Abstract
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.
Highlights
Cerebral ischemia is a condition of significant mortality and morbidity that arises from a sudden loss of blood flow and a consequent failure to meet the demands of the brain for oxygen and glucose, which leads to functional and structural damages in different brain regions (Liang et al, 2015), such as the learning and memory impairments in the hippocampus (Gondard et al, 2019; Yao et al, 2019)
In the current study, we explore whether cordycepin ameliorates cognitive impairments induced by cerebral ischemia via reducing synaptic dysfunction and dendrite morphology damage and whether adenosine A1 receptors or A2A receptors are involved in the process
In the in vitro experiments, we focused on the protective effect of cordycepin on oxygen-glucose deprivation (OGD) by using mice brain slices
Summary
Cerebral ischemia is a condition of significant mortality and morbidity that arises from a sudden loss of blood flow and a consequent failure to meet the demands of the brain for oxygen and glucose, which leads to functional and structural damages in different brain regions (Liang et al, 2015), such as the learning and memory impairments in the hippocampus (Gondard et al, 2019; Yao et al, 2019). Learning and memory impairments caused by cerebral ischemia were often closely related to the damages of synaptic transmission (Neumann et al, 2013) and dendritic morphological structure (Rojas et al, 2013; Zhu et al, 2017). Previous studies have reported that cognitive impairments after cerebral ischemia could be alleviated by improving synaptic plasticity (Li et al, 2017; Yu et al, 2018). In the current study, we explore whether cordycepin ameliorates cognitive impairments induced by cerebral ischemia via reducing synaptic dysfunction and dendrite morphology damage and whether adenosine A1 receptors or A2A receptors are involved in the process
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