The metaplastic effects of cordycepin in hippocampal CA1 area of rats.

Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS. Furthermore, we found that 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptors antagonist, could block the roles of cordycepin on LTD and LTP. Collectively, cordycepin was able to modulate metaplasticity in hippocampal CA1 area of rats through adenosine A1 receptors. These findings would be helpful to reconcile the conflicting reports in the literatures and provided new insights into the mechanisms underlying cognitive function promotions with cordycepin treatment.

Cordycepin Ameliorates Synaptic Dysfunction and Dendrite Morphology Damage of Hippocampal CA1 via A1R in Cerebral Ischemia.

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.

Cordycepin decreases activity of hippocampal CA1 pyramidal neuron through membrane hyperpolarization.

Cordycepin (3'-deoxyadenosine) is the main functional component of Cordycepins militaris, a renowned traditional Chinese medicine, which has been shown to possess anti-tumor, anti-inflammatory, anti-diabetic and neuro-protective effects. However, the effect of cordycepin on the central nervous system (CNS) remains unclear. In this study, the effects of cordycepin on neuronal activity were investigated on the CA1 pyramidal neurons in rat hippocampal brain slices using a whole-cell patch clamp technique. Our results revealed that cordycepin significantly decreased the frequency of both the spontaneous and evoked action potential (AP) firing. While AP spike width, the amplitude of fast after hyperpolarization (fAHP), and membrane input resistance were not altered by cordycepin, the neuronal membrane potential was hyperpolarized by cordycepin. Collectively, these results demonstrate that cordycepin reduces neuronal activity by inducing membrane hyperpolarization, indicating that cordycepin may be a potential therapeutic strategy for ischemic and other excitotoxic disorders.