Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway

Pazini, Francis L.; Cunha, Maurício P.; Rosa, Júlia M.; Colla, André R.S.; Lieberknecht, Vicente; Oliveira, Ágatha; Rodrigues, Ana Lúcia S.

doi:10.1007/s12035-015-9580-9

Cited by 120 publications

(68 citation statements)

References 85 publications

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“…Time ( (R)-ketamine. In the present study, whereas both (R)-ketamine and (S)-ketamine exerted long-lasting antidepressant effects even when they were no longer present in the brain and CSF, only (R)-ketamine exerted sustained antidepressant effects in the repeated CORT treatment model, in which reduced synaptic plasticity has been reported (Pazini et al, 2016). Therefore, the difference in the potency of the effects on synaptic plasticity may be responsible for the differences in the sustained antidepressant effects.…”

Section: Dosementioning

confidence: 46%

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine

Fukumoto

Toki

Iijima

et al. 2017

J Pharmacol Exp Ther

221

143

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The rapid-acting and long-lasting antidepressant effects of ()-ketamine have recently gained much attention. Although ()-ketamine has been studied as an active isomer, recent evidence suggests that ()-ketamine exhibits longer-lasting antidepressant effects than ()-ketamine in rodents. However, the antidepressant potential of ()-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of ()-ketamine with those of ()-ketamine in animal models of depression, including a model that is refractory to current medications. Both ()-ketamine and ()-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, ()-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of ()-ketamine was no longer observed. Moreover, ()-ketamine, but not ()-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both ()-ketamine and ()-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 hours). The present results confirmed the previous findings that ()-ketamine exerted longer-lasting antidepressant effects than ()-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that ()-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.

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Section: Dosementioning

confidence: 46%

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine

Fukumoto

Toki

Iijima

et al. 2017

J Pharmacol Exp Ther

221

143

View full text Add to dashboard Cite

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“…c shows the notable CCs of neurons that may be regulated by target genes predicted using fold enrichment Table 5 The signaling pathways that may be regulated by targeted genes of the differentially expressed rno_circRNA_014900(p < 0.05) signaling, dopaminergic synapses, mTOR signaling, p53 signaling, apoptosis, MAPK signaling, TGF-beta signaling, axon guidance, Hippo signaling, etc.. These signaling pathways may be involved in the occurrence and development of depression, because some researches found that the Wnt signaling pathway played important roles in the depression-like behaviors [26][27][28], the PI3K-Akt signaling pathway was related to the rapid antidepressant-like effects of some drugs [29][30][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of rno_circRNA_014900 and rno_circRNA_005442 induced by ketamine in the rat hippocampus

et al. 2020

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Background: Recent studies have shown that circular RNA (circRNA) is rich in microRNA (miRNA) binding sites. We have previously demonstrated that the antidepressant effect of ketamine is related to the abnormal expression of various miRNAs in the brain. This study determined the expression profile of circRNAs in the hippocampus of rats treated with ketamine. Methods: The aberrantly expressed circRNAs in rat hippocampus after ketamine injection were analyzed by microarray chip, and we further validated these circRNAs by quantitative reverse-transcription PCR (qRT-PCR). The target genes of the different circRNAs were predicted using bioinformatic analyses, and the functions and signal pathways of these target genes were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Results: Microarray analysis showed that five circRNAs were aberrantly expressed in rat hippocampus after ketamine injection (fold change > 2.0, p < 0.05). The results from the qRT-PCR showed that one of the circRNAs was significantly increased (rno_circRNA_014900; fold change = 2.37; p = 0.03), while one was significantly reduced (rno_ circRNA_005442; fold change = 0.37; p = 0.01). We discovered a significant enrichment in several GO terms and pathways associated with depression. Conclusion: Our findings showed the abnormal expression of ketamine-induced hippocampal circRNAs in rats.

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“…Previous study has revealed that autophagy contributes to synaptic plasticity and other brain functions through PI3K–Akt–mTOR pathway inhibition (Shehata et al, 2012). Another study found that creatine and ketamine can reverse depressive-like behavior and the underlying mechanism is through regulation of the PI3K/AKT/mTOR pathway, and modulation of synaptic proteins and BDNF in the hippocampus (Pazini et al, 2015). Currently, it has been discovered that stressful events could affect BDNF expression level in hippocampal thus induce depressive phenotypes.…”

Section: Discussionmentioning

confidence: 99%

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

Yang

et al. 2017

Front. Neurosci.

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In the clinic selective serotonin reuptake inhibitors (SSRIs), like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT) via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS) depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3′UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new treatments for depression.

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Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway

Cited by 120 publications

References 85 publications

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine

Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine

Abnormal expression of rno_circRNA_014900 and rno_circRNA_005442 induced by ketamine in the rat hippocampus

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

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