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Background: The potential neuroprotective effects of dexmedetomidine against ketamine-induced neurotoxicity remain inconclusive. This study aims to investigate the influence of dexmedetomidine on ketamine-induced neuronal apoptosis and neurodevelopmental toxicity., Methods: In vitro experiments employed concentrations of 0.1 uM for dexmedetomidine and 50 uM for ketamine individually as well as their combination. Changes in apoptotic proteins and dendritic development in neurons were assessed after a 6-h exposure to the drugs with evaluations conducted 24 hs' post-treatment. In vivo experiments entailed intraperitoneal administration starting from postnatal Day 7 (P7) continuously for 3 days (P7-P9) using dosages of 100 mg/kg for ketamine and 1 mg/kg for dexmedetomidine alone or combined. Learning, memory and motor coordination abilities were evaluated via rotary rod tests and shuttle box experiments at P30 and P60, respectively., Results: Dexmedetomidine effectively mitigated ketamine-induced apoptosis in hippocampal neurons but did not alleviate associated dendritic developmental abnormalities. Although causing reduced motor coordination in mice, no improvement was observed with regard to this effect or reaction speed when treated with dexmedetomidine alongside ketamine., Conclusion: This study demonstrates that while dexmedetomidine can mitigate ketamine-induced neuronal apoptosis, it has limited impact on its associated neurodevelopmental toxicities., (© 2024 The Author(s). International Journal of Developmental Neuroscience published by Wiley Periodicals LLC on behalf of International Society for Developmental Neuroscience.)

The incidence of schizophrenia in young adulthood may be associated with intrauterine factors, such as gestational alcohol consumption. This study investigated the relationship between a single high dose of alcohol during pregnancy in Wistar rats and the development of schizophrenia in the adult life of the offspring. On the 11th day of gestation, pregnant rats received either water or alcohol via intragastric gavage. Male and female offspring were subjected to behavioral tests at 30 days of age according to the maternal group. At 60 days of age, offspring received intraperitoneal injections of ketamine (ket) or saline (SAL). After the final ketamine administration, the adult offspring underwent behavioral tests, and their brain structures were removed for biochemical analysis. Alcohol binge drinking during pregnancy induces hyperlocomotion in both young female and male offspring, with males of alcohol-exposed mothers showing reduced social interactions. In adult offspring, ketamine induced hyperlocomotion; however, only females in the alcohol + ket group exhibited increased locomotor activity, and a decrease in the time to first contact was observed in the alcohol group. Cognitive impairment was exclusively observed in male animals in the alcohol group. Increased serotonin and dopamine levels were observed in male rats in the alcohol + ket group. Biochemical alterations indicate the effects of intrauterine alcohol exposure associated with ketamine in adult animals. These behavioral and biochemical changes suggest that the impact of prenatal stressors such as alcohol persists throughout the animals' lives and may be exacerbated by a second stressor in adulthood, such as ketamine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats received intraperitoneal (i.p.) injection of 40 mg/kg ketamine for four consecutive times at 1 h intervals. The present findings revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal neural stem cells (NSCs) by downregulating Mitofusin 2 (Mfn2) expression. In the in vitro study, ketamine treatment at 100 μM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The effects of exposure to environmental pollutants on neurological processes are of increasing concern due to their potential to induce oxidative stress and neurotoxicity. Considering that many industries are currently using different types of plastics as raw materials, packaging, or distribution pipes, microplastics (MPs) have become one of the biggest threats to the environment and human health. These consequences have led to the need to raise the awareness regarding MPs negative neurological effects and implication in neuropsychiatric pathologies, such as schizophrenia. The study aims to use three zebrafish models of schizophrenia obtained by exposure to ketamine (Ket), methionine (Met), and their combination to investigate the effects of MP exposure on various nervous system structures and the possible interactions with oxidative stress. The results showed that MPs can interact with ketamine and methionine, increasing the severity and frequency of optic tectum lesions, while co-exposure (MP+Met+Ket) resulted in attenuated effects. Regarding oxidative status, we found that all exposure formulations led to oxidative stress, changes in antioxidant defense mechanisms, or compensatory responses to oxidative damage. Met exposure induced structural changes such as necrosis and edema, while paradoxically activating periventricular cell proliferation. Taken together, these findings highlight the complex interplay between environmental pollutants and neurotoxicants in modulating neurotoxicity.

Although the stimulative effects on the normal behaviors of fish posed by ketamine (KET) were well-studied, the adverse effects on the behavioral functions induced by KET at nighttime were unknown. Here, we used zebrafish larvae as a model exposed to KET (10, 50, 100, and 250 ng/L) at environmental levels for 21 days. The behavioral functions at nighttime, morphological changes during exposure stage, and alterations on the associated genes transcriptional levels of fish were determined. The difficultly initiating sleep was found in the fish exposed to KET, while the sleep duration of the animals was at the normal levels in exposure groups. The significant suppressions of the developmentally relevant genes, including bmp2, bmp4, and pth2ra were consistent with the developmental abnormalities of fish found in exposure groups. Moreover, the expression of γ-aminobutyric acid (GABA) receptor increased and melatonin (MTN) receptor decreased while the levels of GABA and MTN remained unchanged after exposure, by gene expression analysis and molecular docking. In addition, the transcriptional expression of apoptotic genes, including tp53, aifm1, and casp6, was significantly upregulated by KET. After a 7-day recovery, the insomnia-like behaviors (shorter sleep duration) were observed in zebrafish from the 250 ng/L-KET group. Accordingly, the adverse outcome pathway framework of KET was constructed by prognostic assessment of zebrafish larvae. This study suggested that the adverse outcomes of KET on the sleep health of organisms at environmentally relevant concentrations should be concerned., (© 2024 Wiley Periodicals LLC.)

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats., (U.S. Government work not protected by U.S. copyright.)

Background: Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system., Methods: Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA., Results: Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment., Conclusions: Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Schizophrenia, a complex psychiatric disorder with diverse symptoms, has been linked to ketamine, known for its N-methyl-D-aspartate (NMDA) receptor antagonistic properties. Understanding the distinct roles and mechanisms of ketamine is crucial, especially regarding its induction of schizophrenia-like symptoms. Recent research highlights the impact of ketamine on key brain regions associated with schizophrenia, specifically the prefrontal cortex (PFC) and hippocampus (Hip). This study focused on these regions to explore proteomic changes related to anxiety and cognitive impairment in a chronic ketamine-induced mouse model of schizophrenia. After twelve consecutive days of ketamine administration, brain tissues from these regions were dissected and analyzed. Using tandem mass tag (TMT) labeling quantitative proteomics techniques, 34,797 and 46,740 peptides were identified in PFC and Hip, corresponding to 5,668 and 6,463 proteins, respectively. In the PFC, a total of 113 proteins showed differential expression, primarily associated with the immuno-inflammatory process, calmodulin, postsynaptic density protein, and mitochondrial function. In the Hip, 129 differentially expressed proteins were screened, mainly related to synaptic plasticity proteins and mitochondrial respiratory chain complex-associated proteins. Additionally, we investigated key proteins within the glutamatergic synapse pathway and observed decreased expression levels of phosphorylated CaMKII and CREB. Overall, the study unveiled a significant proteomic signature in the chronic ketamine-induced schizophrenia mouse model, characterized by anxiety and cognitive impairment in both the PFC and Hip, and this comprehensive proteomic dataset may not only enhance our understanding of the molecular mechanisms underlying ketamine-related mental disorders but also offer valuable insights for future disease treatments., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

Aim: We aimed to investigate the preventive effects of carvacrol against ketamine-induced cardiotoxicity biochemically and histopathologically in an experimental model., Material and Method: The rats were divided into three groups; healthy control (HC), ketamine alone (KG), and ketamine + carvacrol (KCG) groups. Serum Creatine Kinase Myocardial Band (CK-MB) and Troponin I (TP I) levels were determined. Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Tumor Necrosis Factor α (TNF-α), Interleukin 1 beta (IL-1beta), and Interleukin 6 (IL-6) levels were measured in the heart tissues of the rats. Heart tissues were also evaluated histopathologically., Results: In the ketamine-treated group, tissue MDA, TNF-α, IL-1beta, and IL-6 levels increased while tissue GSH and SOD levels decreased significantly compared with the control group. However, in the ketamine plus carvacrol applied group, all those alterations were significantly less pronounced, close to the healthy controls. Severe mononuclear cell infiltrations, degenerated myocytes and hemorrhage were determined in the ketamine alone administered group, and these alterations were at a mild level in the carvacrol + ketamine administered group., Conclusion: Prolonged exposure to ketamine resulted in induced oxidative stress in rat heart tissue; concomitant carvacrol application could counteract the negative effects of ketamine by protecting tissues from lipid peroxidation and decreasing the inflammatory response.

Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent evidence showed that general anesthesia produces long-term neurotoxicity and cognitive dysfunction. However, it remains unclear whether maternal non-obstetric surgery under ketamine anesthesia during second trimester causes cognitive impairment in offspring. The present study assigned pregnant rats into three groups: 1) normal control group receiving no anesthesia and no surgery, 2) ketamine group receiving ketamine anesthesia for 2 h on the 14th day of gestation but no surgery, and 3) surgery group receiving abdominal surgery under ketamine anesthesia on the 14th day of gestation. On postnatal day 1, the offspring rats in Ketamine group and surgery group were assigned to receive intra-peritoneal injection of Senegenin (15 mg/kg), once per day for consecutive 14 days. The offspring's spatial perception, anxiety-like behavior, and learning and memory were evaluated. Then the offspring's hippocampal tissues were collected. The offspring of the surgery group were impaired in the spatial perception in the cliff avoidance test and the spatial learning and memory in the Morris water maze test. Accordingly, the activity of histone deacetylases increased, the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 decreased, and the density of dendritic spines reduced in the hippocampus of the offspring of the surgery group, and such effects were not seen in the offspring of the ketamine group, neither in the offspring of control group. Senegenin alleviated the learning and memory impairment, and increased the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 and the density of dendritic spines in the offspring of the surgery group. ketamine anesthesia plus surgery during second trimester impairs hippocampus-dependent learning and memory, and the deficits could be rescued by treatment with Senegenin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Repeated exposure to ketamine during the neonatal period in mice leads to cognitive impairments in adulthood. These impairments are likely caused by synaptic plasticity and excitability damage. We investigated the precise role of brain-derived neurotrophic factor (BDNF) in the cognitive impairments induced by repeated ketamine exposure during the neonatal period., Methods: We evaluated the cognitive function of mice using the Morris water maze test and novel object recognition test. Western blotting and immunofluorescence were used to detect the protein levels of BDNF. Western blotting, Golgi-Cox staining, transmission electron microscopy, and long-term potentiation (LTP) recordings were used to assess synaptic plasticity in the hippocampus. The excitability of neurons was evaluated using c-Fos. In the intervention experiment, pAdeno-CaMKIIα-BDNF-mNeuronGreen was injected into the hippocampal CA1 region of mice to increase the level of BDNF. The excitability of neurons was enhanced using a chemogenetic approach., Results: Our findings suggest that cognitive impairments in mice repeatedly exposed to ketamine during the neonatal period are associated with downregulated BDNF protein level, synaptic plasticity damage, and decreased excitability of glutamatergic neurons in the hippocampal CA1 region. Furthermore, the specific upregulation of BDNF in glutamatergic neurons of the hippocampal CA1 region and the enhancement of excitability can improve impaired synaptic plasticity and cognitive function in mice., Conclusion: BDNF downregulation mediates synaptic plasticity and excitability damage, leading to cognitive impairments in adulthood following repeated ketamine exposure during the neonatal period., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Nanotechnology and its application to manipulate herbal compounds to design new neuroprotective agents to manage neurotoxicity has recently increased. Cur-ZnO conjugated nanoparticles were synthesized and used in an experimental model of ketamine-induced neurotoxicity., Methods: Cur-ZnO conjugated nanoparticles were chemically characterized, and the average crystalline size was determined. Forty-nine adult mice were divided into seven groups of seven animals each. Normal saline was given to control mice (group 1). Ketamine (25 mg/kg) was given to a second group. A third group of mice was given ketamine (25 mg/kg) in combination with curcumin (40 mg/kg), while mice in groups 4, 5, and 6 received ketamine (25 mg/kg) plus Cur-ZnO nanoparticles (10, 20, and 40 mg/kg). Group 7 received only ZnO (5 mg/kg). All doses were ip for 14 days. Hippocampal mitochondrial quadruple complex enzymes, oxidative stress, inflammation, and apoptotic characteristics were assessed., Results: Cur-ZnO nanoparticles and curcumin decreased lipid peroxidation, GSSG content, IL-1β, TNF-α, and Bax levels while increasing GSH and antioxidant enzymes like GPx, GR, and SOD while increasing Bcl-2 level and mitochondrial quadruple complex enzymes in ketamine treatment groups., Conclusion: The neuroprotective properties of Cur-ZnO nanoparticles were efficient in preventing ketamine-induced neurotoxicity in the mouse brain. The nanoparticle form of curcumin (Cur-ZnO) required lower doses to produce neuroprotective effects against ketamine-induced toxicity than conventional curcumin., (© 2023 Wiley Periodicals LLC.)

Aim: To determine the function of miR-384-5p in ketamine-induced neurotoxicity., Material and Methods: Neonatal hippocampal neurons were isolated from rats and treated with varying doses of ketamine. RT-qPCR was utilized to measure the miR-384-5p level in ketamine-treated neurons. Neuronal viability was evaluated by MTT assay. TUNEL staining and flow cytometry were applied to measure neuronal apoptosis. H2-DCFDA staining was utilized to detect the intracellular ROS level. Protein levels were measured using Western blotting. A luciferase reporter experiment was used in HEK293T cells to verify the interaction of miR-384-5p with GABRB1., Results: Ketamine induced neurotoxicity and miR-384-5p upregulation in hippocampal neurons. miR-384-5p downregulation mitigated ketamine-induced neurotoxicity by restraining apoptosis and ROS activity in neurons. GABRB1 was demonstrated to be targeted by miR-384-5p. GABRB1 depletion worsened ketamine-induced neurotoxicity. Moreover, GABRB1 depletion lessened the protective effect of miR-384-5p inhibition against ketamine-mediated neurotoxicity., Conclusion: miR-384-5p regulates ketamine-induced neurotoxicity in hippocampal neurons by targeting GABRB1.

Selecting a method of euthanasia is an important step in designing research studies that use animals; euthanasia methods must be humane, cause minimal pain and suffering to the animal, and preserve the tissue architecture of the organs of interest. In this study, we evaluated the histomorphology of the internal organs (lung, spleen, heart, kidney, liver, brain, and adrenal gland) of rats submitted to five different methods of euthanasia, with the goal of determining which protocol caused the least alteration of histomorphology. Twenty adult Wistar Han rats ( Rattus norvegicus ) were divided into 5 groups of 4 rats each (2 females and 2 males) and were euthanized by CO₂ or isoflurane inhalation, sodium thiopental or xylazine plus ketamine overdose, or decapitation. All euthanasia was performed in accordance with published guidelines and local legal require- ments. Necropsy was performed immediately after euthanasia. Specific internal organs were removed and placed in formalin and submitted for routine histologic processing. Histomorphological examination of hematoxylin and eosin-stained tissues revealed circulatory alterations in multiple organs, predominantly congestion in multiple tissues, pulmonary hemorrhage, and hepatic degeneration. The euthanasia methods that induced the most severe alterations were exposure to CO₂ and anesthetic overdose with xylazine plus ketamine or sodium thiopental. Euthanasia by overexposure to isoflurane caused less damage, and the alterations were of minimal severity. Decapitation resulted in the lowest incidence of lesions in multiple organs but due its traumatic nature, it caused the highest incidence of pulmonary hemorrhage. In selecting a method of euthanasia, factors to consider are the species of animal, the purpose of the research, and the practical ability to perform the procedure to achieve maximal animal welfare without iatrogenic changes that could compromise the outcome and reproducibility of the study.

This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear., (© 2023 International Society for Developmental Neuroscience.)

Ketamine is generally a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that interrelates with various other receptors, contributing to a wide range of actions. They are mainly approved as a general anesthetic, but a low dose of ketamine is applied for pain management, depression, and as analgesics. However, there is a significant concern regarding the long-term usage as antidepressants and as an abused drug. The study mainly aims to exhibit the possible long-term side effects of ketamine as an antidepressant and in recreational users. The study explores the in vitro cytotoxicity revealed on LN-229 cells in a dose-dependent manner. According to the cell viability assays, there is a dose-dependent response toward ketamine. Morphological and nuclear integrity was changed on exposure and assessed using Giemsa, Rhodamine phalloidin, 4',6-diamidino-2-phenylindole (DAPI), and Acridine orange staining. The apoptotic cell death marked by nuclear condensation, Lactate dehydrogenase leakage, pro-inflammatory cytokine (interleukin [IL]-β) release, and inhibition of cell migration was observed. The study highlights the importance of nonanesthetic usage of ketamine, which can lead to severe adverse side effects on long-term exposure rather than a single exposure as an anesthetic agent., (© 2023 Wiley Periodicals LLC.)

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval ( r = -0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.

Background: Ketamine, despite its efficacy in treating depression, raises concerns regarding safety due to potential abuse, cognitive impairment, and bladder toxicity. Ketamine can affect the locus coeruleus (LC) norepinephrine and attention networks. This study explored the protective effects of electroacupuncture (EA) on the LC of rats exposed to repeated administration of ketamine while investigating the potential role of the Calcium CaM-dependent protein kinase II (CAMK II)/ cAMP response element binding protein (CREB) pathway in mediating EA's impact on ketamine-induced neuronal injury in LC., Methods: Rats were repeatedly injected intraperitoneally with ketamine hydrochloride (50 mg/kg) once daily for seven days. Subsequently, EA was performed at the acupoints "Zusanli" (ST36) and "Sanyinjiao" (SP-6) once daily following ketamine administration. The Morris water maze test was employed to assess behavioral changes in the rats. Neuronal injury was examined using Nissl staining, and the expression of CAMK II, CREB, and phospho-CREB (p-CREB) was evaluated through immunohistochemistry and western blotting., Results: EA mitigated the cognitive and exploratory impairments and attenuated neuronal injury in the LC induced by repeated administration of ketamine. The expression of CAMK II and p-CREB proteins in the LC increased following 7 days of ketamine administration. However, EA treatment led to a downregulation of CAMK II and p-CREB expression., Conclusion: Repeated administration of ketamine in male rats can lead to neuronal injury and neurobehavioral dysfunction. However, EA was found to ameliorate neurodegeneration in the LC and enhance neurobehavioral symptoms. This therapeutic effect of EA may be attributed to its modulation of the CAMKII/CREB pathway, thereby mitigating the aforementioned adverse effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed to determine effects of the resveratrol on ketamine-induced schizophrenia-like behaviors and oxidative damage in mice. Twenty-four male mice were allocated into four experimental groups as control, ketamine (20 mg/kg), resveratrol (80 mg/kg) and co-administration of the ketamine (20 mg/kg) + resveratrol (80 mg/kg). Mice were received resveratrol for 30 days and ketamine was used for an animal model of schizophrenia and was injected from days 16 to 30 of the study. After the drug administration was finished, schizophrenia-like behaviors were evaluated using object recognition test, tail suspension test, forced swimming test and open field test and brain malondialdehyde, glutathione peroxidase, superoxide dismutase and catalase levels were determined. According to the results, ketamine treatment significantly decreased body weight and pretreatment with resveratrol elevated body weight compared to ketamine group (P < 0.05). Ketamine treatment significantly decreased number of the cross in open field test and pretreatment with resveratrol improved i (P < 0.05). Immobility time in tail suspension and forced swimming tests increased in mice treated with ketamine (P < 0.05). Pretreatment with resveratrol diminished immobility time compared to ketamine group (P < 0.05). Ketamine significantly decreased memory deficits while pretreatment with resveratrol significantly reduced the memory deficits induced by ketamine (P < 0.05). Brain MDA increased in both cortical and sub-cortical area in ketamine treated mice while pretreatment with resveratrol decreased ketamine-induced elevation in MDA (P < 0.05). Ketamine significantly decreased brain SOD, GPx and CAT levels while pretreatment with resveratrol improved SOD, GPx and CAT levels (P < 0.05). Findings suggested resveratrol has neuroprotective effects against ketamine-induced behavioral deficits and oxidative damages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Agents that act at the N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have gained increasing attention as rapid-acting antidepressants; however, their use has been limited by potential neurotoxicity. Recent FDA guidance requires a demonstration of safety on histologic parameters prior to the initiation of human studies. D-cycloserine (DCS) is a partial NMDA agonist that, along with lurasidone, is being investigated as a treatment for depression. The current study was designed to investigate the neurologic safety profile of DCS. To this end, female Sprague Dawley rats (n = 106) were randomly divided into 8 study groups. Ketamine was administered via tail vein infusion. DCS and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with 3 different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E, silver, and Fluoro-Jade B stains. No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 (positive control) group. We conclude that NRX-101, a fixed-dose combination of DCS/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at supratherapeutic doses of DCS.

Prenatal exposure to anesthetics has raised increasing attention about the neuronal development in offspring. Animal models are usually used for investigation. As a new drug, esketamine is the s-isoform of ketamine and is twice as potent as the racemic ketamine with less reported adverse effects. Esketamine is currently being used and become more favorable in clinical anesthesia work, including surgeries during pregnancy, yet the effect on the offspring is unknown. The present study aimed to elucidate the effects of gestational administration of esketamine on neuronal development in offspring, using a rat model. Gestational day 14.5 pregnant rats received intravenous injections of esketamine. The postnatal day 0 (P0) hippocampus was digested and cultured in vitro to display the neuronal growth morphology. On Day 4 the in vitro experiments revealed a shorter axon length and fewer dendrite branches in the esketamine group. The results from the EdU- imaging kit showed decreased proliferative capacity in the subventricular zone (SVZ) and dentate gyrus (DG) in both P0 and P30 offspring brains in the esketamine group. Moreover, neurogenesis, neuron maturity and spine density were impaired, resulting in attenuated long-term potentiation (LTP). Compromised hippocampal function accounted for the deficits in neuronal cognition, memory and emotion. The evidence obtained suggests that the neurobehavioral deficit due to prenatal exposure to esketamine may be related to the decrease phosphorylation of CREB and abnormalities in N-methyl-D-aspartic acid receptor subunits. Taken together, these results demonstrate the negative effect of prenatal esketamine exposure on neuronal development in offspring rats. G14.5 esketamine administration influenced the neurobehavior of the offspring in adolescence. Poorer neuronal growth and reduced brain proliferative capacity in late gestation and juvenile pups resulted in impaired P30 neuronal plasticity and synaptic spines as well as abnormalities in NMDAR subunits. Attenuated LTP reflected compromised hippocampal function, as confirmed by behavioral tests of cognition, memory and emotions. This figure was completed on the website of Figdraw., (© 2023. The Author(s).)

Zebrafish is known for its widespread neurogenesis and regenerative capacity, as well as several biological advantages, which turned it into a relevant animal model in several areas of research, namely in toxicological studies. Ketamine is a well-known anesthetic used both in human as well as veterinary medicine, due to its safety, short duration and unique mode of action. However, ketamine administration is associated with neurotoxic effects and neuronal death, which renders its use on pediatric medicine problematic. Thus, the evaluation of ketamine effects administration at early stages of neurogenesis is of pivotal importance. The 1-41-4 somites stage of zebrafish embryo development corresponds to the beginning of segmentation and formation of neural tube. In this species, as well as in other vertebrates, longitudinal studies are scarce, and the evaluation of ketamine long-term effects in adults is poorly understood. This study aimed to assess the effects of ketamine administration at the 1-4 somites stage, both in subanesthetic and anesthetic concentrations, in brain cellular proliferation, pluripotency and death mechanisms in place during early and adult neurogenesis. For that purpose, embryos at the 1-4 somites stage (10.5 h post fertilization - hpf) were distributed into study groups and exposed for 20 min to ketamine concentrations at 0.2/0.8 mg/mL. Animals were grown until defined check points, namely 50 hpf, 144 hpf and 7 months adults. The assessment of the expression and distribution patterns of proliferating cell nuclear antigen (PCNA), of sex-determining region Y-box 2 (Sox 2), apoptosis-inducing factor (AIF) and microtubule-associated protein 1 light chain 3 (LC3) was performed by Western-blot and immunohistochemistry. The results evidenced the main alterations in 144 hpf larvae, namely in autophagy and in cellular proliferation at the highest concentration of ketamine (0.8 mg/mL). Nonetheless, in adults no significant alterations were seen, pointing to a return to a homeostatic stage. This study allowed clarifying some of the aspects pertaining the longitudinal effects of ketamine administration regarding the CNS capacity to proliferate and activate the appropriate cell death and repair mechanisms leading to homeostasis in zebrafish. Moreover, the results indicate that ketamine administration at 1-4 somites stage in the subanesthetic and anesthetic concentrations despite some transitory detrimental effects at 144 hpf, is long-term safe for CNS, which are newly and promising results in this research field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Ketamine, an NMDA antagonist, is widely used in clinical settings. Recently, low-dose ketamine has gained attention because of its promising role as a rapid antidepressant. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaques as subjects and found that acute low-dose ketamine administration significantly impaired the ability for arbitrary visuomotor mapping (AVM), a form of associative learning (AL) essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on combining associative learning and another key higher cognitive function, working memory (WM). Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Zhao et al.)

Ketamine is a dissociative anaesthetic used to induce general anaesthesia in humans and laboratory animals. Due to its hallucinogenic and dissociative effects, it is also used as a recreational drug. Anaesthetic agents can cause toxic effects at the cellular level and affect cell survival, induce DNA damage, and cause oxidant/antioxidant imbalance. The aim of this study was to explore these possible adverse effects of ketamine on hepatocellular HepG2 and neuroblastoma SH-SY5Y cells after 24-hour exposure to a concentration range covering concentrations used in analgesia, drug abuse, and anaesthesia (0.39, 1.56, and 6.25 µmol/L, respectively). At these concentrations ketamine had relatively low toxic outcomes, as it lowered HepG2 and SH-SY5Y cell viability up to 30 %, and low, potentially repairable DNA damage. Interestingly, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) remained unchanged in both cell lines. On the other hand, oxidative stress markers [superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)] pointed to ketamine-induced oxidant/antioxidant imbalance., (© 2023 Andreja Jurič et al., published by Sciendo.)

Ketamine, the widely used intravenous anesthetic, has been reported to cause neurotoxicity and disturbs normal neurogenesis. However, the efficacy of current treatment strategies targeting ketamine's neurotoxicity remains limited. Lipoxin A4 methyl ester (LXA4 ME) is relatively stable lipoxin analog, which serves an important role in protecting against early brain injury. The purpose of this study was to investigate the protective effect of LXA4 ME on ketamine-caused cytotoxicity in SH-SY5Y cells, as well as the underlying mechanisms. Cell viability, apoptosis and endoplasmic reticulum stress (ER stress) were detected by adopting experimental techniques including CCK-8 assay, flow cytometry, western blotting and transmission electron microscope. Furthermore, examining the expression of leptin and its receptor (LepRb), we also measured the levels of activation of the leptin signaling pathway. Our results showed that LXA4 ME intervention promoted the cell viability, inhibited cell apoptosis, and reduced the expression of ER stress related protein and morphological changes induced by ketamine. In addition, inhibition of leptin signaling pathway caused by ketamine could be reversed by LXA4 ME. However, as the specific inhibitor of leptin pathway, leptin antagonist triple mutant human recombinant (leptin tA) attenuated the cytoprotective effect of LXA4 ME against ketamine-induced neurotoxicity. In conclusion, our findings demonstrated LXA4 ME could exert a neuroprotective effect on ketamine-induced neuronal injury via activation of the leptin signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypothermic circulatory arrest is a protective technique used when complete cessation of circulation is required during cardiac surgery. Prior efforts to decrease neurologic injury with the NMDA receptor antagonist MK801 were limited by unacceptable side effects. We hypothesized that ketamine would provide neuroprotection without dose-limiting side effects. Canines were peripherally cannulated for cardiopulmonary bypass, cooled to 18°C, and underwent 90 minutes of circulatory arrest. Ketamine-treated canines (n = 5; total dose 2.85 mg/kg) were compared to untreated controls (n = 10). A validated neurobehavioral deficit score was obtained at 24, 48, and 72 hours (0 = no deficits/normal exam; higher score represents increasing deficits). Biomarkers of neuronal injury in the cerebrospinal fluid were examined at baseline and at 8, 24, 48, and 72 hours. Brain histopathologic injury was scored at 72 hours (higher score indicates more necrosis and apoptosis). Ketamine-treated canines had significantly improved, lower neurobehavioral deficit scores compared to controls (overall P = 0.003; 24 hours: median 72 vs 112, P = 0.030; 48 hours: 47 vs 90, P = 0.021; 72 hours: 30 vs 89, P = 0.069). Although the histopathologic injury scores of ketamine-treated canines (median 12) were lower than controls (16), there was no statistical difference (P = 0.10). Levels of phosphorylated neurofilament-H and neuron specific enolase, markers of neuronal injury, were significantly lower in ketamine-treated animals (P = 0.010 and = 0.039, respectively). Ketamine significantly reduced neurologic deficits and biomarkers of injury in canines after hypothermic circulatory arrest. Ketamine represents a safe and approved medication that may be useful as a pharmacologic neuroprotectant during cardiac surgery with circulatory arrest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ketamine is an intravenous anesthetic. However, whether ketamine can induce neurotoxicity and neurobehavioral deficits remains largely unknown. Delirium is a syndrome of acute brain dysfunction associated with anesthesia and surgery in patients, and tau protein may contribute to postoperative delirium. Finally, ketamine may affect the function of the endosome, the key organelle for tau release from neurons. Therefore, we set out to determine the effects of ketamine on delirium-like behavior in mice and on tau trafficking in cultured cells., Methods: We used the buried-food test, open-field test, and Y-maze test in adult mice to assess the presence of delirium-like behavior in mice. We quantified tau amounts in the serum of mice. We used cell fraction methods to determine the effects of ketamine on tau intracellular trafficking, extracellular release, and endosome trafficking in cultured cells., Results: Ketamine induced delirium-like behavior in mice and increased tau amounts in serum of mice. The ketamine treatments also led to increased accumulation of endosomes, as evidenced by increased endosomal markers Rab5 and Rab7. Moreover, ketamine inhibited endosome maturation, demonstrated by decreased membrane-bound but increased cytoplasm amounts of Rab5 and Rab7. Consequently, ketamine increased tau in the endosomes of cultured cells and the cell culture medium., Conclusions: These data suggest that ketamine may interfere with intracellular tau trafficking and induce delirium-like behavior, promoting future research regarding the potential neurotoxicity of anesthetics., Competing Interests: Conflicts of Interests: See Disclosure at the end of the article., (Copyright © 2020 International Anesthesia Research Society.)

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential β-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine's clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20 mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14 days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum, prefrontal-cortex and hippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: To investigate curcumin's protective effect on nerve damage caused by ketamine anesthesia via the Nrf2 signaling pathway. Rats and PC12 cells were used in this experiment to investigate the mechanism of nerve injury caused by ketamine anesthesia. Furthermore, our findings suggest that curcumin may affect oxidative stress and apoptosis by targeting the Nrf2 pathway, thereby alleviating the nerve injury caused by ketamine., Methods: The rat cerebral cortex and hippocampus were stained with Nissl and immunohistochemistry to determine the number of neurons and the expression of Caspase-3, Bcl-2, and Bax. CCK-8 assay was used to determine the optimal concentration of ketamine, curcumin, and H 2 O 2 in PC12 cells. Flow cytometry was used to detect changes in reactive oxygen species and the rate of apoptosis in each group. To determine whether Nrf2 entered the nucleus, immunofluorescence was used. Both tissues and cells were subjected to RT-PCR and Western blotting detection at the same time. The levels of oxidative stress were determined using a malondialdehyde (MDA) and superoxide dismutase (SOD) assay kit., Results: Ketamine reduced the number of neurons in the cortex and hippocampus of rats. The proteins Bax and Caspase-3 were upregulated, while Bcl-2 was down-regulated in the cortex and hippocampus. The viability of PC12 cells has decreased. MDA content increased while SOD activity decreased in cortex, hippocampus, and PC12 cells. Ketamine had an effect on the expression of some genes in the Nrf2 signaling pathway as well as apoptosis. Curcumin pretreatment may be able to prevent ketamine-induced damage., Conclusions: The oxidative stress and apoptosis caused by ketamine during growth of the cerebral cortex, hippocampus, and PC12 cells may be decreased by curcumin's activation of the Nrf2 signaling pathway. Our research provides a potential strategy for the secure administration of anesthetics in medical settings., (© 2022 Wiley Periodicals LLC.)

Ketamine, a popular anesthetic, is often abused by people for its hallucinogenic effect. Thus, the safety of ketamine in pediatric populations has been called into question for potential neurotoxic effects. However, ketamine also has neuroprotective effects in many brain injury models. The differentiation of neural stem cells (NSCs) was influenced significantly by ketamine, but the molecular mechanism is still unclear. NSCs were extracted from the hippocampi of postnatal day 1 rats and treated with ketamine to induce NSCs differentiation. Our results found that ketamine promoted neuronal differentiation of NSCs dose-dependently in a small dose range (P < 0.001). The main types of neurons from NSCs were cholinergic (51 ± 4 %; 95 % CI: 41-61 %) and glutamatergic neurons (34 ± 3 %; 95 % CI: 27-42 %). Furthermore, we performed RNA sequencing to promise a more comprehensive understanding of the molecules regulated by ketamine. Finally, we combined bioimaging and multiple molecular biology techniques to clarify that ketamine influences NSC differentiation by regulating transient receptor potential canonical 3 (TRPC3) expressions. Ketamine dramatically repressed TRPC3 expression (MD [95 % CI]=0.67 [0.40-0.95], P < 0.001) with a significant increase of phosphorylated glycogen synthase kinase 3β (p-GSK3β; MD [95 % CI]=1.00 [0.74-1.27], P < 0.001) and a decrease of β-catenin protein expression (MD [95 % CI]=0.60 [0.32-0.89], P = 0.001), thereby promoting the differentiation of NSCs into neurons and inhibiting their differentiation into astrocytes. These results suggest that TRPC3 is necessary for ketamine to modulate NSC differentiation, which occurs partly via regulation of the GSK3β/β-catenin pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Cholinergic, oxidative, nitrergic alterations, and neuroinflammation are some key neuropathological features common in schizophrenia disease. They involve complex biological processes that alter normal behavior. The present treatments used in the management of the disorder remain ineffective together with some serious side effects as one of their setbacks. Taurine is a naturally occurring essential β-amino acid reported to elicit antipsychotic property in first episode psychosis in clinical setting, thus require preclinical investigation. Hence, we set out to investigate the effects of taurine in the prevention and reversal of ketamine-induced psychotic-like behaviors and the associated putative neurobiological mechanisms underlying its effects. Adult male Swiss mice were sheared into three separate cohorts of experiments (n = 7): drug alone, preventive and reversal studies. Treatments consisted of saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) with concomitant ketamine (20 mg/kg/i.p./day) injections between days 8-14, or 14 days entirely. Behavioral hyperactivity, despair, cognitive impairment, and catalepsy were measured. Brain oxidative/nitrergic imbalance, immunoreactivity (COX-2 and iNOS), and cholinergic markers were determined in the striatum, prefrontal-cortex, and hippocampus. Taurine abates ketamine-mediated psychotic-like episodes without cataleptogenic potential. Taurine attenuated ketamine-induced decrease in glutathione, superoxide-dismutase and catalase levels in the striatum, prefrontal-cortex and hippocampus. Also, taurine prevented and reversed ketamine-mediated elevation of malondialdehyde, nitrite contents, acetylcholinesterase activity, and suppressed COX-2 and iNOS expressions in a brain-region dependent manner. Conclusively, taurine insulates against ketamine-mediated psychotic phenotype by normalizing brain central cholinergic neurotransmissions, oxidative, nitrergic and suppression of immunoreactive proteins in mice brains., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As a clinically widely used anesthetic, ketamine (KET) has been reported to cause neurotoxicity in patients. Our work aimed to probe the function of long-chain non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) in KET-induced neurotoxicity. HT22 cells were subjected to KET to build the cell model. 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide (MTT) assay was employed to determine cell viability. Additionally, cell apoptosis was evaluated by flow cytometry. The binding relationships among TUG1, DEAD-box RNA helicase 3X (DDX3X), and Bcl-2-associated athanogene 5 (BAG5) were verified by RIP and RNA pull-down assays. Cell viability was impaired and cell apoptosis was increased in KET-treated HT22 cells accompanied by increased TUG1, DDX3X, and BAG5 expressions. TUG1 knockdown dramatically enhanced cell viability and repressed the of KET-induced apoptosis in HT22 cells, while TUG1 overexpression presented the opposite effects. In addition, we found that TUG1 promoted DDX3X expression via directly binding with DDX3X. As expected, DDX3X overexpression abolished the palliative effect of TUG1 knockdown on KET-induced neurotoxicity. Further research proved that TUG1 increased the stability of BAG5 through interacting with DDX3X. Finally, as expected, the moderating effect of TUG1 knockdown on KET-induced neuron injury was abolished by BAG5 overexpression. Taken together, TUG1 promoted BAG5 expression by binding DDX3X to exacerbate KET-induced neurotoxicity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Preclinical models demonstrate that nearly all anesthetics cause widespread neuroapoptosis in the developing brains of infant rodents and non-human primates. Anesthesia-induced developmental apoptosis is succeeded by prolonged neuropathology in the surviving neurons and lasting cognitive impairments, suggesting that anesthetics interfere with the normal developmental trajectory of the brain. However, little is known about effects of anesthetics on stereotyped axonal pruning, an important developmental algorithm that sculpts neural circuits for proper function. Here, we proposed that neonatal ketamine exposure may interfere with stereotyped axonal pruning of the infrapyramidal bundle (IPB) of the hippocampal mossy fiber system and that impaired pruning may be associated with alterations in the synaptic transmission of CA3 neurons. To test this hypothesis, we injected postnatal day 7 (PND7) mouse pups with ketamine or vehicle over 6 h and then studied them at different developmental stages corresponding to IPB pruning (PND20-40). Immunohistochemistry with synaptoporin (a marker of mossy fibers) revealed that in juvenile mice treated with ketamine at PND7, but not in vehicle-treated controls, positive IPB fibers extended farther into the stratum pyramidale of CA3 region. Furthermore, immunofluorescent double labeling for synaptoporin and PSD-95 strongly suggested that the unpruned IPB caused by neonatal ketamine exposure makes functional synapses. Importantly, patch-clamp electrophysiology for miniature excitatory postsynaptic currents (mEPSCs) in acute brain slices ex vivo revealed increased frequency and amplitudes of mEPSCs in hippocampal CA3 neurons in ketamine-treated groups when compared to vehicle controls. We conclude that neonatal ketamine exposure interferes with normal neural circuit development and that this interference leads to lasting increase in excitatory synaptic transmission in hippocampus., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Background: Ketamine anesthesia increased glucose metabolism in most brain regions compared to another intravenous anesthetic propofol. However, whether the changes in cerebral metabolic networks induced by ketamine share the same mechanism with propofol remains to be explored. The purpose of the present study was to identify specific features of metabolic network in rat brains during ketamine-induced subanesthesia state and anesthesia state compared to awake state., Methods: We acquired fluorodeoxyglucose positron emission tomography (FDG-PET) images in 20 healthy adult Sprague-Dawley rats that were intravenously administrated saline and ketamine to achieve different conscious states: awake (normal saline), subanesthesia (30 mg kg -1 h -1 ), and anesthesia (160 mg kg -1 h -1 ). Based on the FDG-PET data, the alterations in cerebral glucose metabolism and metabolic topography were investigated by graph-theory analysis., Results: The baseline metabolism in rat brains was found significantly increased during ketamine-induced subanesthesia and anesthesia. The graph-theory analysis manifested a reduction in metabolism connectivity and network global/local efficiency across cortical regions and an increase across subcortical regions during ketamine-induced anesthesia (nonparametric permutation test: global efficiency between awake and anesthesia, cortex: P = .016, subcortex: P = .015; global efficiency between subanesthesia and anesthesia, subcortex: P = .012)., Conclusions: Ketamine broadly increased brain metabolism alongside decreased metabolic connectivity and network efficiency of cortex network. Modulation of these cortical metabolic networks may be a candidate mechanism underlying general anesthesia-induced loss of consciousness., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Background: Anesthesia and psychotropic drugs in pregnant women may cause long-term effects on the brain development of unborn babies. The authors set out to investigate the neurotoxicity of S-ketamine, which possesses anesthetic and antidepressant effects and may cause attention deficit hyperactivity disorder (ADHD)- and depression-like behaviors in offspring mice., Methods: Pregnant mice were administered with low-, medium-, and high-dose S-ketamine (15, 30, and 60 mg/kg) by intraperitoneal injection for 5 days from gestational day 14-18. At 21 days after birth, an elevated plus-maze test, fear conditioning, open field test, and forced swimming test were used to assess ADHD- and depression-like behaviors. Neuronal amount, glial activation, synaptic function indicated by ki67, and inhibitory presynaptic proteins revealed by GAD2 in the hippocampus, amygdala, habenula nucleus, and lateral hypothalamus (LHA) were determined by immunofluorescence assay., Results: All the pregnant mice exposed to high-dose S-ketamine administration had miscarriage after the first injection. Both low-dose and medium-dose S-ketamine administration significantly increased the open-arm time and attenuated frozen time in the fear conditioning, which indicates impulsivity and memory dysfunction-like behaviors. Medium-dose S-ketamine administration reduced locomotor activity in the open field and increased immobility time in the forced swimming test, indicating depression-like behaviors. Changes in astrocytic activation, synaptic dysfunction, and decreased inhibitory presynaptic proteins were found in the hippocampus, amygdala, and habenula nucleus., Conclusions: These results demonstrate that S-ketamine may lead to detrimental effects, including ADHD-and depression-like behaviors in offspring mice. More studies should be promoted to determine the neurotoxicity of S-ketamine in the developing brain., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. Many experimental studies have shown that ketamine can induce cognitive impairments and schizophrenia-like symptoms. While much data have demonstrated that glial cells are associated with the pathophysiology of psychiatric disorders, including schizophrenia, the response of glial cells to ketamine and its significance to schizophrenia are not clear. The present study was intended to explore whether chronic ketamine treatment would induce behavioral and glial changes in mice. First, ketamine was used to stimulate behavioral abnormalities similar to schizophrenia evaluated by the open field test, elevated plus-maze test, Y maze test, novel object recognition test, and tail suspension test. Secondly, histopathology and Nissl staining were performed. Meanwhile, immunofluorescence was used to evaluate the expression levels of IBA-1 (a microglial marker) and GFAP (an astrocyte marker) in the mouse hippocampus for any change. Then, ELISA was used to analyze proinflammatory cytokine levels for any change. Our results showed that ketamine (25 mg/kg, i.p., qid, 12 days) induced anxiety, recognition deficits, and neuronal injury in the hippocampus. Moreover, chronic ketamine treatment enhanced GFAP expression in CA1 and DG regions of the hippocampus but did not influence the expression of IBA-1. Ketamine also increased the levels of IL-1β, IL-6, and TNF-α in the mouse hippocampus. Our study created a new procedure for ketamine administration, which successfully induce negative symptoms and cognitive-behavioral defects in schizophrenia by chronic ketamine. This study further revealed that an increase in astrocytosis, but not microglia, is associated with the mouse model of schizophrenia caused by ketamine. In summary, hippocampal astrocytes may be involved in the pathophysiology of ketamine-induced schizophrenia-like phenotypes through reactive transformation and regulation of neuroinflammation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ketamine is a widely-used anesthetic in the field of pediatrics and obstetrics. Multiple studies have revealed that ketamine causes neurotoxicity in developing animals. However, further studies are needed to determine whether clinical doses of ketamine (20 mg/kg) are able to cause kidney damage in developing animals. Herein, we investigated the effects of continuous ketamine exposure on kidney injury and pyroptosis in seven-day-old rats. Serum renal function indicators, renal histopathological analysis, pyroptosis, as well as oxidative stress indicators, were tested. Additionally, the NLRP3 inhibitor MCC950 and the Caspase-1 inhibitor VX765 were used to evaluate the role of the NLRP3/Caspase-1 axis in ketamine-induced kidney injury among developing rats. Our findings indicate that ketamine exposure causes renal histopathological injury, increased the levels of blood urea nitrogen (BUN) and creatinine (Cre), and led to upregulation in the levels of pyroptosis. Furthermore, we found that ketamine induced an increase in levels of reactive oxygen species (ROS) and malonaldehyde (MDA), as well as a decrease in the content of glutathione (GSH) and catalase (CAT) in the kidneys of neonatal rats. Moreover, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis and reduced renal damage after continuous ketamine exposure. In conclusion, this study suggested that continued exposure to ketamine caused kidney damage among neonatal rats and that the NLRP3/Caspase-1 axis-related pyroptosis may be involved in this process., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Early exposures to anesthetics can cause long-lasting changes in excitatory/inhibitory synaptic transmission (E/I imbalance), an important mechanism for neurodevelopmental disorders. Since E/I imbalance is also involved with addiction, we further investigated possible changes in addiction-related behaviors after multiple ketamine anesthesia in late postnatal mice. Postnatal day (PND) 16 mice received multiple ketamine anesthesia (35 mg kg -1 , 5 days), and behavioral changes were evaluated at PND28 and PND56. Although mice exposed to early anesthesia displayed normal behavioral sensitization, we found significant increases in conditioned place preference to both low-dose ketamine (20 mg kg -1 ) and nicotine (0.5 mg kg -1 ). By performing transcriptome analysis and whole-cell recordings in the hippocampus, a brain region involved with CPP, we also discovered enhanced neuronal excitability and E/I imbalance in CA1 pyramidal neurons. Interestingly, these changes were not found in female mice. Our results suggest that repeated ketamine anesthesia during neurodevelopment may influence drug reward behavior later in life., (© 2022. The Author(s).)

Ketamine has traditionally been used as a dissociative anesthetic agent and more recently as a treatment for treatment-resistant depression. However, there is growing concern over the increased use of ketamine in recreational and therapeutic settings due to the potential neurotoxic effects. Recent studies have demonstrated that ketamine is cytotoxic in several cell types, such as fibroblasts, hepatocytes, uroepithelial cells, and adult induced pluripotent stem cells (iPSCs). Ketamine has been shown to dysregulate calcium signalling, increase reactive oxygen species (ROS) production, and impair mitochondrial function, ultimately leading to apoptosis. However, it is unclear whether endoplasmic reticulum (ER) stress plays a role in ketamine associated neurotoxicity in striatal neurons. Disruption to ER homeostasis can initiate ER-mediated cell death, which has been implicated in several neurodegenerative diseases. Thus, the purpose of this study was to determine whether ketamine's neurotoxic effects involve an ER stress-dependent pathway and to elucidate the underlying mechanisms involved in its neurotoxic effects. Mouse striatal cells were treated with various concentrations of ketamine (10 μM, 100 μM, 1 mM) or DMEM for 9-72 hrs. Cell viability was assessed using the MTT assay, and changes in gene expression of ER stress markers were evaluated using RT-qPCR. MTT results revealed that 1 mM ketamine decreased cell viability in striatal cells after 24 h of treatment. Gene expression studies complemented these findings such that ketamine upregulated pro-apoptotic ER stress markers, including X-box binding protein 1 (XBP1), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) and downregulated pro-survival ER stress proteins such as GRP78, MANF and CDNF. Ketamine activated all three stress sensing pathways including PERK, IRE1, and ATF6. Taken together, our results show that ketamine-induced neurotoxicity is mediated through an ER stress-dependent apoptotic pathway., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The abnormal expression of the dopamine D1 receptor (DRD1) may be associated with schizophrenia. MicroRNAs (miRNAs) can post-transcriptionally regulate DRD1 expression. Here, we established a ketamine-induced schizophrenia-like behavior mouse model and investigated the changes in miR-15a-3p, miR-15b-3p, miR-16-1-3p, and DRD1 in response to ketamine. Administration of high-dose ketamine for seven consecutive days to mice simulated the main symptoms of schizophrenia. The mice exhibited increasing excitability and autonomous activity and reduced learning and memory, including spatial memory. Moreover, ketamine decreased miR-15a-3p, miR-15b-3p, and miR-16-1-3p expression levels in the prefrontal cortex (PFC) and miR-16-1-3p expression in the hippocampus, whereas DRD1 expression increased in these brain regions. In HT22 mouse hippocampal neuronal cells, ketamine induced a dose-dependent increase of endogenous DRD1, which was partially attenuated by a combination of miR-15b-3p and miR-16-1-3p mimics. Indeed, the miR-15b-3p and miR-16-1-3p mimics could significantly inhibit endogenous DRD1expression. We identified +72 to +78 bp (TGCTGCT) of the DRD1 3'UTR as the core regulatory region recognized by the target miRNAs. In summary, we developed a ketamine-induced schizophrenia-like behavior mouse model and found that ketamine inhibited the levels of miR-15a-3p, miR-15b-3p, miR-16-1-3p and increased DRD1 expression in mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Ketamine, a multimodal dissociative anesthetic drug, is widely used as an analgesic following traumatic injury. Although ketamine may produce anti-inflammatory effects when administered after injury, the immunomodulatory properties of intravenous (IV) ketamine in a non-inflammatory condition are unclear. In addition, most preclinical studies use an intraperitoneal (IP) injection of ketamine, which limits its clinical translation as patients usually receive an IV ketamine infusion after injury., Methods: Here, we administered sub-anesthetic doses of a single IV ketamine infusion (0, 10, or 40 mg/kg) to male and female Sprague-Dawley rats over a 2-h period. We collected blood samples at 2- and 4-h post-ketamine infusion to determine plasma inflammatory cytokine levels using multiplex immunoassays., Results: The 10 mg/kg ketamine infusion reduced spontaneous locomotor activity in male and female rats, while the 40 mg/kg infusion stimulated activity in female, but not male, rats. The IV ketamine infusion produced dose-dependent and sex-specific effects on plasma inflammatory cytokine levels. A ketamine infusion reduced KC/GRO and tumor necrosis factor alpha (TNF-α) levels in both male and female rats, interleukin-6 (IL-6) levels in female rats, and interleukin-10 (IL-10) levels in male rats. However, most cytokine levels returned to control levels at 4-h post-infusion, except for IL-6 levels in male rats and TNF-α levels in female rats, indicating a different trajectory of certain cytokine changes over time following ketamine administration., Conclusions: The current findings suggest that sub-anesthetic doses of an IV ketamine infusion may produce sex-related differences in the effects on peripheral inflammatory markers in rodents, and further research is warranted to determine potential therapeutic effects of an IV ketamine infusion in an inflammatory condition., (© 2022. The Author(s).)

Ketamine is a dissociative anesthetic in human and veterinary clinic, as well as an abuse drug that acts on several neurotransmitter systems. The use of alternative animal models, such as zebrafish, is emerging to study the effects of drugs on neurobehavioral responses. Here, we evaluated the effects of ketamine on memory consolidation (acute protocol), as well as on anxiety-, aggressive-like behavior, and whole-body cortisol levels in adult zebrafish after a repeated exposure. For the acute protocol, fish were tested in the inhibitory avoidance task (training and testing with a 24-hour interval). Immediately after the training session, fish were exposed to ketamine (0, 2, 20, or 40 mg/L) for 20 min. The exploratory activity was also measured 24 h after acute exposure to exclude the influence of impaired locomotion on memory performance. For the repeated exposure, animals were exposed to the same concentrations of ketamine for 20 min (7 days). After the last exposure (24 h later), anxiety- and aggression-like behaviors were quantified in the novel tank and mirror-induced aggression tests, respectively, as well as whole-body cortisol levels measurements were performed. The highest ketamine concentration tested (40 mg/L) acutely induced a slight memory impairment in the inhibitory avoidance task without changing locomotion and anxiety-like behaviors. Although locomotion, anxiety-, aggressive-like behaviors, and whole-body cortisol levels did not change after repeated exposure, 40 mg/L ketamine increased circling behavior. Overall, our data reinforce that ketamine acutely affects multiple behavioral domains in zebrafish, in which repeated ketamine exposure elicits stereotyped behavior, without changing locomotion, aggression, and anxiety/stress-related parameters., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In the literature, it has been suggested that ketamine-related oxidative organ damage results from increased blood adrenaline level, and thiopental-related oxidative damage is caused by decreased adrenaline level, suggesting that ketamine-thiopental combination (KT) may be beneficial in reducing the hepatotoxic effect of ketamine., Objectives: To biochemically investigate the effects of ketamine, thiopental and KT on the liver in rats., Material and Methods: Male albino Wistar type rats received intraperitoneally (ip.) 30 mg/kg ketamine in the ketamine alone (KG) group (n = 6), 15 mg/kg thiopental in the thiopental alone (TG) group (n = 6), and 30 mg/kg ketamine + 15 mg/kg thiopental in the ketamine+thiopental (KTG) group (n = 6). The same volume of distilled water as solvent was given to the healthy (HG) animal group. This procedure was repeated once daily for 30 days. At the end of this period, the animals were killed by decapitation and their livers were removed. In liver tissue, malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-6 (IL-6) levels were measured. The IL-1β, IL-6, TNF-α, adrenalin (ADR), noradrenalin (NDR), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were determined in blood samples taken from the tail veins., Results: In the group treated with ketamine and thiopental alone, MDA, TOS, IL-1β, IL-6, TNF-α, ADR, NDR, ALT, and AST levels were found to be high, and those of tGSH and TAS to be low. However, there was no significant change in the levels of these parameters in the KTG., Conclusions: These results indicate that oxidative stress and inflammation developed in the liver tissue of the group that used ketamine and thiopental alone, suggesting that the KT form may be safer in terms of toxicity in the clinical usage.

Ketamine is a chiral drug used for various clinical purposes but often misused. It is metabolized to norketamine, an active chiral metabolite. Both substances have been detected in environmental matrices, but studies about their enantioselective toxic effects are scarce. In the present study, the enantiomers of ketamine and norketamine were separated by a semipreparative enantioselective liquid chromatography method, and their toxicity was investigated in different aquatic organisms. The enantioseparation was achieved using a homemade semipreparative chiral column. Optimized conditions allowed the recovery of compounds with enantiomeric purity higher than 99%, except for (R)-ketamine (97%). The absolute configuration of the enantiomers was achieved by experimental electronic circular dichroism (ECD). The ecotoxicity assays were performed with the microcrustacean Daphnia magna and the protozoan Tetrahymena thermophila using Toxkit MicroBioTests. Different concentrations were tested (0.1-10 000 µg/L) to include environmental levels (~0.5-~100 µg/L), for racemates (R,S) and the isolated enantiomers (R or S) of ketamine and norketamine. No toxicity was observed in either organism at environmental levels. However, at greater concentrations, (R,S)-ketamine presented higher mortality for D. magna compared with its metabolite (R,S)-norketamine (85 and 20%, respectively), and the (S)-ketamine enantiomer showed higher toxicity than the (R)-ketamine enantiomer. In addition, (S)-ketamine also presented higher growth inhibition than (R)-ketamine for T. thermophila at the highest concentrations (5000 and 10 000 µg/L). Contrary to D. magna, growth inhibition was observed for both enantiomers of norketamine and in the same magnitude order of the (S)-ketamine enantiomer. The results showed that the 2 organisms had different susceptibilities to norketamine and that the toxicity of ketamine at high concentrations is enantioselective for both organisms. Environ Toxicol Chem 2022;41:569-579. © 2020 SETAC., (© 2020 SETAC.)

Introduction: Ketamine-induced cystitis (KIC) is a disease caused by ketamine that can cause lower urinary tract symptoms (LUTS). Its end-stage is bladder contracture, which is related to bladder fibrosis and poses a serious burden to patient lives., Methods: We established a KIC model in female Sprague Dawley rats and verified bladder fibrosis in the model by Masson trichrome staining and western blot analysis. The bladders of the rats from the ketamine and control groups were used to perform transcriptome analysis. In particular, association analysis with metabolomics was also used to determine the potential mechanisms of ketamine-induced bladder fibrosis., Results: A total of 685 differentially expressed messenger RNAs, 71 differentially expressed long noncoding RNAs, 23 differentially expressed microRNAs, and 68 differentially expressed circular RNAs were identified. We found that ribosome, Wnt signaling, vascular endothelial growth factor signaling, cytoskeleton organization, and cytoskeletal protein binding may be potential pathways in ketamine-induced bladder fibrosis as identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In addition, the mitogen-activated protein kinase pathway appeared to be closely related to the development of ketamine-induced bladder fibrosis according to association analysis., Conclusions: In this study, using transcriptomic and correlation analyses of metabolomics, we identified pathways that may be potential targets for the prevention and treatment of ketamine-induced bladder fibrosis., (© 2022 Wiley Periodicals LLC.)

Ketamine is a non-competitive antagonist of NMDA glutamate receptor. It is used as an anesthetic, analgesic, sedative, and anti-depressive agent in clinical practice and also an illegal recreational drug. The increasing use has contributed to the measurable levels of ketamine in both wastewaters and hospital effluents, thereby classified as an emergent contaminant. Lately, the potential toxicity of ketamine has raised serious concerns about its iatrogenic or illicit use during pregnancy, neonatal and childhood stages. However, to assess its long-term toxicity potentially by the use of early life stages in human and rodents is limited. In this regard, the zebrafish has been considered as excellent model organism for biosafety assessments of ketamine due to it boasts an in vivo model with the advantages of an in vitro assay. In this review, we summarize the current understanding of the reported toxicity studies with ketamine in early life stage of zebrafish. The adverse effects of ketamine are known to cause overall developmental and multi-organ toxicity, including cardio-, neuro-, and skeletal toxicity. Furthermore, multiple mechanisms are found to be responsible for perpetrating toxicity of ketamine. The current findings confluence to emphasize the zebrafish embryo as an appealing model system for developmental toxicity testing in higher vertebrates., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although ketamine (KET) has been widely detected in aquatic environments, the ecotoxicity data in aquatic invertebrates and associated risk remained unclear. This study aimed to investigate the adverse effects on benthos (Caenorhabditis elegans (C.elegans)) posed by KET from chronic (10 days) and multigenerational (four generations) exposure. Such exposure induced dose-dependent alterations on apoptosis, reactive oxygen species (ROS) induction, locomotion activity, feeding rate, chemotaxis, and brood size of nematodes, showing a cumulative damage through generations. KET posed vulva deformations and worm bags of C. elegans with a dosed-dependent increase. As a consequence, the fecundity and viability of worms would be impaired, which could eventually impact aquatic ecosystem equilibrium. Meanwhile, the bioactivation/detoxification process of xenobiotics and longevity regulating pathway induced by KET might be responsible for the physiological function disorders. Accordingly, the risk quotients (RQ) of KET in surface water in China were calculated using the 90% indicator protection concentration (C 0.1 ) derived from multiple toxicity indicators cumulative analyses. The results would be more objective considering numerous biomarkers changes of one species in comparison with traditional method using no observed effect concentrations (NOEC) of teratogenesis. The risk in surface water in southern China was up to high level (RQ > 1), suggesting long-term monitoring was imperative., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C) is one of the most important genes associated with schizophrenia. In this study, 45 male Wistar rats were divided into 5 groups of saline, control, ketamine, clozapine, and risperidone. Animals in ketamine, risperidone, and clozapine groups received ketamine (30 mg/kg-i.p.) for 10 days. After the last injection of ketamine, we started injecting clozapine (7.5 mg/kg-i.p.), risperidone (1 mg/kg-i.p.), up to 28 days. Twenty-four hours after the last injection, open field, social interaction, and elevated plus-maze tests and gene expression in hippocampus were performed. The results of the social interaction test revealed a significant decrease in cumulative time with ketamine, compared with the saline group, and an increase with clozapine and risperidone compared with the ketamine group. Moreover, results from the elevated plus-maze test demonstrated a critical decrease in open arm time and increase in close arm time with ketamine compared with saline, as well as increased in open arm time with risperidone compared with ketamine. Further results revealed a significant increase in rearing and grooming with ketamine compared to saline, as well as a decrease with risperidone and clozapine compared to ketamine. There were no significant differences in CACNA1C gene expression between groups in the rat hippocampus. In brief, the results of this study indicated that clozapine and risperidone could partially improve cognitive impairments in the rat. However, our findings demonstrated that this treatment is not related to CACNA1C gene expression., (Copyright © 2021 Elsevier B.V. All rights reserved.)