Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway

Camargo, Anderson; Dalmagro, Ana Paula; Fraga, Daiane B.; Rosa, Júlia M.; Zeni, Ana Lúcia Bertarello; Kaster, Manuella P.; Rodrigues, Ana Lúcia S.

doi:10.1007/s00213-021-05879-8

Cited by 16 publications

(2 citation statements)

References 79 publications

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“…From a pharmacological point of view, the dissociation of ambulation from rearing is not unusual ( Lever et al, 2006 ). Moreover, increased anxiety in rodents can increase rearing behavior without affecting the locomotor activity ( Camargo et al, 2021) , whereas anxiolytic drugs such as buspirone may reduce rearing behavior at doses that do not affect the ambulatory activity ( Panickar and McNaughton 1991 ). Since temsirolimus can attenuate anxiogenic-like effects of Δ 9 -THC ( Puighermanal et al, 2013 ), one explanation for the attenuated rearing behavior in shrews injected with 10 mg/kg temsirolimus could be due to a high level of anxiety prior and/ or during emesis.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva)

2022

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Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg (p < 0.05 and p < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg (p < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D2/3 receptors (apomorphine and quinpirole); 2) serotonergic 5-HT3 receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M1 receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK1 receptors (GR73632); 5) the L-type calcium (Ca2+) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca2+ ATPase inhibitor, thapsigargin; 7) the CB1 receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.

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Section: Discussionmentioning

confidence: 99%

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva)

2022

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“…Other studies, however, suggest that R‐ket may have more clinical relevance as it is associated with fewer unwanted psychotomimetic or dissociative symptoms and thus might be better tolerated by patients (Fukumoto et al, 2017; Leal et al, 2021) and several preclinical studies report that R‐ket has longer lasting anti‐depressant effects (Scotton et al, 2022; Yang et al, 2015; Zhang et al, 2014). While multiple rodent studies have shown anxiolytic effects of acute RS‐ket at sub‐anesthetic doses (.1–15 mg/kg) (Camargo et al, 2021; Fraga et al, 2018; Hou et al, 2022), limited studies have investigated the differential effects and behavioral responses induced by the two enantiomers in mice. A better understanding of the role of specific NMDAR subunits, such as the GluN2D subunit, in mediating enantiomer‐specific effects is needed.…”

Section: Introductionmentioning

confidence: 99%

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis‐like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia‐relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia‐relevant NMDAR antagonist‐induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia‐relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S‐ketamine enantiomer (S‐ket), and the ketamine metabolite R‐norketamine (R‐norket) on locomotor activity, anxiety‐related behavior, and recognition and short‐term spatial memory. GluN2D‐KO mice showed a blunted locomotor response to R‐norket, S‐ket, and PCP, a phenotype present in both sexes. GluN2D‐KO mice of both sexes showed an anxious phenotype and S‐ket, R‐norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S‐ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex‐specific effects of NMDAR antagonists and on the differential effects of the R‐ and S‐ket enantiomers.

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Prospecting for a quinoline containing selenium for comorbidities depression and memory impairment induced by restriction stress in mice

et al. 2022

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Rationale Depression is often associated with memory impairment, a clinical feature of Alzheimer’s disease (AD), but no effective treatment is available. 7-Chloro-4-(phenylselanyl) quinoline (4-PSQ) has been studied in experimental models of diseases that affect the central nervous system. Objectives The pharmacological activity of 4-PSQ in depressive-like behavior associated with memory impairment induced by acute restraint stress (ARS) in male Swiss mice was evaluated. Methods ARS is an unavoidable stress model that was applied for a period of 240 min. Ten minutes after ARS, animals were intragastrically treated with canola oil (10 ml/kg) or 4-PSQ (10 mg/kg) or positive controls (paroxetine or donepezil) (10 mg/kg). Then, after 30 min, mice were submitted to behavioral tests. Corticosterone levels were evaluated in plasma and oxidative stress parameters; monoamine oxidase (MAO)-A and MAO -B isoform activity; mRNA expression levels of kappa nuclear factor B (NF-κB); interleukin (IL)-1β, IL-18, and IL-33; phosphatidylinositol-se-kinase (PI3K); protein kinase B (AKT2), as well as acetylcholinesterase activity were evaluated in the prefrontal cortex and hippocampus. Results 4-PSQ attenuated the depressive-like behavior, self-care, and memory impairment caused by ARS. Based on the evidence, we believe that effects of 4-PSQ may be associated, at least in part, with the attenuation of HPA axis activation, attenuation of alterations in the monoaminergic system, modulation of oxidative stress, reestablishment of AChE activity, modulation of the PI3K/AKT2 pathway, and reduction of neuroinflammation. Conclusions These results suggested that 4-PSQ exhibited an antidepressant-like effect and attenuated the memory impairment induced by ARS, and it is a promising molecule to treat these comorbidities.

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Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway

Cited by 16 publications

References 79 publications

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva)

Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew (Cryptotis parva)

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Prospecting for a quinoline containing selenium for comorbidities depression and memory impairment induced by restriction stress in mice

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