Cordycepin

Molecular mechanisms of cordycepin emphasizing its potential against neuroinflammation: An update
Anusha Govindula , Anuja Pai , Saahil Baghel , Jayesh Mudgal *
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India

A R T I C L E I N F O

Keywords: Neuroinflammation Cordycepin
CNS disorders Cordyceps militaris
Neuroinflammatory targets
A B S T R A C T

Recent research emphasizes the central role of neuroinflammation in complex neurological disorders such as Alzheimer’s disease, Parkinson’s disease, depression, multiple sclerosis, and traumatic brain injury. Multiple pathological variables with identical molecular mechanisms have been implicated in the development of CNS inflammatory diseases. Therefore, one of the most crucial tasks in the management of CNS disorders is the alleviation of neuroinflammation. However, there are many drawbacks of new pharmacological drugs used in the management of CNS disorders, including medication side effects, and treatment complications. There is a growing inclination towards bioactive constituents of natural origin to unearth the potential remedies. Cordy- cepin, an adenosine analogue, is one such bioactive constituent with multiple actions, viz., anticancer, anti- inflammatory, hepato-protective, antidepressant, anti-Alzheimer’s, anti-Parkinsonian and immunomodulatory effects, along with the promotion of remyelination. This review highlights the converging neuroinflammatory targets of cordycepin in Alzheimer’s disease, Parkinson’s disease, and depression, to substantiate its anti- neuroinflammatory property. Cordycepin acts by downregulation of adenosine A2 receptor, inhibition of microglial activation, and subsequent inhibition of several neuroinflammatory markers (NF-κB, NLRP3 inflam- masome, IL-1β, iNOS, COX-2, TNF-α, and HMGB1). Cordycepin mitigates LPS-mediated toll-like receptor acti- vation by activating adenosine receptor A1, thereby improving antioxidant enzymes (superoxide dismutase, glutathione peroxidase) levels. These pieces of evidence point to the probable anti-neuroinflammatory mecha- nisms of cordycepin, which could facilitate the development of new remedies against neuroinflammation- associated CNS disorders.

1.Neuroinflammation
Neuroinflammation is the dynamic inherent immune response of neural tissue, to prevent infection and generally remove bacteria, cell waste, and misfolded proteins from the brain and spinal cord. It is an integral part of the innate immunity of the central nervous system (CNS) and involves neural tissue fixation and resolution. However, in chronic neurological disorders, neuroinflammation turns both recurrent and harmful to neuronal cells, resulting in the secretion of chemokines, proinflammatory cytokines, and reactive oxygen species (ROS) (Welcome, 2020; Yang and Zhou, 2019). A pro-inflammatory and pro-oxidizing climate, maintained by repeated activation of microglia progresses towards neurodegenerative conditions.
Microglial cells of the nervous system are native macrophages of mesenchymal origin. In the context of neurodegenerative disorders, they are hypothesized to demonstrate functional plasticity (Shippy and

Ulland, 2020). However, in response to adverse stimuli in the CNS, such as injury or dysregulation, microglial cells in association with astrocytes and neurons contribute to neurodegeneration, synapse phagocytosis, reduced synaptic activity, and the release of inflammatory cytokines.
At the molecular level, a few pathways are responsible for facilitating neuroinflammation. For example, NF-κB pathway activation leads to the activation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), cJun N terminal kinase (JNK), and p38, all of which cause oxidative stress and promote a pro-inflammatory milieu (Picca et al., 2020; Ramesh, 2014). Activation of neuronal NF-κB normally stimulates cell durability and may mediate activation, replication, and inflammation of glial cells. NF-κB sequestering is ach- ieved when the PI3K-Akt-mTOR pathway is stimulated with the release of the inhibitor of nuclear factor kappa B (IκB). This leads to the expression of NF-κB proinflammatory target genes to trigger the in- flammatory cascade. Proinflammatory cytokines can, in turn, induce

* Corresponding author.
E-mail addresses: [email protected], [email protected] (J. Mudgal). https://doi.org/10.1016/j.ejphar.2021.174364
Received 15 February 2021; Received in revised form 8 July 2021; Accepted 19 July 2021 Available online 21 July 2021
0014-2999/© 2021 Elsevier B.V. All rights reserved.

inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) expression, further contributing to the ROS-mediated persistent oxida- tive stress. Continuous cytokine production induces neurotoxicity and hampers neuronal activity (Jung et al., 2019).
Further, inflammasomes are crucial constituents of the innate im- mune system. They are a complex of macromolecular proteins assem- bling the germline-encoded pattern recognition receptor (PRR) within the cytosol. They are released when astrocytes or microglia sense pathogen-associated molecular patterns (PAMPs) and damage- associated molecular patterns (DAMPs). Over-activated inflammasome NOD-like receptor pyrin domain 3 (NLRP3) has been extensively recognized and investigated in neurodegenerative diseases as a marker of worsening of pathology (Wu et al., 2020).

2.Plausible mechanisms of anti-neuroinflammatory effects of cordycepin
Cordycepin is an adenosine analogue (3′ -deoxyadenosine), detected from the fermented broth of Cordyceps militaris, a medicinal mushroom. This agent has demonstrated a wide variety of biological roles, with massive implications in many therapeutic areas (Yang et al., 2020). By inhibiting mRNA polyadenylation and controlling several targets involved in multiple cell processes, it interferes with many pathological processes. Primarily, it has been demonstrated to provide defense against ageing, suppress fatigue, and exert anti-cancer, anti-in- flammatory, antioxidant, antipathogenic, antihyperlipidemic, anti- hepatotoxic, antifibrotic, and neuroprotective actions (Qin et al., 2019).
Cordyceps is one of the safest medicinal fungi, with various positive pharmacological effects (Elkhateeb et al., 2019). Some studies have been conducted on its adverse gastrointestinal effects, such as dry mouth, nausea, and diarrhoea (Zhu et al., 1998). When administered alone at 8 mg/kg/day to beagle dogs, there were no drug-related clinical signs of toxicity. However, lethality was noted with doses of 10 and 20 mg/kg/day when combined with deoxycoformycin (adenosine deami- nase inhibitor) (Rodman et al., 1997). Cordyceps dosages of up to 80 g/kg body weight/day were injected intraperitoneally in mice for 7 days and did not result in mortality. In another study, rabbits fed with cor- dyceps orally for three months at a dosage of 10 g/kg/day showed no abnormalities in blood, renal and liver function. In general, researchers found that 3–4.5 g of cordyceps per day is acceptable, except in patients with severe liver disease (Tuli et al., 2014).

2.1.Protective effect of cordycepin in Alzheimer’s disease
Alzheimer’s disease (AD) primarily characterized by the reduction in memory and learning capability. Recent studies have reported that age- mediated inflammation leads to the progression of age-related disorders (Rea et al., 2018). Patients of AD have been found to possess high levels of serum amyloid A (SAA), a liver protein. SAA incites the development of cytokines (such as TNFα and IL-1β), in response to tissue damage. Emerging studies also propose that microglial NLRP3 inflammasome development, activated by disease markers such as brain β-amyloid plaques and neurofibrillary tangles (tau phosphorylation), and tangen- tial factors such as SAA, propel the pathogenesis and progression of AD. Therefore, the NLRP3 inflammasome appears to be a promising new therapeutic target in AD (Milner et al., 2021). Growing information has advocated the importance of receptors for advanced glycation end products (RAGE) in the pathogenesis of AD. This is exemplified by the overexpression of RAGE ligands in the brain of AD patients. In specific, High Mobility Group Box Protein 1 (HMGB1) and S100 calcium-binding protein B (S100B) have been linked with Aβ plaques and the formation of advanced glycation end products (AGEs) in the brain of AD patients (Bortolotto and Grilli, 2016). The involvement of Aβ-TLR4-NLRP3-IL-1β signaling has been linked with AD neuroinflammation. It is evident from in vitro and in vivo experiments when BV2 cells and rat astrocytes were incubated with synthetic Aβ1-42 soluble oligomers, provoked the toll-like
receptor 4 (TLR4) reaction which sensitized over time, resulting in increased IL-1β development (Liu et al., 2020; Murphy et al., 2014). In the CNS, TLR4 primes the NLRP3 inflammasome as Aβ forms aggregate, and in microglia, a noxious circuit of Aβ/TLR4/NLRP3/IL-1β encourages AD neuroinflammation (Yang et al., 2020). Soluble Aβ aggregates also caused long-term potentiation (LTP) deficiency and neuronal death due to TLR4 signaling via autocrine/paracrine mechanisms. This evidence indicates that a crucial pathophysiological pathway for AD could be the inflammatory TLR4-mediated reaction (Hughes et al., 2020). Low pathological concentrations of Aβ oligomers could also induce impaired LTP via the RAGE-mediated MAPK p38/CREB pathway activation (Origlia et al., 2008). Adenosine A2A receptors are also found strongly associated with AD pathology and are upregulated in various tauo- pathies in neurons, revealing that neurodegeneration is accelerated by these upregulated neuronal receptors (Carvalho et al., 2019; Gonçalves et al., 2019). Glial cells are subject to concern because of their impact on the pathophysiology of AD. Initially, by inducing phagocytosis and clearance, they cause a decline in Aβ aggregation. However, chronic microglial activity results in the release of proinflammatory cytokines (Thawkar and Kaur, 2019).
Cordycepin inhibits iNOS, Akt, MAPKs, NF-κB, COX-2, and the proinflammatory expression of cytokines in microglia, indicating its usefulness in the treatment of neurodegenerative disorders like AD (Jeong et al., 2010). It had been reported that cordycepin attenuated lipopolysaccharide (LPS)-induced microglial over-activation by reducing the release of TNFα, IL-1β, downregulated iNOS, and COX-2 mRNA levels and reversed LPS-induced activation of NF-κB in BV2 microglial cell line (Fig. 1). The reduced neuronal growth in primary hippocampal neurons cultivated in LPS-conditioned media was restored by cordycepin, along with enhanced cell viability, growth cone expan- sion, neurite sprouting, and spinogenesis (Peng et al., 2015). These outcomes concluded that cordycepin could have neuroprotective action.
CD11b is a known marker of activated microglia in immunocyto- chemical analysis. In rats, CD11b is most frequently observed using the monoclonal antibody OX-42 in microglia (Korzhevskii and Kirik, 2016). It is active in various interactions with cells linked to adhesion such as monocytes, macrophages, natural killer (NK) cells, and granulocytes. In a recent report, cordycepin was demonstrated to inhibit microglial activation manifested by a reduction in the number of microglia expressing OX-42 (Fig. 2). The neuroprotective effect of cordycepin delayed the deprivation of neurons in the CA1 region of the hippo- campus and improved cognitive function (Kim et al., 2019).
Extreme neuronal membrane depolarization and neuronal hyperac- tivity are the dominant causes of neuronal excitotoxicity and death. By inhibiting oxidative stress and pathological calcium-dependent cyto- toxicity, cordycepin offers significant neuroprotection against Aβ25–35–induced neurotoxicity in the hippocampal neurons. Besides, cordycepin inhibits the overstimulated AChE activity and phosphory- lated tau protein (p-tau) expression caused by Aβ25-35. The adenosine A1 receptor antagonist 8-cyclopentyl 1,3-dipropylxanthine (DPCPX) hin- ders the cytoprotective effect of cordycepin. This suggests that cordy- cepin could elicit neuroprotective action on hippocampal neurons from Aβ25–35–induced impairment, partly through activation of adenosine A1 receptor (Song et al., 2018). The neuroprotective activity of cordycepin against amyloid β- and ibotenic acid (IBO)-induced insult is selectively exerted through A1 receptor activation. Thereby it enhances neuronal electrophysiological activity, delays depolarization of the neuronal membrane, and enhances neuronal hyperactivity (Fig. 2). Pretreatment with A1 receptor-antagonist DPCPX completely inhibits cordycepin’s delayed action on Aβ + IBO-induced rapid neuronal membrane and neuronal hyperactivity. Interestingly, this activity is not observed with the A2 receptor antagonist, caffeine (Yao et al., 2019). Collectively, these findings demonstrate that cordycepin can be a possible curative agent for neuronal diseases such as AD.

Fig. 1. Schematic representation of underlying neuroinflammatory mecha- nisms and the targets pertinent to cor- dycepin.
Abbreviations: COR: cordycepin; LPS: lipopolysaccharide; MyD88: myeloid differentiation primary response pro- tein; IRAK-4: interleukin 1 receptor associated protein kinase-4; IRAK-1: interleukin receptor associated protein kinase-1; TRAF-6: tumor necrosis factor receptor associated factor-6; NEMO: nuclear factor kappa-B essential modu- lator; IKKγ: inhibitor of nuclear factor kappa B kinase gamma; IKKα: inhibitor of nuclear factor kappa B kinase alpha; IKKβ: inhibitor of nuclear factor kappa B kinase beta; IKBα: nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha; NF-κB: nuclear factor kappa light chain enhancer of activated B cells; PI3K:
phosphoionositide-3-kinase; PIP3: phosphotidylionositol-3,4,5- trisphosphate; AKT: protein kinase B; MEK-1: mitogen activated protein ki-
nase kinase; ERK1/2: extracellular signal regulated kinase; AP-1: activator protein-1; JAK: janus kinase; P: phos- phorylation; STAT-1: signal transducer and activator of transcription-1; MMP: mitochondrial membrane potential; mt- ROS: mitochondrial reactive oxygen species; mt-DNA: mitochondrial DNA;
HMGB1: high mobility group box protein-1; RAGE: receptor for advanced glycation end products; NLRP3: nod-like receptor pyrin domain containing protein 3; ASC: apoptosis associated speck like protein containing a caspase recruitment domain; CARD: caspase activation and recruitment domain; GASD: gasdermin.

Fig. 2. Schematic representation of adeno- sine receptor signalling mechanism of cor- dycepin; Abbreviations: A2R: adenosine 2 receptor; A1R: adenosine 1 receptor; Gαs: stimulatory G-protein α subunit; Gαi; inhib- itory G-protein α subunit; βγ: beta-gamma complex of G-protein; AC: adenylyl cyclase; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; PKA: protein ki- nase A; CREB: cAMP-response element- binding protein; P: phosphorylation; NT: neurotransmitter; ROS: reactive oxygen species; CDD11b: microglial marker.

2.2.Implications of cordycepin in Parkinson’s disease
Parkinson’s disease (PD) is a chronic and progressive neurodegen- erative disease distinguished by extreme dopaminergic neuronal loss in
the substantia nigra and eventual dopamine depletion in the striatum, contributing to motor disability. Positron emission tomography (PET) imaging studies along with other pieces of evidence have revealed that the pathogenesis of PD is linked to chronic low-grade inflammation

(Cerami et al., 2017; Hirsch et al., 2012; Khan et al., 2013). The presence of activated microglial cells near the selectively dying dopaminergic neurons in the nigrostriatal pathway of PD patients has highlighted the importance of inflammation and microgliosis in PD pathogenesis. Also, glial stimulation enhances the expression of proinflammatory cytokines such as TNFα and IL-1β in cerebrospinal fluid and substantia nigra of PD patients, corroborating the linkage of inflammation to PD pathogenesis. In exchange, proinflammatory cytokines stimulate the expression of other inflammatory mediators, such as NF-κB and COX-2, which may promote direct or indirect neurodegeneration (Chauhan et al., 2018; Choi et al., 2009; Teismann and Schulz, 2004). In the LPS-induced neuroinflammation and 6- hydroxy dopamine (6-OHDA) induced PD paradigm, it was confirmed that the NLRP3-caspase1-IL-1β axis belongs to a feedback loop in the pathogenesis of PD. Widespread regulation over the whole network can be accomplished by controlling main con- nections in this pathway, such that a novel target for the treatment of PD can be identified (Mao et al., 2017). Interestingly, dopamine had been shown to negatively regulate NLRP3 inflammasome activation by uplifting cyclic AMP (cAMP)-mediated ubiquitination and NLRP3 degradation in primary mouse bone marrow-derived macrophages and astrocytes (Swanton et al., 2018; Yan et al., 2015).
The co-administration of A2A receptor antagonists with L-DOPA is the primary method used in clinical trials to reduce the dose and lower the side effects of the latter (Armentero et al., 2011; Sachdeva and Gupta, 2013). Under oxidative stress conditions in PD, astrocytes un- dergo morphologic changes that release DAMPs such as S100B, heat shock proteins, and HMGB1. Hence it was reported that astrocyte secreted HMGB1 may be a major mediator that supports the neuro- degeneration in PD (Kim et al., 2019). Among other aspects, the signaling cascade of MAPKs is reported to mediate the decline in neuronal activity in PD. Studies focusing on the MAPK pathway need to be improved as this can delay neuronal degeneration in patients with PD and improve therapeutic outcomes (Bohush et al., 2018; Gil-martinez et al., 2020). Overall, abnormal neuroinflammation and oxidative stress play a crucial role in dopaminergic neuron destruction.
In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced PD model in rats, cordycepin strengthened motor neurons and alleviated response to inflammation and oxidative stress both in vivo and in vitro, by blocking the TLR-NF-κB pathway (Cheng and Zhu, 2019). Cordycepin inhibits caspase-3, cellular malondialdehyde, and intracel- lular ROS. In 6-OHDA-treated PC12 cells, cordycepin also greatly improved antioxidant enzymes superoxide dismutase and glutathione peroxidase activity. These findings indicate that cordycepin defends PC12 cells by its powerful antioxidant activity against 6-OHDA-induced neurotoxicity (Olatunji et al., 2016). Cordycepin also blocks the cascade of TLR4, NF-κB and NLRP3 inflammasome activation, which may be an important approach to prevent pyroptosis and eventual neuro- degeneration in PD. These results offer innovative insight into the neuroprotective effects of cordycepin, as a potential candidate for the prevention and management of PD (Sun et al., 2020).

2.3.Implications of cordycepin in depression
Depression is a multifactorial disease with persistent fatigue, grief, sleeplessness, and anhedonia. It is assumed to be a consequence of immunological, metabolic, and neurotransmitter dysregulation (Berton and Nestler, 2006; Dowlati et al., 2010; Yang et al., 2020).
Reports show that microglial activation and deviant neuroplasticity in depression may have certain common cellular and molecular path- ways (Guo et al., 2020). Microglial activation and neuronal damage have been demonstrated in bipolar disorder, as well (Haarman et al., 2016). In stress-induced depression models, multiple damage-associated molecular patterns, including S100 proteins, HMGB1, heat shock pro- teins, ATP, and uric acid, have been demonstrated to cause depression-like behaviour. Microglial HMGB1 interacts with RAGE, increasing the susceptibility to depressive-like behaviour after chronic
stress exposure (Franklin et al., 2018a). HMGB1 signaling is essential to amplify the expression of NLRP3 inflammasome and proinflammatory cytokines for stress-induced microglia sensitization. HMGB1-induced inflammation contributes to neurotransmitter deficiency and affects dopaminergic circuitry, providing neurobiological foundations for reduced motivation in depression (Franklin et al., 2018b; Weber et al., 2015; Zhang et al., 2019). Numerous animal and human trials have demonstrated that the NLRP3 inflammasome is stimulated in the event of stress, resulting in the activation of the hypothalamus-pituitary-adrenal axis to release glucocorticoids, gener- ating or exacerbating the stress response (Alcocer-G´omez et al., 2014; Kaufmann et al., 2017). In the chronic unpredictable mild stress (CUMS) paradigm of depression in rats, activation of the NF-κB/NLRP3 axis was found to cause major hippocampal neuronal injury, heightened inflammation, and oxidative stress. This further skewed M1 microglial polarization and resulted in IL-1β-mediated CNS inflammation, indi- cating that these markers of neuroinflammation could be clinical targets for the management and cure of depression (Guo et al., 2020; Pan et al., 2014). The inflammatory response has also been found to play a crucial aspect in the pathogenesis of depression (Leonard and Maes, 2012; Maes, 2011). Of significance, in the serum of animals subjected to chronic stress paradigms and depressed behaviour, an increase in TNFα, IL-1β, IL-6, and caspase 1 was identified (Zhao et al., 2019).
Adenosine receptors are targets in many neurodegenerative disor- ders including depression (Merighi et al., 2018). Overexpression of A2A receptors in the forebrain neurons of transgenic rats is consistent with enhanced depressive-like behaviour. Stimulation of A1 receptors elicit- ing pronounced antidepressant effects has been seen in transgenic mice where A1 receptors can be turned on and off. Therefore, A1 receptor activation and A2A receptor inhibition can be said to induce antide- pressant effects (Coelho et al., 2014; Szopa et al., 2019; van Calker et al., 2019).
Chronic treatment with cordycepin for 6 weeks reversed CUMS exposure-induced behavioural deficiency and stabilized the levels of TNFα, IL-6, 5-HT, and NE, indicating its ability to partly reverse CUMS- induced 5-HT2A receptor upregulation and inflammation (Tianzhu et al., 2014). Clinical research had demonstrated that in patients with depression, the expression of AMPA receptors especially GluR1 (one of its four subunits), is reduced in the brain (Beneyto et al., 2007) The ability of AMPA receptor currents may be associated with phosphory- lation of GluR1 (Wang et al., 2005). In both the prefrontal cortex and hippocampus, cordycepin strengthened GluR1 S845 phosphorylation after 5 days of treatment in male CD-1 mice suggesting its antidepressant activity (Li et al., 2016). Cordycepin also improved CUMS-induced depressive-like symptoms, which may be related to its controlling the expressions of hippocampal 5-HT2A receptors and BDNF proteins (Tianzhu et al., 2014). A randomized double-blinded placebo-controlled prospective trial had shown that cordycepin has specific antidepressant benefits, but there is no evidence about its use in the treatment of depressive sleep disorder (Chen et al., 2018).

2.4.Other facets of cordycepin
The inflammasome is a multiprotein cluster expressed in myeloid cells that are involved in the intrinsic immune response to both exoge- nous and endogenous signals. Activation of caspase 1, along with the nucleotide-binding and oligomerization domain (NOD)-like receptor and the apoptosis-associated speck-like protein (ASC), stimulates the maturation of IL-1β and IL-18 (Zhang et al., 2016). NLRP3 inflamma- some receptor family is recognized as a core neuroinflammatory agent and is a central contributor to the release of proinflammatory cytokines and the inflammatory response (Xiao et al., 2020). ROS, K+ efflux, and Ca2+ signaling have been proposed in the activation of NLRP3 (He et al., 2016). By modifying immune response or manipulating the quality of intestinal homeostasis, NLRP3 plays an eminent role in various inflam- matory diseases. Cordycepin inhibits NLRP3 inflammasome activation

by interfering with inflammatory complex assembly, phosphorylation inhibition of ERK1/2, and also COX-2-mediated inflammation in LPS-stimulated macrophages. This indicates that cordycepin may miti- gate inflammatory tissue damage by inhibiting NLRP3 inflammatory activation (Yang et al., 2017).
Neuroinflammation is alleged to contribute greatly to intracerebral haemorrhage (ICH)-mediated brain injury. Cordycepin has demon- strated to downregulate the expression of NLRP3 inflammasome com- ponents and reduce the release of IL-1β and IL-18 inflammasome substrates. Besides, cordycepin has also been shown to improve neuronal cell loss in the perihematomal regions and a substantial decrease in the expression of HMGB1 protein levels after ICH (Cheng et al., 2017).
In the cuprizone-induced mouse demyelination model (linked to inflammation), cordycepin has been shown to enhance remyelination at many levels. It improves motor dysfunction, promotes myelination of corpus callosum, stimulates myelin basic protein (MBP) expression, re- duces glial cell counts, induces inflammatory cytokine (IL-1β, IL-6), upregulates anti-inflammatory cytokines (IL-4) production, and expression of neurotrophic factor (Jia et al., 2019). These mechanisms indicate that by suppressing neuroinflammation, cordycepin can be a beneficial therapeutic agent for diseases linked to demyelination.
A major cytoplasmic transcription factor, the signal transducer and activator of transcription protein (STAT) play a crucial role in the transduction of cytokine signals. It has been identified as a key indicator for M1 or M2 macrophage polarization (Ju et al., 2013; Liang et al., 2016). While the STAT family includes STAT1-STAT6, it is STAT1 activation that facilitates the advancement of the inflammatory reaction by causing the expression of IL-1β and TNFα-coding genes (Wager et al., 2015; Xiao et al., 2020). Cordycepin blocked STAT1 activity in the complete Freund’s adjuvant (CFA)-induced inflammatory model in mice and was demonstrated to resist proinflammatory chemokine IP-10 and Mig sequences in IFN-γ-induced activated macrophages, leading to a decrease in inflammatory cell infiltration (Yang et al., 2020).
Cordycepin elicits anti-inflammatory action by blocking the gene expression of iNOS and COX-2 and proinflammatory mediators like ni- tric oxide (NO) and prostaglandin E2 by (PGE2) downregulating the corresponding mRNA transcription. It also blocks binding of LPS to TLR4 thereby attenuates translocation of NF-κB such that production of proinflammatory cytokines (TNFα and IL-1β), phosphorylation of MAPK, and expression of myeloid differentiation factor 88 (MyD88) was suppressed in RAW 264.7 murine macrophage cell lines (Choi et al., 2014).
As an intracellular second messenger, cAMP is accountable for multiple cell signalling cascades, including inflammatory response. It is produced by the metabolism of ATP via adenylyl cyclase (AC). The extract of Cordyceps militaris stimulated chloride secretion across human bronchial surface epithelia via both Ca+2 and cAMP/PKA-dependent pathways, leading to activation of apical Cl- and K+ channels in 16HBE14o-human bronchial epithelial cell line. Therefore, this study mechanistically validates the traditional use of this herbal medicine in respiratory diseases (Fung et al., 2011). Cordycepin inhibits ACTH secretion and lowers adenylyl cyclase activity in isolated rat pituitary cells. These results suggest that, while cAMP could be involved in CRF-stimulated ACTH secretion, it is more likely to act as a potentiator than a mandatory intermediate (W.J. Brattin and Ronald Portanova, 1978). Cordycepin interferes with the metabolism of adenosine and prevents the synthesis of NO in LPS-stimulated RAW 264.7 cells. Hence adenylate cyclase may also be a target for cordycepin, helps to prevent the production of cAMP and thereby counteract inflammatory signalling (Imamura et al., 2015).
Adenosine receptors have recently emerged as an appealing thera- peutic target for modulating neuroinflammation through activation of A1 and inhibition of A2A receptors, respectively. Overexpression of A2A receptors facilitates microglial activation as a result of brain injury (Martí Navia et al., 2020). Cordycepin lowered the density of A2A
receptors in the hippocampal subareas and promoted cognition in Kunming mice (Cao et al., 2018). Such observations indicate that cor- dycepin could be a cynosure in neuroinflammatory conditions.
It is suspected that LTP, an essential form of synaptic plasticity, un- derlies learning and memory. In synaptic plasticity, A2 receptors are important for mediating the activation of LTP in the hippocampus. In the hippocampal CA1 region, cordycepin enhanced the behavioral-LTP and increased the overall length, number of junctions, and spine density of basal dendrites. These findings demonstrated that cordycepin adminis- tration might promote neuroprotection through A2 receptors through morphological alterations in dendrites of pyramidal neurons (Han et al., 2019). Cordycepin greatly alleviated LTP deficiency and shielded the pyramidal cells of the hippocampal CA1 region from cerebral ischemia and excitotoxicity, as well as NMDA currents (Dong et al., 2019). This indicates that modulation of both A1 and A2 receptors was essential for the neuroprotective effect of cordycepin. These results further confirm that cordycepin can be a promising compound to promote cognitive function in cerebral ischemia and glutamate-associated excitotoxicity.

3.Conclusion
Inflammatory phenomena in various CNS disorders have been identified and are being explored as major components of neurological pathophysiology. Neuroprotective strategies against neuroinflammation are therefore essential and can potentially mitigate brain injuries and their complications. Although a vast number of neuroprotective agents have been explored, there remains a lack of targeted and effective treatment choices. Preliminary findings suggest cordycepin has an important role in modulating multiple targets in inhibiting the molec- ular pathways implicated in CNS disorders through different experi- mental designs. Investigation of the mechanisms mainly projects the protective effect of cordycepin against neuroinflammation (Figs. 1 and 2). However, additional research is essential to unravel the specific pharmacodynamic effects of cordycepin on different systems while testing against CNS-related diseases. We believe that these findings offer guidance that can drive both fundamental and clinical research.

Funding None.
CRediT authorship contribution statement

Anusha Govindula: Writing – original draft, Writing – review &
editing. Anuja Pai: Writing – original draft, Writing – review & editing. Saahil Baghel: Writing – original draft, Writing – review & editing. Jayesh Mudgal: Conceptualization, Supervision, Writing – review &
editing.

Declaration of competing interest
The authors declare no conflict of interest. Acknowledgements
The authors wish to acknowledge the infrastructural support pro- vided by the Department of Pharmacology, Manipal College of Phar- maceutical Sciences, and Manipal Academy of Higher Education, Manipal-576104, India. The authors also would like to thank the All India Council for Technical Education (AICTE), New Delhi, India for appointing AG under Quality Improvement Programme (QIP) scheme.

References

Alcocer-G´omez, E., de Miguel, M., Casas-Barquero, N., Nú˜nez-Vasco, J., S´anchez- Alcazar, J.A., Fern´andez-Rodríguez, A., Cordero, M.D., 2014. NLRP3 inflammasome

is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun. 36, 111–117. https://doi.org/10.1016/j.bbi.2013.10.017.
Armentero, M.T., Pinna, A., Ferr´e, S., Lanciego, J.L., Müller, C.E., Franco, R., 2011. Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol. Ther. 132, 280–299. https://doi.org/10.1016/j. pharmthera.2011.07.004.
Beneyto, M., Kristiansen, L.V., Oni-Orisan, A., McCullumsmith, R.E., Meador- Woodruff, J.H., 2007. Abnormal glutamate receptor expression in the medial
temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32, 1888–1902. https://doi.org/10.1038/sj.npp.1301312.
Berton, O., Nestler, E.J., 2006. New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7, 137–151. https://doi.org/10.1038/nrn1846.
Bohush, A., Niewiadomska, G., Filipek, A., 2018. Role of mitogen activated protein kinase signaling in Parkinson’s disease. https://doi.org/10.3390/ijms19102973.
Bortolotto, V., Grilli, M., 2016. Every cloud has a silver lining: proneurogenic effects of Aβ oligomers and HMGB-1 via activation of the RAGE-NF-κB Axis. CNS Neurol. Disord. – Drug Targets 16, 1066–1079. https://doi.org/10.2174/
1871527315666160803153459.
Brattin, W.J., Portanova, Ronald, 1978. Effect of cordycepin on CRH stimulation and steroid inhibition of ACTH secretion by rat pituitary cells. Mol. Cell. Endocrinol. 9, 279–289.
Cao, Z.P., Dai, D., Wei, P.J., Han, Y.Y., Guan, Y.Q., Li, H.H., Liu, W.X., Xiao, P., Li, C.H., 2018. Effects of cordycepin on spontaneous alternation behavior and adenosine receptors expression in hippocampus. Physiol. Behav. 184, 135–142. https://doi. org/10.1016/j.physbeh.2017.11.026.
Carvalho, K., Faivre, E., Pietrowski, M.J., Marques, X., Gomez-Murcia, V., Deleau, A., Huin, V., Hansen, J.N., Kozlov, S., Danis, C., Temido-Ferreira, M., Coelho, J.E., M´eriaux, C., Eddarkaoui, S., Le Gras, S., Dumoulin, M., Cellai, L., Landrieu, I., Chern, Y., Hamdane, M., Bu´ee, L., Boutillier, A.L., Levi, S., Halle, A., Lopes, L.V., Blum, D., 2019. Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor. Brain 142, 3636–3654. https://doi.org/10.1093/brain/awz288.
Cerami, C., Iaccarino, L., Perani, D., 2017. Molecular imaging of neuroinflammation in neurodegenerative dementias: the role of in vivo PET imaging. Int. J. Mol. Sci. 18 https://doi.org/10.3390/ijms18050993.
Chauhan, A.K., Mittra, N., Patel, D.K., Singh, C., 2018. Cyclooxygenase-2 directs microglial activation-mediated inflammation and oxidative stress leading to intrinsic apoptosis in Zn-induced Parkinsonism. Mol. Neurobiol. 55, 2162–2173. https://doi. org/10.1007/s12035-017-0455-0.
Chen, X., Zhang, X.-L., Wang, C.-M., Feng, L., Wang, G., 2018. Cordyceps sinensis combined with duloxetine improves sleep symptoms in patients with depression: a randomized, double-blind, placebo-controlled study. Asia Pacific J. Clin. Trials Nerv. Syst. Dis. 3, 136. https://doi.org/10.4103/2542-3932.245217.
Cheng, C., Zhu, X., 2019. Cordycepin mitigates MPTP-induced Parkinson’s disease through inhibiting TLR/NF-κB signaling pathway. Life Sci. 223, 120–127. https://
doi.org/10.1016/j.lfs.2019.02.037.
Cheng, Y., Wei, Y., Yang, W., Song, Y., Shang, H., Cai, Y., Wu, Z., Zhao, W., 2017. Cordycepin confers neuroprotection in mice models of intracerebral hemorrhage via suppressing NLRP3 inflammasome activation. Metab. Brain Dis. 32, 1133–1145. https://doi.org/10.1007/s11011-017-0003-7.
Choi, D.Y., Liu, M., Hunter, R.L., Cass, W.A., Pandya, J.D., Sullivan, P.G., Shin, E.J., Kim, H.C., Gash, D.M., Bing, G., 2009. Striatal neuroinflammation promotes parkinsonism in rats. PLoS One 4. https://doi.org/10.1371/journal.pone.0005482.
Choi, Y.H., Kim, G.Y., Lee, H.H., 2014. Anti-inflammatory effects of cordycepin in lipopolysaccharide-stimulated RAW 264.7 macrophages through Toll-like receptor 4-mediated suppression of mitogen-activated protein kinases and NF-κB signaling pathways. Drug Des. Dev. Ther. 8, 1941–1953. https://doi.org/10.2147/DDDT. S71957.
Coelho, J.E., Alves, P., Canas, P.M., Valadas, J.S., Shmidt, T., Batalha, V.L., Ferreira, D. G., Ribeiro, J.A., Bader, M., Cunha, R.A., do Couto, F.S., Lopes, L.V., 2014. Overexpression of adenosine A2A receptors in rats: effects on depression, locomotion, and anxiety. Front. Psychiatr. 5, 1–8. https://doi.org/10.3389/
fpsyt.2014.00067.
Dong, Z.S.W., Cao, Z.P., Shang, Y.J., Liu, Q.Y., Wu, B.Y., Liu, W.X., Li, C.H., 2019. Neuroprotection of cordycepin in NMDA-induced excitotoxicity by modulating adenosine A1 receptors. Eur. J. Pharmacol. 853, 325–335. https://doi.org/10.1016/
j.ejphar.2019.04.015.
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., Lanctˆot, K.L., 2010. A meta-analysis of cytokines in major depression. Biol. Psychiatr. 67, 446–457. https://doi.org/10.1016/j.biopsych.2009.09.033.
Elkhateeb, W., Daba, G., Thomas, P., Wen, T.-C., 2019. Medicinal mushrooms as a new source of natural therapeutic bioactive compounds. Egypt. Pharm. J. 18, 88–101. https://doi.org/10.4103/epj.epj.
Franklin, T.C., Wohleb, E.S., Zhang, Y., Fogaça, M., Hare, B., Duman, R.S., 2018a. Persistent increase in microglial rage contributes to chronic stress–induced priming of depressive-like behavior. Biol. Psychiatr. 83, 50–60. https://doi.org/10.1016/j. biopsych.2017.06.034.
Franklin, T.C., Xu, C., Duman, R.S., 2018b. Depression and sterile inflammation: essential role of danger associated molecular patterns. Brain Behav. Immun. 72, 2–13. https://doi.org/10.1016/j.bbi.2017.10.025.
Fung, J.C.K., Yue, G.G.L., Fung, K.P., Ma, X., Yao, X.Q., Ko, W.H., 2011. Cordyceps militaris extract stimulates Cl – secretion across human bronchial epithelia by both Ca 2+- and cAMP-dependent pathways. J. Ethnopharmacol. 138, 201–211. https://
doi.org/10.1016/j.jep.2011.08.081.
Gil-martinez, A.L., Cuenca-bermejo, L., Gallo-soljancic, P., Sanchez-rodrigo, C., Izura, V., Steinbusch, H.W.M., Fernandez-villalba, E., Herrero, M.T., 2020. Study of the Link

between Neuronal Death , Glial Response , and MAPK Pathway in Old Parkinsonian Mice, vol. 12, pp. 1–9. https://doi.org/10.3389/fnagi.2020.00214.
Gonçalves, F.Q., Lopes, J.P., Silva, H.B., Lemos, C., Silva, A.C., Gonçalves, N., Tom´e, ˆ R., Ferreira, S.G., Canas, P.M., Rial, D., Agostinho, P., Cunha, R.A., 2019. Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer’s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol. Dis. 132 https://doi.org/10.1016/j.nbd.2019.104570.
Guo, Y., Gan, X., Zhou, Houfeng, Zhou, Hongjing, Pu, S., Long, X., Ren, C., Feng, T., Tang, H., 2020. Fingolimod suppressed the chronic unpredictable mild stress- induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation. Life Sci. 263, 118582 https://doi.org/10.1016/j.lfs.2020.118582.
Guo, X., Rao, Y., Mao, R., Cui, L., Fang, Y., 2020. Common cellular and molecular mechanisms and interactions between microglial activation and aberrant neuroplasticity in depression. Neuropharmacology 181, 108336. https://doi.org/10. 1016/j.neuropharm.2020.108336.
Han, Y.Y., Chen, Z.H., Shang, Y.J., Yan, W.W., Wu, B.Y., Li, C.H., 2019. Cordycepin improves behavioral-LTP and dendritic structure in hippocampal CA1 area of rats. J. Neurochem. 151, 79–90. https://doi.org/10.1111/jnc.14826.
He, Y., Hara, H., Nú˜nez, G., 2016. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021. https://doi.org/10.1016/j. tibs.2016.09.002.
Hirsch, E.C., Vyas, S., Hunot, S., 2012. Neuroinflammation in Parkinson’s disease. Park. Relat. Disord. 18, 210–212. https://doi.org/10.1016/s1353-8020(11)70065-7.
Hughes, C., Choi, M.L., Yi, J.H., Kim, S.C., Drews, A., George-Hyslop, P.S., Bryant, C., Gandhi, S., Cho, K., Klenerman, D., 2020. Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death. Commun. Biol. 3 https://doi.org/10.1038/s42003-020-0792-9.
Imamura, K., Asai, M., Sugamoto, K., Matsumoto, T., Yamasaki, Y., Kamei, I., Hattori, T., Kishimoto, M., Niisaka, S., Kubo, M., Nishiyama, K., Yamasaki, M., 2015. Suppressing effect of cordycepin on the lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. Biosci. Biotechnol. Biochem. 79, 1021–1025. https://doi.org/10.1080/09168451.2015.1008977.
Jeong, J.W., Jin, C.Y., Kim, G.Y., Lee, J.D., Park, C., Kim, G. Do, Kim, W.J., Jung, W.K., Seo, S.K., Choi, I.W., Choi, Y.H., 2010. Anti-inflammatory effects of cordycepin via suppression of inflammatory mediators in BV2 microglial cells. Int. Immunopharm. 10, 1580–1586. https://doi.org/10.1016/j.intimp.2010.09.011.
Jia, Y., Li, H., Bao, H., Zhang, D., Feng, L., Xiao, Y., Zhu, K., Hou, Y., Luo, S., Zhang, Y., Xiao, L., Chen, X., Zhou, J., Wang, C., Wang, G., Yu, H., Xiao, C., Du, J., 2019. Cordycepin (3′ -deoxyadenosine) promotes remyelination via suppression of neuroinflammation in a cuprizone-induced mouse model of demyelination. Int. Immunopharm. 75, 105777 https://doi.org/10.1016/j.intimp.2019.105777.
Ju, H., Li, X., Li, H., Wang, X., Wang, H., Li, Y., Dou, C., Zhao, G., 2013. Mediation of multiple pathways regulating cell proliferation, migration, and apoptosis in the human malignant glioma cell line U87MG via unphosphorylated STAT1: laboratory investigation. J. Neurosurg. 118, 1239–1247. https://doi.org/10.3171/2013.3. JNS122051.
Jung, Y.J., Tweedie, D., Scerba, M.T., Greig, N.H., 2019. Neuroinflammation as a factor of neurodegenerative disease: thalidomide analogs as treatments. Front. Cell Dev. Biol. 7, 1–24. https://doi.org/10.3389/fcell.2019.00313.
Kaufmann, F.N., Costa, A.P., Ghisleni, G., Diaz, A.P., Rodrigues, A.L.S., Peluffo, H., Kaster, M.P., 2017. NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings. Brain Behav. Immun. 64, 367–383. https://doi.org/
10.1016/j.bbi.2017.03.002.
Khan, M.M., Kempuraj, D., Thangavel, R., Zaheer, A., 2013. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol. Neurochem. Int. 62, 379–388. https://doi.org/10.1016/j.neuint.2013.01.029.
Kim, S.J., Ryu, M.J., Han, J., Jang, Y., Lee, M.J., Ju, X., Ryu, I., Lee, Y.L., Oh, E., Chung, W., Heo, J.Y., Kweon, G.R., 2019. Non-cell autonomous modulation of tyrosine hydroxylase by HMGB1 released from astrocytes in an acute MPTP-induced Parkinsonian mouse model. Lab. Invest. 99, 1389–1399. https://doi.org/10.1038/
s41374-019-0254-5.
Kim, Y.O., Kim, H.J., Abu-Taweel, G.M., Oh, J., Sung, G.H., 2019. Neuroprotective and therapeutic effect of Cordyceps militaris on ischemia-induced neuronal death and cognitive impairments. Saudi J. Biol. Sci. 26, 1352–1357. https://doi.org/10.1016/j. sjbs.2018.08.011.
Korzhevskii, D.E., Kirik, O.V., 2016. Brain microglia and microglial markers. Neurosci. Behav. Physiol. 46, 284–290. https://doi.org/10.1007/s11055-016-0231-z.
Leonard, B., Maes, M., 2012. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci. Biobehav. Rev. 36, 764–785. https://doi.org/10.1016/j. neubiorev.2011.12.005.
Li, B., Hou, Y., Zhu, M., Bao, H., Nie, J., Zhang, G.Y., Shan, L., Yao, Y., Du, K., Yang, H., Li, M., Zheng, B., Xu, X., Xiao, C., Du, J., 2016. 3′ -Deoxyadenosine (Cordycepin) produces a rapid and robust antidepressant effect via enhancing prefrontal AMPA receptor signaling pathway. Int. J. Neuropsychopharmacol. 19, 1–11. https://doi. org/10.1093/ijnp/pyv112.
Liang, Z., Wu, G., Fan, C., Xu, J., Jiang, S., Yan, X., Di, S., Ma, Z., Hu, W., Yang, Y., 2016. The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. Prog. Neurobiol. 137, 1–16. https://doi.org/
10.1016/j.pneurobio.2015.11.001.
Maes, M., 2011. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 35, 664–675. https://doi.org/10.1016/j.pnpbp.2010.06.014.

Mao, Z., Liu, C., Ji, S., Yang, Q., Ye, H., 2017. The NLRP3 inflammasome is involved in the pathogenesis of Parkinson’s disease in rats. Neurochem. Res. 42, 1104–1115. https://doi.org/10.1007/s11064-017-2185-0.
Martí Navia, A., Dal Ben, D., Lambertucci, C., Spinaci, A., Volpini, R., Marques- Morgado, I., Coelho, J.E., Lopes, L.V., Marucci, G., Buccioni, M., 2020. Adenosine receptors as neuroinflammation modulators: role of A1 agonists and A2A antagonists. Cells 9. https://doi.org/10.3390/cells9071739.
Merighi, S., Gessi, S., Borea, P.A., 2018. Adenosine receptors: structure, distribution, and signal transduction. Receptor 34, 33–57. https://doi.org/10.1007/978-3-319- 90808-3_3.
Milner, M.T., Maddugoda, M., Burgener, S.S., Schroder, K., 2021. ScienceDirect the NLRP3 Inflammasome Triggers Sterile Neuroinflammation and Alzheimer ’ S Disease, vol. 3, pp. 116–124.
Olatunji, O.J., Feng, Y., Olatunji, O.O., Tang, J., Ouyang, Z., Su, Z., 2016. Cordycepin protects PC12 cells against 6-hydroxydopamine induced neurotoxicity via its antioxidant properties. Biomed. Pharmacother. 81, 7–14. https://doi.org/10.1016/j. biopha.2016.03.009.
Origlia, N., Righi, M., Capsoni, S., Cattaneo, A., Fang, F., Stern, D.M., Chen, J.X., Schmidt, A.M., Arancio, O., Shi, D.Y., Domenici, L., 2008. Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-β-mediated cortical synaptic dysfunction. J. Neurosci. 28, 3521–3530. https://doi.org/10.1523/JNEUROSCI.0204-08.2008.
Pan, Y., Chen, X.Y., Zhang, Q.Y., Kong, L.D., 2014. Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats. Brain Behav. Immun. 41, 90–100. https://doi.org/10.1016/j.bbi.2014.04.007.
Peng, J., Wang, P., Ge, H., Qu, X., Jin, X., 2015. Effects of cordycepin on the microglia- overactivation-induced impairments of growth and development of hippocampal cultured neurons. PLoS One 10, 1–18. https://doi.org/10.1371/journal. pone.0125902.
Picca, A., Calvani, R., Coelho-Júnior, H.J., Landi, F., Bernabei, R., Marzetti, E., 2020. Mitochondrial dysfunction, oxidative stress, and neuroinflammation: intertwined roads to neurodegeneration. Antioxidants 9, 1–21. https://doi.org/10.3390/
antiox9080647.
Qin, P., Li, X.K., Yang, H., Wang, Z.Y., Lu, D.X., 2019. Therapeutic potential and biological applications of cordycepin and metabolic mechanisms in cordycepin- producing fungi. Molecules 24, 1–26. https://doi.org/10.3390/molecules24122231.
Ramesh, G., 2014. Novel therapeutic targets in neuroinflammation and neuropathic pain. Inflamm. Cell Signal 1, 1–12. https://doi.org/10.14800/ics.111.
Rea, I.M., Gibson, D.S., McGilligan, V., McNerlan, S.E., Denis Alexander, H., Ross, O.A.,
2018.Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol. 9, 1–28. https://doi.org/10.3389/fimmu.2018.00586 .
Rodman, L.E., Farnell, D.R., Coyne, J.M., Allan, P.W., Hill, D.L., Duncan, K.L.K., Tomaszewski, J.E., Smith, A.C., Page, J.G., 1997. Toxicity of cordycepin in combination with the adenosine deaminase inhibitor 2’-deoxycoformycin in beagle dogs. Toxicol. Appl. Pharmacol. 147, 39–45. https://doi.org/10.1006/
taap.1997.8264.
Sachdeva, S., Gupta, M., 2013. Adenosine and its receptors as therapeutic targets: an overview. Saudi Pharmaceut. J. 21, 245–253. https://doi.org/10.1016/j. jsps.2012.05.011.
Shippy, D.C., Ulland, T.K., 2020. Microglial immunometabolism in Alzheimer’s disease. Front. Cell. Neurosci. 14, 1–8. https://doi.org/10.3389/fncel.2020.563446.
Song, H., Huang, L.P., Li, Y., Liu, C., Wang, S., Meng, W., Wei, S., Liu, X.P., Gong, Y., Yao, L.H., 2018. Neuroprotective effects of cordycepin inhibit Aβ-induced apoptosis in hippocampal neurons. Neurotoxicology 68, 73–80. https://doi.org/10.1016/j. neuro.2018.07.008.
Sun, Y., Huang, W., Tang, P., Zhang, Xin, Zhang, Xiao yan, Yu, B., 2020. Neuroprotective effects of natural cordycepin on LPS-induced Parkinson’s disease through suppressing TLR4/NF-κB/NLRP3-mediated pyroptosis. J. Funct. Foods, 104274.
Swanton, T., Cook, J., Beswick, J.A., Freeman, S., Lawrence, C.B., Brough, D., 2018. Is targeting the inflammasome a way forward for neuroscience drug discovery? SLAS Discov. 23, 991–1017. https://doi.org/10.1177/2472555218786210.
Szopa, A., Bogatko, K., Serefko, A., Wyska, E., Wo´sko, S., ´Swiąder, K., Doboszewska, U., Wla´z, A., Wr´obel, A., Wla´z, P., Dudka, J., Poleszak, E., 2019. Agomelatine and tianeptine antidepressant activity in mice behavioral despair tests is enhanced by DMPX, a selective adenosine A2A receptor antagonist, but not DPCPX, a selective adenosine A1 receptor antagonist. Pharmacol. Rep. 71, 676–681. https://doi.org/
10.1016/j.pharep.2019.03.007.
Teismann, P., Schulz, J.B., 2004. Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res. 318, 149–161. https://doi.org/
10.1007/s00441-004-0944-0.
Thawkar, B.S., Kaur, G., 2019. Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: novel therapeutic opportunities in neuroinflammation induced early- stage Alzheimer’s disease. J. Neuroimmunol. 326, 62–74. https://doi.org/10.1016/j. jneuroim.2018.11.010.

Tianzhu, Z., Shihai, Y., Juan, D., 2014. Antidepressant-like effects of cordycepin in a mice model of chronic unpredictable mild stress. Evidence-Based Complement. Altern. Med. 2014, 1–9. https://doi.org/10.1155/2014/438506.
Tuli, H.S., Sandhu, S.S., Sharma, A.K., 2014. Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin. 3 Biotech (4), 1–12. https://doi. org/10.1007/s13205-013-0121-9.
van Calker, D., Biber, K., Domschke, K., Serchov, T., 2019. The role of adenosine receptors in mood and anxiety disorders. J. Neurochem. 151, 11–27. https://doi. org/10.1111/jnc.14841.
Wager, C.M.L., Hole, C.R., Wozniak, K.L., Olszewski, M.A., Mueller, M., Wormley, F.L., 2015. STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans. Infect. Immun. 83, 4513–4527. https://doi.org/
10.1128/IAI.00935-15.
Wang, J.Q., Arora, A., Yang, L., Parelkar, N.K., Zhang, G., Liu, X., Eun, S.C., Mao, L., 2005. Phosphorylation of AMPA receptors: mechanisms and synaptic plasticity. Mol. Neurobiol. 32, 237–249. https://doi.org/10.1385/mn:32:3:237.
Weber, M.D., Frank, M.G., Tracey, K.J., Watkins, L.R., Maier, S.F., 2015. Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male sprague dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J. Neurosci. 35, 316–324. https://doi.org/10.1523/JNEUROSCI.3561-14.2015.
Welcome, M.O., 2020. Neuroinflammation in CNS diseases: molecular mechanisms and the therapeutic potential of plant derived bioactive molecules. PharmaNutrition 11, 100176. https://doi.org/10.1016/j.phanu.2020.100176.
Wu, A.-G., Zhou, X.-G., Qiao, G., Yu, L., Tang, Y., Yan, L., Qiu, W.-Q., Pan, R., Yu, C.-L., Law, B.Y.-K., Qin, D.-L., Wu, J.-M., 2020. Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases. Ageing Res. Rev. 65, 101202 https://doi.org/10.1016/j.arr.2020.101202.
Xiao, L., Zheng, H., Li, J., Wang, Q., Sun, H., 2020. Neuroinflammation mediated by NLRP3 inflammasome after intracerebral hemorrhage and potential therapeutic targets. Mol. Neurobiol. 57, 5130–5149. https://doi.org/10.1007/s12035-020-02 082-2.
Yan, Y., Jiang, W., Liu, L., Wang, X., Ding, C., Tian, Z., Zhou, R., 2015. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 62–73. https://doi.org/10.1016/j.cell.2014.11.047.
Yang, J., zhou, Li Y., Hylemon, P.B., Zhang, L. yong, Zhou, H. ping, 2017. Cordycepin inhibits LPS-induced inflammatory responses by modulating NOD-like receptor protein 3 inflammasome activation. Biomed. Pharmacother. 95, 1777–1788. https://
doi.org/10.1016/j.biopha.2017.09.103.
Yang, Q., qiao, Zhou, wei, J., 2019. Neuroinflammation in the central nervous system: symphony of glial cells. Glia 67, 1017–1035. https://doi.org/10.1002/glia.23571.
Yang, R., Wang, X., Xi, D., Mo, J., Wang, K., Luo, S., Wei, J., Ren, Z., Pang, H., Luo, Y., 2020. Cordycepin attenuates IFN-γ-Induced macrophage IP-10 and Mig expressions by inhibiting STAT1 activity in CFA-induced inflammation mice model. Inflammation 43, 752–764. https://doi.org/10.1007/s10753-019-01162-3.
Yang, J., Wise, L., Fukuchi, K.I., 2020a. TLR4 cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer’s disease. Front. Immunol. 11, 1–16. https://doi.org/10.3389/fimmu.2020.00724 .
Yang, L., Li, G., Chai, Z., Gong, Q., Guo, J., 2020b. Synthesis of cordycepin: current scenario and future perspectives. Fungal Genet. Biol. 143, 103431 https://doi.org/
10.1016/j.fgb.2020.103431.
Yang, Q., Luo, L., Sun, T., Yang, L., Cheng, L.F., Wang, Y., Liu, Q.Q., Liu, A., Liu, H.Y., Zhao, M.G., Wu, S.X., Feng, B., 2020c. Chronic minocycline treatment exerts antidepressant effect, inhibits neuroinflammation, and modulates gut microbiota in mice. Psychopharmacology (Berlin) 237, 3201–3213. https://doi.org/10.1007/
s00213-020-05604-x.
Yao, L.H., Wang, J., Liu, C., Wei, S., Li, G., Wang, S., Meng, W., Liu, Z. Bin, Huang, L.P.,
2019.Cordycepin protects against β-amyloid and ibotenic acid-induced hippocampal CA1 pyramidal neuronal hyperactivity. KOREAN J. PHYSIOL. PHARMACOL. 23, 483–491. https://doi.org/10.4196/kjpp.2019.23.6.483.
Zhang, Z., Du, X., Ma, X., Zong, Y., Chen, J., Yu, C., Liu, Y., Chen, Y., Zhao, L., Lu, G., 2016. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. J. Neuroinflammation 1–11. https://doi.org/10.1186/s12974-016-0539-1.
Zhang, H., Ding, L., Shen, T., Peng, D., 2019. HMGB1 involved in stress-induced depression and its neuroinflammatory priming role: a systematic review. Gen. Psychiatr. 32, 1–9. https://doi.org/10.1136/gpsych-2019-100084.
Zhao, J., Gao, X., Wang, A., Wang, Y., Du, Y., Li, L., Li, M., Li, C., Jin, X., Zhao, M., 2019. Depression comorbid with hyperalgesia: different roles of neuroinflammation induced by chronic stress and hypercortisolism. J. Affect. Disord. 256, 117–124. https://doi.org/10.1016/j.jad.2019.05.065.
Zhu, J.S., Halpern, G.M., Jones, K., 1998. The scientific rediscovery of a precious ancient Chinese herbal regimen: cordyceps sinensis Part II. J. Alternative Compl. Med. 4, 429–457. https://doi.org/10.1089/acm.1998.4.429.