- 1Departamento de Ciências Biológicas, Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil
- 2Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- 3Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
Introduction
Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide, and the leading disability causes a well-documented syndrome (Liu et al., 2020). MDD treatments are often ineffective, leading to a sizable economic impact onto society and governments (Mauskopf et al., 2009), demanding over 238.3 billion dollars per year in the United States alone (Breslow et al., 2019). Noteworthy, although MDD symptomatology can be found in Hippocratic writings, its pathophysiology remains to be established (Wong and Licinio, 2001). The ability to increase monoamine levels (Rosenblat and McIntyre, 2020) shared by antidepressant agents is the basis for the monoaminergic hypothesis of depression (Hirschfeld, 2000). Although such a neurochemical oriented hypothesis of depression was pioneer and revolutionary in the development of psychopharmacology (Pereira and Hiroaki-Sato, 2018), it has also led to a lack of diversity of strategies in the development of antidepressant agents. As a result until 2009, except for the nonmainstream agomelatine (Norman and Olver, 2019), all antidepressants in the clinic acted by modulating monoaminergic neurotransmission (Berton and Nestler, 2006). Yet 50–60% of the patients do not attain complete remission (Kok and Reynolds, 2017), and respondents require 4–6 weeks for therapeutic effect (Brent, 2016). Developing innovative and fast-acting antidepressants is thus decisive for treating MDD.
The observation of abnormal plasma and cerebrospinal glutamate levels in MDD patients (Machado-Vieira et al., 2009) prompted the suggestion that the glutamatergic system plays a role in the MDD pathogenesis (Scarr et al., 2003; Hashimoto et al., 2007). The hypothesis that modulating the glutamatergic system can be the basis of a new strategy to improve MDD symptomatology was advanced by preclinical models. Various glutamatergic inhibitors exhibit antidepressant-like effect in mice submitted to the forced swim test (FST) (Maj et al., 1992a; Maj et al., 1992b; Moryl et al., 1993; Przegaliński et al., 1997), the tail suspension test (TST) (Trullas and Skolnick, 1990; Layer et al., 1995), and in the chronic stress protocols (Papp and Moryl, 1994; Ossowska et al., 1997; Skolnick et al., 2009). A landmark in this developing line of reasoning was the observation by Berman and collaborators on the rapid and robust antidepressant effect of sub-anesthetic doses of the glutamate NMDA receptor ketamine (Berman et al., 2000), subsequently confirmed by double-blinded clinical trial (Zarate et al., 2006).
Besides the well-documented ketamine mechanism of action in glutamatergic neurotransmission, advances in its pharmacological effect demonstrate that ketamine significantly enriches purinergic metabolism (Weckmann et al., 2017; McGowan et al., 2018). Systemic ketamine increases ATP/ADP and decreases the GTP/GDP ratios in mice hippocampi (Weckmann et al., 2017). A single dose of ketamine administered to mice before contextual fear conditioning-induced depression reveal, by metabolomic analysis, a significantly ATP, AMP, GTP, and GDP increased in the prefrontal cortex, and ADP, AMP, GTP, and GDP boost in the hippocampus, while HYPOX, IMP, and INO levels were found to be decreased in these same structures (McGowan et al., 2018). Changes in purine metabolism were still present after 2 weeks of the ketamine challenge, apparently a pattern for those responsive to ketamine treatment (McGowan et al., 2018). The ketamine incremental effect on nucleotide levels is in line with the demonstration that ketamine enriches the pyrimidine and purine intermediates (Weckmann et al., 2014; McGowan et al., 2018). A possible interpretation is that ketamine can increase the activity of salvage pathways; another is an increase in biosynthesis coupled to a decreased conversion of nucleotides into nucleosides. In any case, increased levels of purine intermediates corroborate the hypothesis raised by Ali-Sisto and colleagues that a hyperactive purine degradation cycle is present in untreated MDD patients (Ali-Sisto et al., 2016).
The pentose phosphate pathway (PPP) is composed by oxidative and non-oxidative phases (Ge et al., 2020); the oxidative phase converts glucose-6-phosphate into ribose-5-phosphate and produces two NADPH molecules (Ge et al., 2020). Ribose-5-phosphate and NADPH are key substrates to protein synthesis, redox balance, and cell integrity (Ge et al., 2020). A single ketamine administration increases mice plasma levels of PPP intermediates (D-ribose-5-phosphate and D-ribulose-5-phosphate), the substrates for purine de novo synthesis (McGowan et al., 2018). In agreement with these findings, it has been shown that a single administration of ketamine increased PPP 6-phospho-d-gluconate metabolite in mice hippocampal (Weckmann et al., 2014). Since the metabolites 6-phospho-D-gluconate and D-ribulose-5-phosphate are the result of enzymatic reactions (glucose-6-phosphate dehydrogenase, 6-phosphoglucolactonase, and 6-phosphogluconate dehydrogenase) in a pathway that reduces NADP + to NADPH (Ge et al., 2020), it is plausible to expect that ketamine also increased the NADPH/NADP + ratio. An increased in NADPH/NADP + ratio is in line with the ketamine-induced downstream neuroplasticity-related pathways (e.g., BDNF and mTORC1) (Zanos et al., 2016), protein synthesis, and synaptic plasticity (Zanos et al., 2016; Molero et al., 2018). Since ketamine also modulates purinergic neurotransmission, the ketamine-induced nucleotide and NADPH augmentation might be, at least in part, responsible for the cell proliferation, morphogenesis, and protein synthesis observed after ketamine administration, all of which are relevant for its antidepressant effect.
Adenine-Based Purines as Antidepressants
Substantial preclinical and clinical data advanced and sustained the involvement of adenosine nucleoside in MDD; see Yamada et al. (2014), López-Cruz et al. (2018), Calker et al. (2019), Bartoli et al. (2020) for reviews. Antidepressant-like effect was obtained by enhancing ATP release from astrocytes, which activated P2X2 receptors in the prefrontal cortex of mice subjected to the social stress depression model (Cao et al., 2013). On the contrary, blocking astrocytic ATP release led to extended depression-like phenotype in the same model (Ren et al., 2018). The relevance of the P2X2 receptor was shown comparing the antidepressant effects of ATP alone and ATP combined with Cu2+, a P2X2 receptor enhancer; whereas ATP (4 µM) combined with Cu2+ substantially decreased the immobility time in the FST, while ATP (4 µM) alone did not (Cao et al., 2013). Of relevance to antidepressant activity are the data associated with ATP neuroprotection (Jacobson et al., 2012; Ulrich and Illes, 2014; Gampe et al., 2015; Miras-Portugal et al., 2016). ATP can activate GSK3 phosphorylation (at Ser9/21 residues) inhibiting GSK3 activity, thus facilitating neuronal survival and/or function restoration (Jope and Roh, 2006). Ketamine, by affecting purine metabolism and increasing the extracellular nucleotide availability, can activate neuronal and glial nucleotide receptors and regulate intracellular kinases pathways (e.g., PI3K/Akt, GSK3, and ERK1,2) associated with synapto/neurogenesis (Scheuing et al., 2015; Deyama and Duman, 2020). Although these evidences were supported by robust data, several preclinical studies have indicated that the antidepressant effect can also result from P2X7 receptor antagonism (Krügel, 2016; Cheffer et al., 2018). As an immune-modulatory receptor, P2X7 activation is involved with neuroinflammation through microglial activation and interleukin-1β production and also associated with MDD (Krügel, 2016; Cheffer et al., 2018). In fact, the pharmacological inhibition or genetic manipulation of P2X7 has been suggested as a strategy for treating MDD (Iwata et al., 2016; Yue et al., 2017; Farooq et al., 2018; Aricioglu et al., 2019).
In 2005, Calker and Biber (van Calker and Biber, 2005) reported the antidepressant effects of A1 adenosine agonists, and the antidepressant effect of extracellular adenosine signaling was reinforced by others (Hines et al., 2013; Serchov et al., 2015). The enhancement in neuronal A1 receptor expression exerts prophylactic antidepressant effect, while A1 receptor knockout (KO) mice increased depressive-like behavior and were resistant to antidepressant effects of sleep deprivation (Serchov et al., 2015). Additionally, caffeine, a nonselective adenosine receptor antagonist, prevented depressive-like behavior and synaptic changes induced by chronic unpredictable stress (Kaster et al., 2015). Coherent with preclinical observation, important reviews also sustain that caffeine consumption decreases the incidence of depression and suicide risk in patients (Kawachi et al., 1996; Lucas et al., 2014). In the same way, the selective antagonism of A2a adenosine receptors KW6002 or the A2a genetic inactivation mice model of depression seems key to the antidepressant activity (Yacoubi et al., 2001; Kaster et al., 2004; Yamada et al., 2013; Kaster et al., 2015).
Guanine-Based Purines as Antidepressants
Guanine-based purines, including the nucleotides guanosine 5′-triphosphate (GTP), guanosine 5′-diphosphate (GDP), and guanosine 5′-monophosphate (GMP), the nucleoside guanosine (GUO), and the nucleobase guanine (GUA), have received less attention than classic neurotransmitter as targets in psychiatry. GUO protects against a wide range of deleterious effects in various animal models of neurological disorders (Sopko et al., 2008; Khan et al., 2012). It has been postulated that GTP (as ATP) acts as neurotransmitter (Santos et al., 2006), supporting the idea of a guanine-based purine signaling system (Schmidt et al., 2007). The hypothesis is that various brain insults augment nucleotide release, followed by increased extracellular nucleoside levels, working as part of a restorative arrangement (Pimentel et al., 2013).
The antidepressant-like effect obtained with systemic (i.p.) or central (i.c.v.) GUO in mice models with predictive validity [tail suspension test (TST) and forced swimming test (FST)] was reported in 2012; GUO antidepressant–like activity was blocked by selective inhibitors suggesting the involvement of glutamate NMDA receptors, l-arginine-NO-cGMP, and PI3K-mTOR pathways (Bettio et al., 2012). Prior to this identification of GUO antidepressant-like, it was reported that GUO and guanine derivatives can act as competitive inhibitors of NMDA receptors, prevent NMDA-induced neurotoxicity, and protect against quinolinic acid–induced seizures (Schmidt et al., 2007). Differently than the ketamine modulation in different NMDAR isoforms [selectively inhibition on NMDAR expressed on GABAergic inhibitory interneurons or extra-synaptic GluN2B-containing NMDARs (Zanos and Gould, 2018)], the NMDAR involvement on GUO mechanism of action needs further investigation. Of note, aside for the antidepressant effect, ketamine and GUO share other biological effects, such as amnesic, antinociceptive, and neuroprotective.
Additionally, systemic GUO was also effective in diminishing acute restraint stress-induced depressive-like behavior in the same species (Bettio et al., 2014); biochemical correlates included the attenuation of the stress-induced hippocampal malondialdehyde increase the prevention of changes in the activity of antioxidant enzymes such as glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and the superoxide dismutase (SOD)/CAT activity ratio (Bettio et al., 2014). Chronic (21 days) orally administered GUO decreased the immobility time in the TST in female mice, positively correlated with increased neuronal differentiation in the ventral (but not dorsal) hippocampal dentate gyrus (Bettio et al., 2016). GUO antidepressant effects were also reported with the combination of subthreshold doses of GUO and ketamine in the novelty-suppressed feeding test (NSFT) (Camargo et al., 2020). Neurochemical analysis showed that 60 min after GUO, there was an increase in mTOR phosphorylation (Ser2448) and phospho-p70S6K immunocontent (but no changes in PSD-95, GluA1, and synapsin) in the hippocampus, whereas no changes in phospho-mTOR and phospho-p70S6K were seen in the prefrontal cortex, which presented increased PSD-95, GluA1, and synapsin immunocontent (Camargo et al., 2020). The prefrontal cortex (especially the medial portion), the lateral habenula, and the hippocampus (ventral region) have been consistently implicated in MDD and in antidepressants efficacy (Kupfer et al., 2012; Bettio et al., 2014; Yang et al., 2018).
Using logistic regression, clinical longitudinal studies showed that serum GUO levels are decreased in MDD patients in comparison with healthy controls (Ali-Sisto et al., 2016). Increased uric acid levels were also reported in MDD patients (Kesebir et al., 2014), reinforcing the hypothesis of a hyperactive purine degradation cycle in MDD. Such boosted turnover of nucleotides to nucleosides can be interpreted as an attempt to reestablish the redox homeostasis altered in MDD (Bartoli et al., 2020), congruent with the effect of ketamine on purine metabolism (Weckmann et al., 2017; McGowan et al., 2018). Reinforcing that PI3K/Akt/mTOR is required for GUO antidepressant–like effects, Rosa and colleagues (Rosa et al., 2019) reported that sub-effective doses of GUO combined with GSK-3β inhibitors reduced immobility at the TST, a result compatible with the PI3k/Akt ability to inhibit GSK-3β signaling. To explain the increased β-catenin content found at the hippocampus and prefrontal cortex cell nuclear fractions, the same authors suggested that GSK-3β is inhibited by GUO, resulting in cytosol β-catenin accumulation and subsequent translocated into the nucleus (Rosa et al., 2019). GUO antidepressant–like effects were blocked by MEK1/2 inhibitors, suggesting that GUO can also activate the MAPK/ERK pathway, further reinforcing the involvement of the mTOR signaling in GUO effects. GUO antidepressant–like effects were abolished by the co-administration of GUO and HO-1 inhibitors, while systemic GUO increased the nuclear factor Nrf-2 in the hippocampus and prefrontal cortex (Rosa et al., 2019) observations compatible with the known MAPK/ERK and/or GSK-3β/PI3K/Akt activation of Nrf2.
The bilateral olfactory bulbectomy (OBX) is considered as the best suited rodent model to investigate novel fast-onset antidepressants (Ramaker and Dulawa, 2017). We established that a single intraperitoneal injection of GUO (7.5 mg/kg) reversed the OBX-induced anhedonia-like behavior and recognition memory impairment in mice (Almeida et al., 2020). As the effects of GUO and ketamine were comparable at OBX and both abolished by rapamycin, the study provided additional evidence for the requirement of the mTOR pathway in GUO and ketamine mechanism of action as antidepressant agents (Almeida et al., 2020).
Ketamine antidepressant effects apparently require the activation of molecular targets downstream to mTOR (primarily the protein kinase p70S6K) (Duman et al., 2012; Fraga et al., 2020), ultimately facilitating protein translation, cell growth, proliferation, formation, maturation, and function of new spine synapses (Zito et al., 2009). Considering that (Liu et al., 2020), GUO and ketamine show fast-onset antidepressant-like effect requiring the mTOR pathway (Bettio et al., 2012; Mauskopf et al., 2009). GUO and ketamine modify purine metabolism (Almeida et al., 2017; McGowan et al., 2018) and (Breslow et al., 2019) that the in vitro (Su et al., 2013) and in vivo (Bettio et al., 2012) GUO neurotrophic and neuritogenic effects involve the same pathways reported for ketamine; it is tempting to speculate that scrutiny of neurochemical correlates of compounds that present fast-onset antidepressant effects might reveal a common set of molecular targets (Weckmann et al., 2017; McGowan et al., 2018).
Although ketamine opened a whole new avenue and hope for a more efficacious management of MDD, other compounds with fast-onset antidepressant agents did not come forward. Exploratory studies support the potential of GUO as a fast-onset antidepressant, with a safe profile (Molz et al., 2011; Tasca et al., 2018). The use of ketamine is limited by its adverse profile, including psychomotor and addictive effects (Lener et al., 2017). On the contrary, compelling evidence shows that GUO is safe, well tolerated, and not associated with major side effects (Molz et al., 2011; Tasca et al., 2018), which increase the chance of well tolerability in long-term treatments. The commonalities of ketamine and GUO mechanisms of action suggest that a better understanding on the role of guanine-based purines in MDD is relevant and necessary for innovation in the field.
Disclaimer
This is an opinion article based on literature review. No experiments have been conducted or data collected.
Author Contributions
RFA conceived the manuscript. TPF, CVCD, PCAS, and SAS performed literature review, collected relevant data, and contributed to the initial drafting of the manuscript. RFA, ALSR, and EE developed the initial draft. RFA and EE produced the final version of the manuscript. The authors are grateful to Roberto Regensteiner and David C. Oren for language review.
Funding
This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), the Programa de Pós Graduação em Ciências Biológicas at UFOP, and UFOP/PROPP 19/2020 (No. 23109.000929/2020-88).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Ali-Sisto, T., Tolmunen, T., Toffol, E., Viinamäki, H., Mäntyselkä, P., Valkonen-Korhonen, M., et al. (2016). Purine metabolism is dysregulated in patients with major depressive disorder. Psychoneuroendocrinology 70, 25–32. doi:10.1016/j.psyneuen.2016.04.017
Almeida, R. F., Comasseto, D. D., Ramos, D. B., Hansel, G., Zimmer, E. R., Loureiro, S. O., et al. (2017). Guanosine anxiolytic-like effect involves adenosinergic and glutamatergic neurotransmitter systems. Mol. Neurobiol. 54 (1), 423–436. doi:10.1007/s12035-015-9660-x
Almeida, R. F., Pocharski, C. B., Rodrigues, A. L. S., Elisabetsky, E., and Souza, D. O. (2020). Guanosine fast onset antidepressant-like effects in the olfactory bulbectomy mice model. Sci. Rep. 10 (1), 8429. doi:10.1038/s41598-020-65300-w
Aricioglu, F., Ozkartal, C. S., Bastaskin, T., Tüzün, E., Kandemir, C., Sirvanci, S., et al. (2019). Antidepressant-like effects induced by chronic blockade of the purinergic 2X7 receptor through inhibition of non-like receptor protein 1 inflammasome in chronic unpredictable mild stress model of depression in rats. Clin. Psychopharmacol. Neurosci. 17 (2), 261–272. doi:10.9758/cpn.2019.17.2.261
Bartoli, F., Burnstock, G., Crocamo, C., and Carrà, G. (2020). Purinergic signaling and related biomarkers in depression. Brain Sci. 10 (3), 160. doi:10.3390/brainsci10030160
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47 (4), 351–354. doi:10.1016/s0006-3223(99)00230-9
Berton, O., and Nestler, E. J. (2006). New approaches to antidepressant drug discovery: beyond monoamines. Nat. Rev. Neurosci. 7 (2), 137–151. doi:10.1038/nrn1846
Bettio, L. E. B., Cunha, M. P., Budni, J., Pazini, F. L., Oliveira, Á., Colla, A. R., et al. (2012). Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways. Behav. Brain Res. 234 (2), 137–148. doi:10.1016/j.bbr.2012.06.021
Bettio, L. E. B., Freitas, A. E., Neis, V. B., Santos, D. B., Ribeiro, C. M., Rosa, P. B., et al. (2014). Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress. Pharmacol. Biochem. Behav. 127, 7–14. doi:10.1016/j.pbb.2014.10.002
Bettio, L. E. B., Neis, V. B., Pazini, F. L., Brocardo, P. S., Patten, A. R., Gil-Mohapel, J., et al. (2016). The antidepressant-like effect of chronic guanosine treatment is associated with increased hippocampal neuronal differentiation. Eur. J. Neurosci. 43 (8), 1006–1015. doi:10.1111/ejn.13172
Brent, D. A. (2016). Antidepressants and suicidality. Psychiatr. Clin. North America 39 (3), 503–512. doi:10.1016/j.psc.2016.04.002
Breslow, A. S., Tran, N. M., Lu, F. Q., Alpert, J. E., and Cook, B. L. (2019). Depression treatment expenditures for adults in the USA: a systematic review. Curr. Psychiatry Rep. 21 (10), 105. doi:10.1007/s11920-019-1083-3
Calker, D., Biber, K., Domschke, K., and Serchov, T. (2019). The role of adenosine receptors in mood and anxiety disorders. J. Neurochem. 151 (1), 11–27. doi:10.1111/jnc.14841
Camargo, A., Dalmagro, A. P., Zeni, A. L. B., and Rodrigues, A. L. S. (2020). Guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine: possible role of pro-synaptogenic signaling pathway. J. Affect. Disord. 271, 100–108. doi:10.1016/j.jad.2020.03.186
Cao, X., Li, L. P., Wang, Q., Wu, Q., Hu, H. H., Zhang, M., et al. (2013). Astrocyte-derived ATP modulates depressive-like behaviors. Nat. Med. 19 (6), 773–777. doi:10.1038/nm.3162
Cheffer, A., Castillo, A. R. G., Corrêa-Velloso, J., Gonçalves, M. C. B., Naaldijk, Y., Nascimento, I. C., et al. (2018). Purinergic system in psychiatric diseases. Mol. Psychiatry 23 (1), 94–106. doi:10.1038/mp.2017.188
Deyama, S., and Duman, R. S. (2020). Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacol. Biochem. Behav. 188, 172837. doi:10.1016/j.pbb.2019.172837
Duman, R. S., Li, N., Liu, R. J., Duric, V., and Aghajanian, G. (2012). Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 62 (1), 35–41. doi:10.1016/j.neuropharm.2011.08.044
Farooq, R. K., Tanti, A., Ainouche, S., Roger, S., Belzung, C., and Camus, V. (2018). A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice. Psychoneuroendocrinology 97, 120–130. doi:10.1016/j.psyneuen.2018.07.016
Fraga, D. B., Costa, A. P., Olescowicz, G., Camargo, A., Pazini, F. L., Freitas, A. E., et al. (2020). Ascorbic acid presents rapid behavioral and hippocampal synaptic plasticity effects. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 96, 109757. doi:10.1016/j.pnpbp.2019.109757
Gampe, K., Stefani, J., Hammer, K., Brendel, P., Pötzsch, A., Enikolopov, G., et al. (2015). NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain. Stem Cells 33 (1), 253–264. doi:10.1002/stem.1846
Ge, T., Yang, J., Zhou, S., Wang, Y., Li, Y., and Tong, X. (2020). The role of the pentose phosphate pathway in diabetes and cancer. Front. Endocrinol. 11, 365. doi:10.3389/fendo.2020.00365
Hashimoto, K., Sawa, A., and Iyo, M. (2007). Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 62 (11), 1310–1316. doi:10.1016/j.biopsych.2007.03.017
Hines, D. J., Schmitt, L. I., Hines, R. M., Moss, S. J., and Haydon, P. G. (2013). Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling. Transl. Psychiatry 3, e212. doi:10.1038/tp.2012.136
Hirschfeld, R. M. A. (2000). History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61 (Suppl. 6), 4–6.
Iwata, M., Ota, K. T., Li, X. Y., Sakaue, F., Li, N., Duman, R. S, et al. (2016). Psychological stress activates the inflammasome via release of ATP and stimulation of the P2X7 receptor. Biol. Psychiatry 80, 12–22. doi:10.1016/j.biopsych.2015.11.026
Jacobson, K. A., Balasubramanian, R., Deflorian, F., and Gao, Z. G. (2012). G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions. Purinergic Signal. 8 (3), 419–436. doi:10.1007/s11302-012-9294-7
Jope, R., and Roh, M.-S. (2006). Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr. Drug Targets 7 (11), 1421–1434. doi:10.2174/1389450110607011421
Kaster, M. P., Rosa, A. O., Rosso, M. M., Goulart, E. C., Santos, A. R., and Rodrigues, A. L. S. (2004). Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci. Lett. 355 (1, 2), 21–24. doi:10.1016/j.neulet.2003.10.040
Kaster, M. P., Machado, N. J., Silva, H. B., Nunes, A., Ardais, A. P., Santana, M., et al. (2015). Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc. Natl. Acad. Sci. USA 112 (25), 7833–7838. doi:10.1073/pnas.1423088112
Kawachi, I., Willett, W. C., Colditz, G. A., Stampfer, M. J., and Speizer, F. E. (1996). A prospective study of coffee drinking and suicide in women. Arch. Intern. Med. 156 (5), 521–525. doi:10.1001/archinte.156.5.521
Kesebir, S., Tatlıdil Yaylacı, E., Gültekin, Ö., and Gultekin, B. K. (2014). Uric acid levels may be a biological marker for the differentiation of unipolar and bipolar disorder: the role of affective temperament. J. Affect. Disord. 165, 131–134. doi:10.1016/j.jad.2014.04.053
Khan, A., Faucett, J., Lichtenberg, P., Kirsch, I., and Brown, W. A. (2012). A systematic review of comparative efficacy of treatments and controls for depression. PLoS one 7 (7), e41778. doi:10.1371/journal.pone.0041778
Kok, R. M., and Reynolds, C. F. (2017). Management of depression in older adults. JAMA 317 (20), 2114–2122. doi:10.1001/jama.2017.5706
Krügel, U. (2016). Purinergic receptors in psychiatric disorders. Neuropharmacology 104, 212–225. doi:10.1016/j.neuropharm.2015.10.032
Kupfer, D. J., Frank, E., and Phillips, M. L. (2012). Major depressive disorder: new clinical, neurobiological, and treatment perspectives. The Lancet 379 (9820), 1045–1055. doi:10.1016/S0140-6736(11)60602-8
Layer, R. T., Popik, P., Olds, T., and Skolnick, P. (1995). Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715). Pharmacol. Biochem. Behav. 52 (3), 621–627. doi:10.1016/0091-3057(95)00155-p
Lener, M. S., Kadriu, B., and Zarate, C. A. (2017). Ketamine and beyond: investigations into the potential of glutamatergic agents to treat depression. Drugs 77 (4), 381–401. doi:10.1007/s40265-017-0702-8
Liu, Q., He, H., Yang, J., Feng, X., Zhao, F., and Lyu, J. (2020). Changes in the global burden of depression from 1990 to 2017: findings from the global burden of disease study. J. Psychiatr. Res. 126, 134–140. doi:10.1016/j.jpsychires.2019.08.002
López-Cruz, L., Salamone, J. D., and Correa, M. (2018). Caffeine and selective adenosine receptor antagonists as new therapeutic tools for the motivational symptoms of depression. Front. Pharmacol. 9, 526. doi:10.3389/fphar.2018.00526
Lucas, M., O’Reilly, E. J., Pan, A., Mirzaei, F., Willett, W. C., Okereke, O. I., et al. (2014). Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults. World J. Biol. Psychiatry 15 (5), 377–386. doi:10.3109/15622975.2013.795243
Machado-Vieira, R., Salvadore, G., Ibrahim, L., Diaz-Granados, N., and Zarate, C. (2009). Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr. Pharm. Des. 15 (14), 1595–1611. doi:10.2174/138161209788168010
Maj, J., Rogóz, Z., Skuza, G., and Sowińska, H. (1992a). The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test. Pol. J. Pharmacol. Pharm. 44 (4), 337–346.
Maj, J., Rogóż, Z., Skuza, G., and Sowińska, H. (1992b). Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur. Neuropsychopharmacol. 2 (1), 37–41. doi:10.1016/0924-977x(92)90034-6
Mauskopf, J. A., Simon, G. E., Kalsekar, A., Nimsch, C., Dunayevich, E., and Cameron, A. (2009). Nonresponse, partial response, and failure to achieve remission: humanistic and cost burden in major depressive disorder. Depress. Anxiety 26 (1), 83–97. doi:10.1002/da.20505
McGowan, J. C., Hill, C., Mastrodonato, A., LaGamma, C. T., Kitayev, A., Brachman, R. A., et al. (2018). Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress. Neuropsychopharmacology 43 (9), 1813–1821. doi:10.1038/s41386-018-0043-7
Miras-Portugal, M. T., Gomez-Villafuertes, R., Gualix, J., Diaz-Hernandez, J. I., Artalejo, A. R., Ortega, F., et al. (2016). Nucleotides in neuroregeneration and neuroprotection. Neuropharmacology 104, 243–254. doi:10.1016/j.neuropharm.2015.09.002
Molero, P., Ramos-Quiroga, J. A., Martin-Santos, R., Calvo-Sánchez, E., Gutiérrez-Rojas, L., and Meana, J. J. (2018). Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs 32 (5), 411–420. doi:10.1007/s40263-018-0519-3
Molz, S., Dal-Cim, T., Budni, J., Martín-de-Saavedra, M. D., Egea, J., Romero, A., et al. (2011). Neuroprotective effect of guanosine against glutamate-induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase 3β pathway activation and inducible nitric oxide synthase inhibition. J. Neurosci. Res. 89 (9), 1400–1408. doi:10.1002/jnr.22681
Moryl, E., Danysz, W., and Quack, G. (1993). Potential antidepressive properties of amantadine, memantine and bifemelane. Pharmacol. Toxicol. 72 (6), 394–397. doi:10.1111/j.1600-0773.1993.tb01351.x
Norman, T. R., and Olver, J. S. (2019). Agomelatine for depression: expanding the horizons? Expert Opin. Pharmacother. 20 (6), 647–656. doi:10.1080/14656566.2019.1574747
Ossowska, G., Klenk-Majewska, B., and Szymczyk, G. (1997). The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats. J. Physiol. Pharmacol. 48 (1), 127–135.
Papp, M., and Moryl, E. (1994). Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur. J. Pharmacol. 263 (1, 2), 1–7. doi:10.1016/0014-2999(94)90516-9
Pereira, V. S., and Hiroaki-Sato, V. A. (2018). A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatr. 30 (6), 307–322. doi:10.1017/neu.2017.39
Pimentel, V. C., Zanini, D., Cardoso, A. M., Schmatz, R., Bagatini, M. D., Gutierres, J. M., et al. (2013). Hypoxia-ischemia alters nucleotide and nucleoside catabolism and Na+,K+-ATPase activity in the cerebral cortex of newborn rats. Neurochem. Res. 38 (4), 886–894. doi:10.1007/s11064-013-0994-3
Przegaliński, E., Tatarczyńska, E., Dereń-Wesołek, A., and Chojnacka-Wojcik, E. (1997). Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology 36 (1), 31–37. doi:10.1016/s0028-3908(96)00157-8
Ramaker, M. J., and Dulawa, S. C. (2017). Identifying fast-onset antidepressants using rodent models. Mol. Psychiatry 22 (5), 656–665. doi:10.1038/mp.2017.36
Ren, Q., Wang, Z. Z., Chu, S. F., Xia, C. Y., and Chen, N. H. (2018). Gap junction channels as potential targets for the treatment of major depressive disorder. Psychopharmacology 235 (1), 1–12. doi:10.1007/s00213-017-4782-7
Rosa, P. B., Bettio, L. E. B., Neis, V. B., Moretti, M., Werle, I., Leal, R. B., et al. (2019). The antidepressant-like effect of guanosine is dependent on GSK-3β inhibition and activation of MAPK/ERK and Nrf2/heme oxygenase-1 signaling pathways. Purinergic Signal. 15 (4), 491–504. doi:10.1007/s11302-019-09681-2
Rosenblat, J. D., and McIntyre, R. S. (2020). “Pharmacological treatment of major depressive disorder,” in Major depressive disorder. Editor R. S. McIntyre (Amsterdam, Netherlands: Elsevier). 103–119. doi:10.1016/b978-0-323-58131-8.00008-2
Santos, T. G., Souza, D. O., and Tasca, C. I. (2006). GTP uptake into rat brain synaptic vesicles. Brain Res. 1070 (1), 71–76. doi:10.1016/j.brainres.2005.10.099
Scarr, E., Pavey, G., Sundram, S., MacKinnon, A., and Dean, B. (2003). Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord. 5 (4), 257–264. doi:10.1034/j.1399-5618.2003.00024.x
Scheuing, L., Chiu, C. T., Liao, H. M., and Chuang, D. M. (2015). Antidepressant mechanism of ketamine: perspective from preclinical studies. Front. Neurosci. 9, 249. doi:10.3389/fnins.2015.00249
Schmidt, A. P., Lara, D. R., and Souza, D. O. (2007). Proposal of a guanine-based purinergic system in the mammalian central nervous system. Pharmacol. Ther. 116 (3), 401–416. doi:10.1016/j.pharmthera.2007.07.004
Serchov, T., Clement, H. W., Schwarz, M. K., Iasevoli, F., Tosh, D. K., Idzko, M., et al. (2015). Increased signaling via adenosine A1 receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of Homer1a. Neuron 87 (3), 549–562. doi:10.1016/j.neuron.2015.07.010
Skolnick, P., Popik, P., and Trullas, R. (2009). Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30 (11), 563–569. doi:10.1016/j.tips.2009.09.002
Sopko, M. A., Ehret, M. J., and Grgas, M. (2008). Desvenlafaxine: another “me too” drug? Ann. Pharmacother. 42 (10), 1439–1446. doi:10.1345/aph.1k563
Su, C., Wang, P., Jiang, C., Ballerini, P., Caciagli, F., Rathbone, M. P., et al. (2013). Guanosine promotes proliferation of neural stem cells through cAMP-CREB pathway. J. Biol. Regul. Homeost Agents 27 (3), 673–680.
Tasca, C. I., Lanznaster, D., Oliveira, K. A., Fernández-Dueñas, V., and Ciruela, F. (2018). Neuromodulatory effects of guanine-based purines in health and disease. Front. Cell. Neurosci. 12, 376. doi:10.3389/fncel.2018.00376
Trullas, R., and Skolnick, P. (1990). Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur. J. Pharmacol. 185 (1), 1–10. doi:10.1016/0014-2999(90)90204-j
Ulrich, H., and Illes, P. (2014). P2X receptors in maintenance and differentiation of neural progenitor cells. Neural Regen. Res. 9 (23), 2040–2041. doi:10.4103/1673-5374.147925
van Calker, D., and Biber, K. (2005). The role of glial adenosine receptors in neural resilience and the neurobiology of mood disorders. Neurochem. Res. 30 (10), 1205–1217. doi:10.1007/s11064-005-8792-1
Weckmann, K., Labermaier, C., Asara, J. M., Müller, M. B., and Turck, C. W. (2014). Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates. Transl Psychiatry 4 (11), e481. doi:10.1038/tp.2014.119
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., et al. (2017). Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system. Sci. Rep. 7 (1), 15788. doi:10.1038/s41598-017-16183-x
Wong, M. L., and Licinio, J. (2001). Research and treatment approaches to depression. Nat. Rev. Neurosci. 2 (5), 343–351. doi:10.1038/35072566
Yacoubi, M. E., Ledent, C., Parmentier, M., Bertorelli, R., Ongini, E., Costentin, J., et al. (2001). Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice. Br. J. Pharmacol. 134 (1), 68–77. doi:10.1038/sj.bjp.0704240
Yamada, K., Kobayashi, M., Mori, A., Jenner, P., and Kanda, T. (2013). Antidepressant-like activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents. Pharmacol. Biochem. Behav. 114-115, 23–30. doi:10.1016/j.pbb.2013.10.022
Yamada, K., Kobayashi, M., and Kanda, T. (2014). Involvement of adenosine A2A receptors in depression and anxiety. Int. Rev. Neurobiol. 119, 373–393. doi:10.1016/B978-0-12-801022-8.00015-5
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., et al. (2018). Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554 (7692), 317–322. doi:10.1038/nature25509
Yue, N., Huang, H., Zhu, X., Han, Q., Wang, Y., Li, B., et al. (2017). Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors. J. Neuroinflammation 14 (1), 1–15. doi:10.1186/s12974-017-0865-y
Zanos, P., and Gould, T. D. (2018). Mechanisms of ketamine action as an antidepressant. Mol. Psychiatry 23 (4), 801–811. doi:10.1038/mp.2017.255
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., et al. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533 (7604), 481–486. doi:10.1038/nature17998
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., et al. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63 (8), 856–864. doi:10.1001/archpsyc.63.8.856
Keywords: major depressive disorder, psychopharmacology, purines (source: MeSH), purinergic signaling system, guanine-based purines, guanosine
Citation: Almeida RF, Ferreira TP, David CVC, Abreu e Silva PC, dos Santos SA, Rodrigues ALS and Elisabetsky E (2021) Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder. Front. Pharmacol. 12:652130. doi: 10.3389/fphar.2021.652130
Received: 11 January 2021; Accepted: 01 March 2021;
Published: 13 April 2021.
Edited by:
Henning Ulrich, University of São Paulo, BrazilReviewed by:
Rodrigo A Cunha, University of Coimbra, PortugalCopyright © 2021 Almeida, Ferreira, David, Abreu e Silva, dos Santos, Rodrigues and Elisabetsky. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Roberto F.Almeida, almeida_rf@yahoo.com.br
†ORCID: Tiago Pedrosa Ferreira, orcid.org/0000-0003-2857-9766; Camila Vieira Chagas David, orcid.org/0000-0002-1216-928X; Paulo Corrêa de Abreu e Silva, orcid.org/0000-0003-3189-9752; Sulamita Aparecida Ambrosia dos Santos, orcid.org/0000-0002-0733-5917; Ana Lúcia S. Rodrigues, orcid.org/0000-0001-6285-8780; Elaine Elisabetsky, orcid.org/0000-0002-9922-2863