Cordycepin improved the cognitive function through regulating adenosine A2A receptors in MPTP induced Parkinson's disease mice model.

BACKGROUND: Parkinson's disease (PD), the most common neurodegenerative disorder, primarily affects dopaminergic neurons in the substantia nigra (SN). In addition to severe motor dysfunction, PD patients appear apparent cognitive impairments in the late stage. Cognitive dysfunction is accompanied by synaptic transmission damage in the hippocampus. Cordycepin has been reported to alleviate cognitive impairments in neurodegenerative diseases. PURPOSE: The study aimed to estimate the protection roles of cordycepin on cognitive dysfunction in PD model and explore the potential mechanisms. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish the PD model in vivo and in vitro experiments. In the in vivo experiments, the C57BL / 6 mice were intraperitoneally injected with MPTP and intragastric administration with cordycepin. Open field test (OFT) was used to estimate the exercise ability. Spontaneous alternation behavioral (SAB) and morris water maze (MWM) tests were used to evaluate the learning and memory abilities. The hippocampal slices from C57BL / 6 and Kunming mice in the in vitro experiments were used to record field excitatory postsynaptic potential (fEPSP) by electrophysiological methods. Western blotting was used to examine the level of tyrosine hydroxylase (TH) in the in vivo experiments and the levels of adenosine A1 and A2A receptors (A1R and A2AR) in the in vitro experiments, respectively. The drugs of MPTP, cordycepin, DPCPX and SCH58261 were perfused through dissolving in artificial cerebrospinal fluid. RESULTS: Cordycepin could significantly reduce the impairments on motor, exploration, spatial learning and memory induce by MPTP. MPTP reduced the amplitude of LTP in hippocampal CA1 area but cordycepin could improve LTP amplitudes. Cordycepin at dosage of 20 mg/kg also increased the TH level in SN. In the in vitro experiments, MPTP inhibited synaptic transmission in hippocampal Schaffer-CA1 pathway with a dose-dependent relationship, while cordycepin could reverse the inhibition of synaptic transmission. Furthermore, the roles of cordycepin on synaptic transmission could been attenuated in the presence of the antagonists of A1R and A2AR, DPCPX and SCH58261, respectively. Interestingly, the level of A2AR rather than A1R in hippocampus was significantly decreased in the cordycepin group as compared to the control. CONCLUSION: The present study has showed that cordycepin could improve cognitive function in the PD model induced by MPTP through regulating the adenosine A2A receptors. These findings were helpful to provide a new strategy for the dementia caused by Parkinson's disease.

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 improves behavioral-LTP and dendritic structure in hippocampal CA1 area of rats.

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.

Neuroprotection of cordycepin in NMDA-induced excitotoxicity by modulating adenosine A1 receptors.

Cerebral ischemia impairs physiological form of synaptic plasticity such as long-term potentiation (LTP). Clinical symptoms of cognitive dysfunction resulting from cerebral ischemia are associated with neuron loss and synaptic function impairment in hippocampus. It has been widely reported that cordycepin displays neuroprotective effect on ameliorating cognitive dysfunction induced by cerebral ischemia. Therefore, it is necessary to study whether cordycepin recovers cognitive function after brain ischemia through improving LTP induction. However, there has been very little discussion about the effects of cordycepin on LTP of cerebral ischemia so far. In the present study, we investigated the effects of cordycepin on LTP impairment and neuron loss induced by cerebral ischemia and excitotoxicity, using electrophysiological recording and Nissl staining techniques. The models were obtained by bilateral common carotid artery occlusion (BCCAO) and intrahippocampal NMDA microinjection. We also explored whether adenosine A1 receptors involve in the neuroprotection of cordycepin by using western blot. We found that cordycepin remarkably alleviated LTP impairment and protected pyramidal cell of hippocampal CA1 region against cerebral ischemia and excitotoxicity. Meanwhile, cordycepin prevented the reduction on adenosine A1 receptor level caused by ischemia but did not alter the adenosine A2A receptor level in hippocampal CA1 area. The improvement of LTP in the excitotoxic rats after cordycepin treatment could be blocked by DPCPX, a selective antagonist of adenosine A1 receptor. In summary, our findings provided new insights into the mechanisms of cordycepin neuroprotection in excitotoxic diseases, which is through regulating adenosine A1 receptor to improve LTP formation and neuronal survival.