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  • Our results showed that oral administration of

    2023-09-15

    Our results showed that oral administration of cordycepin, in the concentrations of 5 and 10mg/kg for 3weeks, exerted no influence on body weight and hippocampus weight in mice. Although some reports have pointed out that cordycepin had toxic effects because it may be potential for inducing cell death and retarding cell growth [32], [33], cordycepin administrated orally as a pellet at daily dose of 20mg/kg for 4months could protect the liver, kidneys, heart and lungs of aged rats from oxidative stress [34]. This inconsistency may result from the different method of IL-18, human recombinant protein cordycepin application. Basically, cordycepin is deaminated quickly by adenosine deaminase and metabolized rapidly to an inactive metabolite, 3′-deoxyhypoxanthinosine, and the half-life of cordycepin is as brief as 1.6min with intravenous treatment [35] but can extend to 2.1h by oral administration [4]. To some extent, the metabolic IL-18, human recombinant protein of cordycepin is related with its method of administration; therefore, the elimination half-life cordycepin varies with different method of drug treatment [35]. In our experiments, cordycepin was dissolved in distilled water and administrated orally twice daily using a feeding needle. Overall, our results displayed that intragastric administration of cordycepin at twice daily dosage of 10mg/kg for 3weeks is safe and effective. Furthermore, cordycepin improved Y-maze learning and memory in both healthy and ischemic mice has been reported [5]. Similarly, our results further confirmed that cordycepin could improve short-term spatial memory. Adenosine, as an extracellular signaling molecule, is important for modulating physiological functions in the central nervous system. Extracellular adenosine usually originates from the extracellular metabolism of nucleotides and the release of cyclic AMP [36]. Under pathological states, extracellular adenosine is released via carrier-mediated mechanisms as a result of the hypoxia-induced massive breakdown of intracellular nucleotides; on the other hand, extracellular ATP is inactivated by a surface-located enzyme chain that results in the extracellular formation of adenosine [37]. Endogenous extracellular adenosine level was unstable in an activity-dependent manner and modulated synaptic transmission as well as short-term plasticity [38]. It is worthy to note that adenosine always regulates the release of various neurotransmitters as a neuromodulator through presynaptic mechanism, and then exerts different roles [7]. For instance, adenosine is able to modulate ACh release from nerve terminals, and then regulates learning and memory [39]. Therefore, we assume that the improvement of cordycepin (an adenosine analogue) on the short-term memory is possibly involved in modulating the release of neurotransmitters. Usually, adenosine acts on the four adenosine receptors: A1R, A2AR, A2BR and A3R. Following the higher density of A1R and A2AR in brain, the impact of adenosine on brain function might mainly be dependent on the actions of A1R and A2AR [39]. A2AR was shown to display a widespread distribution in brain and mostly located in synapses [40]. Presynaptic A2AR facilitated hippocampal synaptic transmission by promoting glutamate release, and showed a major role in shutting down the profound A1R-mediated synaptic transmission inhibition [41]. Postsynaptic A2AR could control NMDA receptors which plays a vital role in long-term potentiation [42]. Blockade of A2AR could attenuate long-term potentiation at excitatory synapses, as reported in the hippocampus, accumbens, striatum, amygdala [43], [44]. Furthermore, A2AR doesn't affect memory performance but A2AR blockade prevents memory deterioration in early AD, diabetic encephalopathy, childhood epilepsy, cerebrospinal ataxia, early stress and aggregated α-synuclein PD model [45], [46], [47], [48]. But the overexpression, as well as the over-activation of A2AR in naïve animals is sufficient to trigger memory deficits [49]. Initial studies characterizing A2AR in the hippocampus showed that the density of A2AR is circa 15–20 times lower than that of A1R [50]. And later studies with antibodies carefully validated in knockout mice pointed out the inability to detect A2AR in the hippocampus using immunohistochemical approaches while EM is only allowed visualizing A2AR in the hippocampal sections [51]. However, a presence of low level A2AR immunoreactivity that we observed is supported by a variety of studies. For example, binding sites for A2AR (~25% of striatal levels) and mRNA for the receptor were found in CA1, CA3, and DG; remaining discrepancies may be due to limits of detectability and persistent and inherent difficulty in measuring G-protein coupled receptors whose level of expression is quite low [52]. In our study, we found that cordycepin significantly lowered the density of A2AR in the hippocampus subareas, suggesting that cordycepin-related improvement of short-term spatial memory may involve in the decrease of A2AR density.