Background: Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by substantial loss of neurons in the substantia nigra pars compacta and depletion of dopamine. Cognitive impairment is one of the primary non-motor symptoms in PD patients. It has been reported that cordycepin (Cor) can alleviate cognitive impairment in neurodegenerative diseases, but it is susceptible to degradation by adenosine deaminase (ADA). This study aims to synthesize Cordycepin-Nano-Particles (CNP) which has resistance to ADA enzyme degradation, and investigate the effects of CNP on PD hippocampal slice models. Methods: Cor was chemically coupled with mPEG and mPEG-biotin to prepare CNP. CNP were determined using infrared spectroscopy, particle size measurement, and transmission electron microscopy. Extracellular electrophysiological recordings were used to record the field excitatory postsynaptic potential (fEPSP) in Schaffer-CA1 pathway of hippocampal slices in mice. An in vitro PD brain slice model was established with 1-methyl-4-phenylpyridinium (MPP+). Results: The proposed CNP was a spherical surface morphology, with an average particle size of about 220 nm. CNP resist the ADA enzyme degradation, exhibit higher viability in HT22 cells compared to Cor, and significantly alleviate cell damage induced by MPP+. CNP enhanced synaptic transmission in the Schaffer-CA1 pathway of hippocampal slices through A2AR pathway, reduced the excitability and tissue activity induced by 40 μM MPP+. Conclusion: CNP was successfully prepared with higher safety compared to Cor, and can protect Cor from ADA degradation. CNP primarily enhances synaptic transmission in mouse hippocampal slices through the adenosine A2AR pathway and reduces the excitability induced by MPP+.

Background and Aims: Cerebral ischemia always led to learning and memory impairments. Cordycepin has been proved to improve cognition but the potential mechanisms are unclear so far. Plasticity 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 ischemia and explored the relevant molecular mechanisms. Experimental Approach: The impact of cordycepin was studied using global cerebral ischemia (GCI) and oxygen glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were investigated with electrophysiological recordings. Dendritic morphology and histological assessment were assessed by Golgi staining and HE staining, respectively. And the densities of adenosine receptors and adenosine content were evaluated with western blotting and HPLC, respectively. Key Results: Cordycepin alleviated the GCI-induced damages of dendritic morphology and behavioral LTP in hippocampal CA1, and improved the learning and memory abilities and up-regulated the expression of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could reduce the hippocampal slices injury and synaptic transmission impairment induced by OGD, accompanied with the increase of adenosine content. 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 ischemia by modulating A1R, which provide conclusive evidence that cordycepin could be used as potential drug for the treatment of cognitive impairment induced by cerebral ischemia