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

Abstract

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 A_2A receptors (A₁R and A_2AR) 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 A_2AR, DPCPX and SCH58261, respectively. Interestingly, the level of A_2AR 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 A_2A receptors. These findings were helpful to provide a new strategy for the dementia caused by Parkinson's disease.

Keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenosine A(2A) receptors; Cognitive impairments; Cordycepin; Parkinson's disease.