Prophylactic (R,S)-ketamine selectively protects against inflammatory stressors

Mastrodonato, Alessia; Cohensedgh, Omid; LaGamma, Christina T; McGowan, Josephine C.; Hunsberger, Holly C.; Denny, Christine A.

doi:10.1016/j.bbr.2019.112238

Cited by 43 publications

(37 citation statements)

References 47 publications

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“…190 A systematic review looking at predictors of response in TRD suggested that the inflammatory markers interleukin-6 (IL-6), CRP and high-sensitivity CRP (hsCRP) may predict response to antidepressant medications with anti- inflammatory properties, including ketamine. 191 While there is some suggestion from animal studies that racemic ketamine may have anti-inflammatory effects, 192 human studies remain contradictory. Some authors have reported that decreases in inflammatory mediators IL-6 and interleukin-1 alpha (IL-1 alpha) following ketamine treatment have been only transient in the form of hours and have not correlated with antidepressant response, 193,194 but changes in fibroblast growth factor (FG-2) were correlated with antidepressant response.…”

Section: Other Potential Biomarkers For Predicting Response To Ketaminementioning

confidence: 99%

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

Matveychuk

Thomas

Swainson

et al. 2020

Therapeutic Advances in Psychopharmacology

132

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Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine’s effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and [Formula: see text]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

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Section: Other Potential Biomarkers For Predicting Response To Ketaminementioning

confidence: 99%

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

Matveychuk

Thomas

Swainson

et al. 2020

Therapeutic Advances in Psychopharmacology

132

View full text Add to dashboard Cite

show abstract

“…(R,S)-ketamine is a N-methyl-d-aspartate (NMDA) antagonist that is not a traditional antidepressant, but does exhibit antidepressant efficacy in MDD patients (Berman et al, 2000), and has been shown to buffer learned fear expression in rodent models (McGowan et al, 2017). Moreover, (R,S)-ketamine serves as a prophylactic against stress-induced depressive like behaviors in rodent models (Brachman RA, 2016;Mastrodonato et al, 2018;Mastrodonato et al, 2020). In mice where LPS was the inflammatory precursor to the depressive-like behavior, (R,S)-ketamine prior to exposure to LPS attenuated learned fear if treatment occurred 1 week before re-exposure to a stressful condition (Mastrodonato et al, 2020).…”

Section: Anti-inflammatory Effects Of Antidepressant Compoundsmentioning

confidence: 99%

“…Moreover, (R,S)-ketamine serves as a prophylactic against stress-induced depressive like behaviors in rodent models (Brachman RA, 2016;Mastrodonato et al, 2018;Mastrodonato et al, 2020). In mice where LPS was the inflammatory precursor to the depressive-like behavior, (R,S)-ketamine prior to exposure to LPS attenuated learned fear if treatment occurred 1 week before re-exposure to a stressful condition (Mastrodonato et al, 2020).…”

Section: Anti-inflammatory Effects Of Antidepressant Compoundsmentioning

confidence: 99%

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy

Martinez-Muniz

Wood

2020

J Pharmacol Exp Ther

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“…Despite the numerous studies investigating the mechanisms of ketamine's antidepressant effects, few studies have focused on the mechanisms underlying the prophylactic effect of this drug. The available mechanistic studies provide evidence that prophylactic ketamine treatment may act by modulating the neural activity ( Dolzani et al, 2018 ; Mastrodonato et al, 2018 ) and promoting synaptic plasticity in the hippocampus and prefrontal cortex ( Krzystyniak et al, 2019 ) as well as modulating the immune system ( Mastrodonato et al, 2020 ), effects likely associated with its prophylactic response. Furthermore, the antidepressant-like effect, but not the prophylactic effect of ketamine was associated with its ability to increase pro-neurogenic markers ( LaGamma et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway

Camargo

Dalmagro

Souza

et al. 2020

Experimental Neurology

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Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT – 20 mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5 mg/kg, i.p.), but not guanosine (1 or 5 mg/kg, p.o.), given 1 week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3 weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1 mg/kg, i.p.) plus guanosine (5 mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser 473 ) and GSK-3β (Ser 9 ) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus.

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Prophylactic (R,S)-ketamine selectively protects against inflammatory stressors

Cited by 43 publications

References 47 publications

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy

Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway

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