term potentiation (LTP) were investigated with electrophysiological recordings. Dendritic morphology was assessed by Golgi staining. The densities of adenosine A1 and A2A receptors (A1R and A2AR) were evaluated with western blots and immunofluorescence. Key Results: Cordycepin alleviated the ischemia-induced damages of dendritic morphology and behavioral LTP in hippocampal CA1 area, improved the learning and memory abilities and up-regulated the expression of A1R but not A2AR in hippocampus of GCI rats. In the in vitro experiments, cordycepin pre-perfusion could reduce the hippocampal slices injury and synaptic transmission impairment induced by OGD, improved adenosine content and reduced the expression of A1R but did not alter A2AR. Furthermore, the protection of cordycepin on synaptic transmission against OGD was eliminated by using the antagonist of A1R instead of A2AR. Conclusion and Implications: These findings indicated that cordycepin alleviated synaptic dysfunction and dendritic injury in vivo and in vitro ischemic models by modulating A1R, which may be the neural mechanisms of cordycepin to improve learning and memory in cerebral ischemic animals.