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; Przegalinski 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), Lopez-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 (Krugel, 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 (Krugel, 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).