The involvement of PI3K/Akt/mTOR/GSK3β signaling pathways in the antidepressant-like effect of AZD6765
Introduction
NMDA receptors are a class of ionotropic glutamatergic receptors related to synaptic plasticity and cell survival (Glasgow et al., 2015). These receptors have been extensively studied in encephalic structures such as cerebral cortex and hippocampus and are highly implicated in psychiatric disorders such as major depressive disorder (MDD) (Hansen et al., 2014; Li et al., 2009). Glutamate excitotoxicity due to over-activation of these receptors has been implicated in the pathophysiology of these disorders (Fan and Raymond, 2007; Wang and Michaelis, 2010).
NMDA receptor antagonists have demonstrated beneficial effects for the treatment of MDD (Dang et al., 2014; Zarate et al., 2010). Preclinical studies have reported that these antagonists exhibit antidepressant-like effect in several animal models of depression (Belzung, 2014; Li et al., 2010). An NMDA receptor antagonist that has emerged as a promising therapeutic agent is ketamine, a dissociative anesthetic that has demonstrated fast and long-lasting antidepressant effects when acutely administered at subanesthetic doses in patients suffering from severe MDD symptoms (Berman et al., 2000; Zarate et al., 2006; Zarate et al., 2013). The antidepressant response elicited by ketamine is proposed to be mediated by glutamate increase with the consequent stimulation of BDNF receptors, which leads to the activation of phosphatidylinositol 3-kinase (PI3K)/Akt, inhibition of glycogen synthase kinase-3β (GSK3β) and stimulation of mammalian target of rapamycin (mTOR) (Monteggia et al., 2013; Wohleb et al., 2017). The activation of mTOR results in the synthesis of synaptic proteins such as synapsin, considered essential for the rapid antidepressant effect of ketamine (Li et al., 2010). However, the psychotomimetic effects of ketamine limit its clinical use (Zarate, 2020) raising the interest in other NMDA receptor antagonists with potential antidepressant effects.
AZD6765 (lanicemine), another non-selective, non-competitive NMDA receptor antagonist with lower trapping than ketamine, has demonstrated antidepressant properties in clinical studies without inducing psychotomimetic effects (Sanacora et al., 2014; Zarate et al., 2013). A single infusion of AZD6765 induced rapid but not sustained antidepressant effects compared to placebo (Sanacora et al., 2014). Of note, a single AZD6765 infusion was more effective than placebo when administered to 22 subjects without causing psychotic or dissociative effects (Zarate et al., 2013). However, a study by Sanacora et al. (2017) demonstrated no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. In preclinical studies, AZD6765 elicited antidepressant-like effect in rodents subjected to forced swim test and learned helplessness paradigm (Sanacora et al., 2014). Furthermore, the co-administration of hyperforin, a natural and biologically active compound extracted from Hypericum perforatum (Cervo et al., 2002) that attenuated symptoms of mild to moderate depression in several clinical trials, displayed long-lasting antidepressant-like effect when administered with AZD6765 in mice (Pochwat et al., 2018). Despite some promising antidepressant effects elicited by AZD6765, the mechanisms and signaling pathways related to its effects have not been investigated. Therefore, the purpose of the present study was to evaluate if the antidepressant effects elicited by AZD6765 are dependent on PI3K/Akt/mTOR and GSK-3β, targets implicated in fast antidepressant responses (Li et al., 2010; Pazini et al., 2016).
Section snippets
Animals
The present study was performed using adult female Swiss mice (30–40 g). Animals were maintained at 20–22 °C with free access to water and food, under a 12/12 h light-dark cycle (lights on at 07:00 a.m.). Mice were allowed to acclimatize to the holding room for 24 h before the behavioral procedures. All manipulations were carried out between 9:00 a.m. and 5:00 p.m. (N = 6–8 animals per group). The procedures in this study were performed in accordance with the National Institutes of Health (NIH)
Effect of AZD6765 administration in the TST and OFT
Fig. 1A shows that the administration of AZD6765 (1 mg/kg, i.p.) produced a significant reduction in the immobility time of animals in the TST [F(1,30) = 4.47, P < 0.01]. Regarding OFT, only the dose of 3 mg/kg of AZD6765 increased the locomotor activity of mice, as compared to the control group (Fig. 1B) [F(1,30) = 6.23, P < 0.01].
Involvement of PI3K and mTOR pathway in the antidepressant-like effect induced by AZD6765 in the TST
As illustrated in Fig. 2A, we next investigated the influence of wortmannin, LY294002 or rapamycin on the antidepressant-like effect of AZD6765 in the TST. Fig. 2B
Discussion
The present study suggests that the antidepressant-like effect induced by AZD6765 in the TST is possibly related to the stimulation of PI3K/Akt/mTOR signaling and inhibition of GSK3β. The antidepressant-like effect of AZD6765 observed 30 min after its administration was accompanied by an increase in the immunocontent of synapsin in prefrontal cortex of mice. We also suggest that the rapid behavioral effect of AZD6765 in the NSF test is dependent on the mTOR-mediated signaling pathway, since the
Conclusion
The identification of potential fast-acting antidepressants with no psychotomimetic effects is highly important for treatment of depression. Our results suggest that AZD6765 possibly acts by enhancing PI3K/Akt/mTOR signaling pathways inhibiting GSK3β and increasing synapsin level in prefrontal cortex of mice, mechanisms related to strengthened synaptic connections. Although we did not show the correlation of PI3K/Akt, mTOR and GSK3β in the antidepressant-like effects of AZD6765, it has been
Role of the funding source
VBN, MM and ALSR designed the study and wrote the protocol. VBN, MM, PBR, YD, IW, AFR and MHB conducted experiments. VBN and FNK analyzed data. VBN, PBR and ALSR wrote the manuscript and managed the literature searches. All authors contributed to the design, acquisition, analysis and interpretation of data. All authors read and approved the manuscript.
Acknowledgements
This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) #310113/2017-2 and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). ALSR is a CNPq Research Fellow. V.B.N. acknowledges postdoctoral funding from CNPq (158126/2018-1).
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2022, European Journal of PharmacologyCitation Excerpt :The PI3K/AKT/GSK-3β pathway also holds relevance in psychiatric illnesses, including depression and other mood disorders, and may serve to be a therapeutic target in the management of such diseases by virtue of its neuroprotective and anti-inflammatory roles (Jope and Roh, 2006; Kitagishi et al., 2012; Matsuda et al., 2019). A variety of compounds with antidepressant properties are PI3K/AKT pathway-dependent (Guo et al., 2019; Kuang et al., 2018; J. Li et al., 2018; Neis et al., 2020; Tao et al., 2016). Even treadmill exercise may exert antidepressant action via PI3K/AKT activation and GSK-3β inhibition (Wang and Baek, 2018).
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2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :In preclinical studies, AZD6765 produced an antidepressant-like effect in rats subjected to forced swim test and learned helplessness paradigm (Sanacora et al., 2014). Moreover, an acute administration of AZD6765 elicited an antidepressant-like response in mice subjected to the tail suspension test (TST), an effect dependent on the activation of mTORC1 with a consequent increase on synapsin immunocontent in the prefrontal cortex (Neis et al., 2020). Through the activation of mTORC1 signaling, AZD6765 was also effective in mice subjected to the novelty-suppressed feeding test (Neis et al., 2020), a behavioral paradigm sensitive to a single administration of fast-acting antidepressants (Camargo et al., 2019; Pazini et al., 2020).
A low-dose combination of ketamine and guanosine counteracts corticosterone-induced depressive-like behavior and hippocampal synaptic impairments via mTORC1 signaling
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :To reinforce the role of mTORC1-driven signaling pathway in the antidepressant-like effect elicited by a low-dose combination of ketamine and guanosine, proteins upstream and downstream to mTORC1 were next investigated. Although questions have been raised about the role of the mTORC1 in the antidepressant effect of ketamine in clinical and preclinical studies (Abdallah et al., 2020; Popp et al., 2016), numerous reports have shown that the mTORC1 signaling is a crucial target for fast antidepressant responses (Li et al., 2010; Neis et al., 2020; Réus et al., 2015; Voleti et al., 2013). Classically, it has been postulated that ketamine blocks NMDA receptors located on inhibitory GABAergic interneurons, resulting in a disinhibition of hippocampal pyramidal cells and consequent release of glutamate in the synaptic cleft (Abdallah et al., 2015).
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2021, Brain ResearchCitation Excerpt :And it was also the main cellular defense pathway activated by oxidative stress (Scapagnini et al., 2011), Nrf2 can induce the expression of HO-1 and other antioxidant enzymes (Nishikawa et al., 2020; Ge et al., 2017), resulting in the production of targeted antioxidants, PI3K/Akt is an upstream signaling pathway involved in the activation of the Nrf2 transcription factor, and gradually becoming a potential new target for the prevention and treatment of depression. ( Neis et al., 2020; Cunha et al., 2016; Hui et al., 2018). Activation of Nrf2 translocation can restore redox homeostasis and reverse the vulnerability of depression (Wang et al., 2019; Bouvier et al., 2017; Nguyen et al., 2009).