3’-Deoxyadenosine (Cordycepin) Produces a Rapid and Robust Antidepressant Effect via Enhancing Prefrontal AMPA Receptor Signaling Pathway

Abstract

Background:The development of rapid and safe antidepressants for the treatment of major depression is in urgent demand. Converging evidence suggests that glutamatergic signaling seems to play important roles in the pathophysiology of depression.Methods:We studied the antidepressant effects of 3’-deoxyadenosine (3’-dA, Cordycepin) and the critical role of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in male CD-1 mice via behavioral and biochemical experiments. After 3’-dA treatment, the phosphorylation and synaptic localization of the AMPA receptors GluR1 and GluR2 were determined in the prefrontal cortex (PFC) and hippocampus (HIP). The traditional antidepressant imipramine was applied as a positive control.Results:We found that an injection of 3’-dA led to a rapid and robust antidepressant effect, which was significantly faster and stronger than imipramine, after 45min in tail suspension and forced swim tests. This antidepressant effect remained after 5 days of treatment with 3’-dA. Unlike the psycho-stimulants, 3’-dA did not show a hyperactive effect in the open field test. After 45min or 5 days of treatment, 3’-dA enhanced GluR1 S845 phosphorylation in both the PFC and HIP. In addition, after 45min of treatment, 3’-dA significantly up-regulated GluR1 S845 phosphorylation and GluR1, but not GluR2 levels, at the synapses in the PFC. After 5 days of treatment, 3’-dA significantly enhanced GluR1 S845 phosphorylation and GluR1, but not GluR2, at the synapses in the PFC and HIP. Moreover, the AMPA-specific antagonist GYKI 52466 was able to block the rapid antidepressant effects of 3’-dA.Conclusion:This study identified 3’-dA as a novel rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the prefrontal AMPA receptor signaling pathway.

A Systematic Review of the Biological Effects of Cordycepin

“…We found 10 papers indicating that cordycepin can have protective effects on the brain in various models of brain dysfunction. For instance, it reduces the effects of chronic unpredictable mild stress in animal models and improves depression-like behaviour [ 119 , 232 ]. Some studies have also shown that cordycepin ameliorates learning and memory deficits in ischemic animal models [ 233 , 234 , 235 , 236 ] and sleep disturbances [ 237 ].…”

Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling

“…Lentinan is a polysaccharide isolated from the fruit body of Shiitake , and recently it has been reported that the antidepressant-like effects of lentinan were due to the enhanced prefrontal cortical expression of phosphorylation of AMPA GluR1 S845 and dendritic cell-associated C-type lectin-1 (Dectin-1), which is an immune regulator and receptor for lentinan [ 104 ]. 3’-Deoxyadenosine (3’-dA, Cordycepin), one of the major bioactive metabolites in the Cordyceps militaris , was identified to produce the rapid antidepressant effects by enhancing GluR1 S845 phosphorylation in the prefrontal cortex and hippocampus, and cordycepin modulates GluR1 synaptic localization in a subtype-specific and brain region-specific manner [ 105 ].…”

Integrating Interleukin-6 into depression diagnosis and treatment

“…Treatment with the antidepressant imipramine blocked social avoidance behavior and reduced microglia IL-6 in animals exposed to stress or those given a systemic injection of LPS (Ramirez et al., 2015). Increased IL-6 protein was reported in the hippocampus of rats that underwent chronic unpredictable stress (Tianzhu et al., 2014) and was attenuated by chronic treatment with the antidepressant fluoxetine or treatment with an alternative medicine Cordycepin, a derivative of adenosine extracted from fungi shown to have antidepressant efficacy (Li et al., 2015). Within the prefrontal cortex, increased levels of IL-6 protein were reported in rats exposed to uncontrollable shock that demonstrated LH behavior, but not in animals that were resilient to the same stressor (Sukoff Rizzo et al., 2012).…”