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Bartlett MJ, Stopera CJ, Cowen SL, Sherman SJ, Falk T. Differential effects of statins on the anti-dyskinetic activity of sub-anesthetic ketamine. Neurosci Lett 2025; 848:138114. [PMID: 39761720 DOI: 10.1016/j.neulet.2025.138114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/18/2024] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Sub-anesthetic ketamine has been demonstrated to reduce abnormal involuntary movements (AIMs) in preclinical models of L-DOPA-induced dyskinesia (LID) and retrospective Parkinson's disease (PD) case reports. In this study, we examined the effects on LID of two different statins alone and in combination with ketamine in unilateral 6-hydroxydopamine-lesioned male rats, the standard model for preclinical LID studies. Ketamine attenuated the development of AIMs, while the non-polar lovastatin only showed anti-dyskinetic activity early in the priming period but did not prevent the development of LID, and the polar pravastatin showed no anti-dyskinetic activity. Furthermore, our main result is that pravastatin blocked the long-term neuroplastic anti-dyskinetic effects of ketamine, while lovastatin did not. This study shows two different statins affect LID and the anti-dyskinetic activity of ketamine differentially, pointing to an important drug interaction. The results further inform and support ongoing clinical testing of sub-anesthetic ketamine to treat LID in individuals with PD.
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Affiliation(s)
- Mitchell J Bartlett
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Department of Surgery, The University of Arizona, Tucson, AZ 85724, USA; Department of Neurosurgery, The University of Arizona, Tucson, AZ 85724, USA.
| | - Carolyn J Stopera
- Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ 85724, USA.
| | - Stephen L Cowen
- Department of Psychology, The University of Arizona, Tucson, AZ 85721, USA.
| | - Scott J Sherman
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA.
| | - Torsten Falk
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ 85724, USA; Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA.
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Bartlett MJ, Stopera CJ, Cowen SL, Sherman SJ, Falk T. Differential effects of statins on the anti-dyskinetic activity of sub-anesthetic ketamine. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.26.625570. [PMID: 39651168 PMCID: PMC11623634 DOI: 10.1101/2024.11.26.625570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Sub-anesthetic ketamine has been demonstrated to reduce abnormal involuntary movements (AIMs) in preclinical models of L-DOPA-induced dyskinesia (LID) and retrospective Parkinson's disease case reports. In this study, we examined the effects on L-DOPA-induced dyskinesia of two statins alone and in combination with ketamine in unilateral 6-hydroxydopamine-lesioned male rats, the standard preclinical LID model. Sub-anesthetic ketamine attenuated the development of AIMs, while lovastatin only showed anti-dyskinetic activity at the beginning of the priming but did not prevent the development of LID. The polar pravastatin blocked the long-term anti-dyskinetic effects of ketamine, while the non-polar lovastatin did not. This study shows different classes of statins affect LID differentially, points to an important drug interaction and further supports ongoing clinical testing of sub-anesthetic ketamine to treat LID in individuals with Parkinson's disease.
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Yan X, Ma Y, Yang J, Chang X, Shi S, Song G. The role and advance of ubiquitination and deubiquitination in depression pathogenesis and treatment. Drug Dev Res 2024; 85:e70005. [PMID: 39417355 DOI: 10.1002/ddr.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/27/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024]
Abstract
Depression is a common neuropsychiatric disease that is characterized by long-term, repeated low mood, pain and despair, pessimism, and even suicidal tendencies. Increasing evidence has shown that ubiquitination and deubiquitination are closely related to the occurrence of depression, including pathological morphogenesis, neuroplasticity, synaptic transmission, neuroinflammation, and so forth. The development of depression is regulated by intracellular proteins that undergo various posttranslational modifications, including ubiquitination, which falls under the epigenetics category. Although there have been studies and reviews of literature on epigenetics and depression, a systematic review of ubiquitination modification and depression has not been reported. In addition, with the deepening of research on depression and ubiquitination, the development of drugs targeting the ubiquitin system has gradually increased, but it is still not mature, so there is an urgent need to find new antidepressant drug targets. E3 ubiquitin ligases and deubiquitinating enzymes can regulate the occurrence and development of depression in a variety of ways, which may be a direction for the treatment of depression in the future. Therefore, this review describes the latest progress of ubiquitination and deubiquitination in the regulation of depression, summarizes the published signal pathways of ubiquitination and deubiquitination involved in depression, emphasizes the targets and mechanisms of E3 ubiquitin ligases and deubiquitinase in the regulation of depression, and further discusses the therapeutic targets of targeting ubiquitination modification systems to regulate depression.
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Affiliation(s)
- Xiaoru Yan
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yunhui Ma
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Junting Yang
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoqi Chang
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Shuxuan Shi
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guohua Song
- Laboratory Animal Center, Shanxi Key Laboratory of Experimental Animal Science and Human Disease Animal Model, Shanxi Medical University, Taiyuan, Shanxi, China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan, China
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Stopera CJ, Bartlett MJ, Liu C, Esqueda A, Parmar R, Heien ML, Sherman SJ, Falk T. Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model. Neuropharmacology 2024; 257:110047. [PMID: 38889877 DOI: 10.1016/j.neuropharm.2024.110047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/06/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.
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Affiliation(s)
- Carolyn J Stopera
- Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ, 85724, USA.
| | | | - Chenxi Liu
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA.
| | - Alexander Esqueda
- Department of Neurology, The University of Arizona, Tucson, AZ, 85724, USA.
| | - Raveena Parmar
- Department of Pharmacology, The University of Arizona, Tucson, AZ, 85724, USA.
| | - M Leandro Heien
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA.
| | - Scott J Sherman
- Department of Neurology, The University of Arizona, Tucson, AZ, 85724, USA.
| | - Torsten Falk
- Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ, 85724, USA; Department of Neurology, The University of Arizona, Tucson, AZ, 85724, USA; Department of Pharmacology, The University of Arizona, Tucson, AZ, 85724, USA.
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Chiriboga N, Spentzas T, Abu-Sawwa R. A systematic review and meta-analysis of ketamine in pediatric status epilepticus. Epilepsia 2024; 65:2200-2212. [PMID: 38881333 DOI: 10.1111/epi.18035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/22/2024] [Accepted: 05/22/2024] [Indexed: 06/18/2024]
Abstract
OBJECTIVE Status epilepticus (SE) is a common neurological medical emergency in the pediatric population, with 10%-40% of cases progressing to refractory SE (RSE), requiring treatment with anesthetic infusions. We present a systematic review and meta-analysis of the use of ketamine for the treatment of pediatric SE and its potential advantages over other anesthetic infusions. METHODS This review follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Electronic databases, including PubMed, Cochrane Library, Ovid, Embase, and Google Scholar, were searched with the keywords "pediatrics," "status epilepticus," and "ketamine treatment." Randomized trials, prospective and retrospective cohort studies, and case reports were considered for inclusion. RESULTS Eighteen publications met the initial inclusion criteria. The 18 publications comprise 11 case reports, one nonconclusive clinical trial, two case series, and four retrospective cohorts. After excluding the case reports because of reporting bias, only the six case series and cohorts were included in the final analysis. There were 172 patients in the six included studies. The weighted age was 9.93 (SD = 10.29) years. The weighted maximum dose was 7.44 (SD = 9.39) mg/kg/h. SE cessation was attained in 51% (95% confidence interval = 43-59) of cases with the addition of ketamine. The heterogeneity was I2 = 0%, t2 = 0, χ2 (5) = 3.39 (p = .64). SIGNIFICANCE Pediatric RSE is difficult to treat, resulting in increased morbidity and mortality. Without strong recommendations and evidence regarding preferred agents, this review provides evidence that ketamine may be considered in managing SE in the pediatric population.
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Affiliation(s)
- Nicolas Chiriboga
- Pediatric Intensive Care Unit Le Bonheur Children's Hospital, Memphis, Tennessee, USA
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Thomas Spentzas
- Pediatric Intensive Care Unit Le Bonheur Children's Hospital, Memphis, Tennessee, USA
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Renad Abu-Sawwa
- Department of Anatomy and Cell Biology, Rush Medical College, Chicago, Illinois, USA
- Department of Pediatric Neurology, Rush University Children's Hospital, Chicago, Illinois, USA
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Berner K, Oz N, Kaya A, Acharjee A, Berner J. mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease. Aging (Albany NY) 2024; 16:11134-11150. [PMID: 39068671 PMCID: PMC11315394 DOI: 10.18632/aging.206033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 07/05/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Gain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. METHODS Twenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response. RESULTS mTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance. CONCLUSIONS The data illustrate the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response.
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Affiliation(s)
- Karl Berner
- Woodinville Psychiatric Associates, Woodinville, WA 98072, USA
| | - Naci Oz
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
- Life Sciences, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Alaattin Kaya
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Animesh Acharjee
- Institute of Cancer and Genomics Sciences, University of Birmingham, Birmingham, UK
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- MRC Health Data Research UK (HDR UK), London, UK
| | - Jon Berner
- Woodinville Psychiatric Associates, Woodinville, WA 98072, USA
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Li M, Huang W, Zhang Y, Du Y, Zhao S, Wang L, Sun Y, Sha B, Yan J, Ma Y, Tang J, Shi J, Li P, Jia L, Hu T, Chen P. Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival. Cell Death Dis 2024; 15:409. [PMID: 38862475 PMCID: PMC11166663 DOI: 10.1038/s41419-024-06808-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 05/27/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.
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Affiliation(s)
- Miaomiao Li
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wenjing Huang
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yuan Zhang
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yue Du
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Shan Zhao
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Longhao Wang
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
| | - Yaxin Sun
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Sanquan College of Xinxiang Medical University, Xinxiang, 453003, China
| | - Beibei Sha
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450014, China
| | - Jie Yan
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
| | - Yangcheng Ma
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China
| | - Jinlu Tang
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jianxiang Shi
- Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences & BGI College, Zhengzhou University, Zhengzhou, 450052, China
| | - Pei Li
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Lijun Jia
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Tao Hu
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Ping Chen
- Academy of Medical Sciences, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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Li H, Ying L, Wan F, Shiqiao K, Yijie F, Chuli X, Xudong Y, Xinhong Y, Zhiyong X. Esketamine enhances memory reconsolidation in the novel object recognition task. Physiol Behav 2024; 277:114461. [PMID: 38215863 DOI: 10.1016/j.physbeh.2024.114461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 12/28/2023] [Accepted: 01/09/2024] [Indexed: 01/14/2024]
Abstract
Esketamine, the right-handed optical isomer of racemic ketamine, is a rapidly acting antidepressant approved by the FDA for treatment-resistant depression in 2019. However, few studies have investigated esketamine's role in learning and memory, particularly in the context of memory reconsolidation. Herein, we evaluated esketamine's role in memory reconsolidation in 7-week-old male Institute of Cancer Research mice subjected to the novel object recognition (NOR) memory task. The NOR reconsolidation procedure comprised three phases: sampling, reactivation, and testing. Esketamine-enhanced NOR memory performance when injected into mice 0 h after reactivation rather than following a 6 h delay. Conversely, administering esketamine 24 h after sampling without reactivation did not enhance NOR memory performance. Notably, esketamine exhibited no discernible effects on nonspecific responses, such as locomotor activity and exploratory behavior. Furthermore, the α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor antagonist NBQX effectively blocked the esketamine-induced enhancement of memory reconsolidation. In conclusion, esketamine treatment markedly improves memory reconsolidation in NOR tasks, and this effect is linked to AMPA receptor activity.
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Affiliation(s)
- Huang Li
- The Brain Cognition and Brain Disease Branch, Pu Ai Medical School, Shaoyang University, 422000, Shaoyang, China
| | - Lu Ying
- The Brain Cognition and Brain Disease Branch, Pu Ai Medical School, Shaoyang University, 422000, Shaoyang, China
| | - Fu Wan
- The First Affiliated Hospital, Department of Neurology, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China
| | - Kang Shiqiao
- The First Affiliated Hospital, Department of Critical Care Medicine, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China
| | - Fang Yijie
- School of Nursing, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China
| | - Xiao Chuli
- The Brain Cognition and Brain Disease Branch, Pu Ai Medical School, Shaoyang University, 422000, Shaoyang, China
| | - Yu Xudong
- The Brain Cognition and Brain Disease Branch, Pu Ai Medical School, Shaoyang University, 422000, Shaoyang, China.
| | - Yin Xinhong
- School of Nursing, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
| | - Xiao Zhiyong
- The First Affiliated Hospital, Department of Critical Care Medicine, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
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Zaccarelli-Magalhães J, Abreu GR, Fukushima AR, Pantaleon LP, Ribeiro BB, Munhoz C, Manes M, de Lima MA, Miglioli J, Flório JC, Lebrun I, Ricci EL, Spinosa HS. Ketamine causes poor maternal care in rats with postpartum depression and leads to few behavioral and neurochemical alterations on male offspring. Behav Brain Res 2024; 459:114799. [PMID: 38065224 DOI: 10.1016/j.bbr.2023.114799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/01/2023] [Accepted: 12/02/2023] [Indexed: 12/18/2023]
Abstract
Ketamine is an anesthetic drug that also has antidepressant properties, with quick action. Despite the great number of studies showing its effectiveness as a treatment for major depression, there is little information about its effects on postpartum depression, as pharmacological treatments bring risks to the health of both mother and child. Thus, this study aimed to evaluate the effects of prolonged treatment with subanesthetic doses of ketamine in a rat model of postpartum depression. Female dams were induced to postpartum depression by the maternal separation model from lactating day (LD) 2-12. They were divided into four groups: one control and three experimental groups, which were treated with different doses of ketamine (5, 10 or 20 mg/kg) from LD 2-21 i.p. Maternal studies were conducted from LD5 to LD21 and the offspring studies from postnatal day 2 through 90. Ketamine causes poor maternal care, with few neurochemical alterations. However, the highest dose used in this study had an antidepressant effect. Regarding the male offspring, indirect exposure to ketamine through breast milk caused few behavioral changes during infancy, but they were not permanent, as they faded in adulthood. Nevertheless, this exposure was able to cause alterations in their monoaminergic neurotransmission systems that were found in both infancy and adulthood periods.
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Affiliation(s)
- Julia Zaccarelli-Magalhães
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil.
| | - Gabriel R Abreu
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil
| | - André R Fukushima
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil; School of Health Sciences IGESP, Rua da Consolação, 1025, 01301-000 São Paulo, Brazil; Centro Universitário das Américas, Rua Augusta, 1508, 01304-001 São Paulo, Brazil
| | - Lorena P Pantaleon
- Health Science Institute, Presbyterian Mackenzie University, Rua da Consolação, 930, 01302-907 São Paulo, Brazil
| | - Beatriz B Ribeiro
- Health Science Institute, Presbyterian Mackenzie University, Rua da Consolação, 930, 01302-907 São Paulo, Brazil
| | - Camila Munhoz
- Health Science Institute, Presbyterian Mackenzie University, Rua da Consolação, 930, 01302-907 São Paulo, Brazil
| | - Marianna Manes
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil
| | - Mayara A de Lima
- Centro Universitário das Américas, Rua Augusta, 1508, 01304-001 São Paulo, Brazil
| | - Júlia Miglioli
- Centro Universitário das Américas, Rua Augusta, 1508, 01304-001 São Paulo, Brazil
| | - Jorge C Flório
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil
| | - Ivo Lebrun
- Laboratory of Biochemistry and Biophysics, Butantan Institute, Avenida Vital Brazil, 1500, 05503-900 São Paulo, Brazil
| | - Esther L Ricci
- School of Health Sciences IGESP, Rua da Consolação, 1025, 01301-000 São Paulo, Brazil; Health Science Institute, Presbyterian Mackenzie University, Rua da Consolação, 930, 01302-907 São Paulo, Brazil
| | - Helenice S Spinosa
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Avenida Professor Doutor Orlando Marques de Paiva, 87, 05508-270 São Paulo, Brazil
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10
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Ren L. The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways. Prog Neuropsychopharmacol Biol Psychiatry 2024; 129:110910. [PMID: 38061484 DOI: 10.1016/j.pnpbp.2023.110910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
Conventional antidepressants that target monoaminergic receptors require several weeks to be efficacious. This lag represents a significant problem in the currently available treatments for serious depression. Ketamine, acting as an N-methyl-d-aspartate receptor antagonist, was shown to have rapid antidepressant-like effects, marking a significant advancement in the study of mood disorders. However, serious side effects and adverse reactions limit its clinical use. Considering the limitations of ketamine, it is crucial to further define the network targets of ketamine. The rapid action of ketamine an as antidepressant is thought to be mediated by the glutamate system. It is believed that synaptic plasticity is essential for the rapid effects of ketamine as an antidepressant. Other mechanisms include the involvement of the γ-aminobutyric acidergic (GABAergic), 5-HTergic systems, and recent studies have linked astrocytes to ketamine's rapid antidepressant-like effects. The interactions between these systems exert a synergistic rapid antidepressant effect through neural circuits and molecular mechanisms. Here, we discuss the neural circuits and molecular mechanisms underlying the action of ketamine. This work will help explain how molecular and neural targets are responsible for the effects of rapidly acting antidepressants and will aid in the discovery of new therapeutic approaches for major depressive disorder.
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Affiliation(s)
- Li Ren
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Sichuan Chengdu 611137, China.
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11
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Elmeseiny OSA, Müller HK. A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine. Pharmacol Res 2024; 200:107081. [PMID: 38278430 DOI: 10.1016/j.phrs.2024.107081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/16/2024] [Accepted: 01/23/2024] [Indexed: 01/28/2024]
Abstract
Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration of ketamine elicits rapid and sustained antidepressant effects in both humans and animals. Current efforts are focused on uncovering molecular mechanisms responsible for ketamine's antidepressant activity. Ketamine primarily acts via the glutamatergic pathway, and increasing evidence suggests that ketamine induces synaptic and structural plasticity through increased translation and release of neurotrophic factors, activation of mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated synaptic potentiation. However, the initial events triggering activation of intracellular signaling cascades and the mechanisms responsible for the sustained antidepressant effects of ketamine remain poorly understood. Over the last few years, it has become apparent that in addition to the fast actions of the ligand-gated AMPARs and NMDARs, metabotropic glutamate receptors (mGluRs), and particularly mGluR5, may also play a role in the antidepressant action of ketamine. Although research on mGluR5 in relation to the beneficial actions of ketamine is still in its infancy, a careful evaluation of the existing literature can identify converging trends and provide new interpretations. Here, we review the current literature on mGluR5 regulation in response to ketamine from a molecular perspective and propose a possible mechanism linking NMDAR inhibition to mGluR5 modulation.
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Affiliation(s)
- Ola Sobhy A Elmeseiny
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Heidi Kaastrup Müller
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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12
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Abstract
Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.
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Affiliation(s)
- Ji-Woon Kim
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
- Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul, Republic of Korea
| | - Kanzo Suzuki
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Katsushika-ku, Tokyo, Japan
| | - Ege T Kavalali
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
| | - Lisa M Monteggia
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
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13
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Bottemanne H, Berkovitch L, Gauld C, Balcerac A, Schmidt L, Mouchabac S, Fossati P. Storm on predictive brain: A neurocomputational account of ketamine antidepressant effect. Neurosci Biobehav Rev 2023; 154:105410. [PMID: 37793581 DOI: 10.1016/j.neubiorev.2023.105410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 08/24/2023] [Accepted: 09/26/2023] [Indexed: 10/06/2023]
Abstract
For the past decade, ketamine, an N-methyl-D-aspartate receptor (NMDAr) antagonist, has been considered a promising treatment for major depressive disorder (MDD). Unlike the delayed effect of monoaminergic treatment, ketamine may produce fast-acting antidepressant effects hours after a single administration at subanesthetic dose. Along with these antidepressant effects, it may also induce transient dissociative (disturbing of the sense of self and reality) symptoms during acute administration which resolve within hours. To understand ketamine's rapid-acting antidepressant effect, several biological hypotheses have been explored, but despite these promising avenues, there is a lack of model to understand the timeframe of antidepressant and dissociative effects of ketamine. In this article, we propose a neurocomputational account of ketamine's antidepressant and dissociative effects based on the Predictive Processing (PP) theory, a framework for cognitive and sensory processing. PP theory suggests that the brain produces top-down predictions to process incoming sensory signals, and generates bottom-up prediction errors (PEs) which are then used to update predictions. This iterative dynamic neural process would relies on N-methyl-D-aspartate (NMDAr) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic receptors (AMPAr), two major component of the glutamatergic signaling. Furthermore, it has been suggested that MDD is characterized by over-rigid predictions which cannot be updated by the PEs, leading to miscalibration of hierarchical inference and self-reinforcing negative feedback loops. Based on former empirical studies using behavioral paradigms, neurophysiological recordings, and computational modeling, we suggest that ketamine impairs top-down predictions by blocking NMDA receptors, and enhances presynaptic glutamate release and PEs, producing transient dissociative symptoms and fast-acting antidepressant effect in hours following acute administration. Moreover, we present data showing that ketamine may enhance a delayed neural plasticity pathways through AMPAr potentiation, triggering a prolonged antidepressant effect up to seven days for unique administration. Taken together, the two sides of antidepressant effects with distinct timeframe could constitute the keystone of antidepressant properties of ketamine. These PP disturbances may also participate to a ketamine-induced time window of mental flexibility, which can be used to improve the psychotherapeutic process. Finally, these proposals could be used as a theoretical framework for future research into fast-acting antidepressants, and combination with existing antidepressant and psychotherapy.
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Affiliation(s)
- Hugo Bottemanne
- Paris Brain Institute - Institut du Cerveau (ICM), UMR 7225 / UMRS 1127, Sorbonne University / CNRS / INSERM, Paris, France; Sorbonne University, Department of Philosophy, Science Norm Democracy Research Unit, UMR, 8011, Paris, France; Sorbonne University, Department of Psychiatry, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
| | - Lucie Berkovitch
- Saclay CEA Centre, Neurospin, Gif-Sur-Yvette Cedex, France; Department of Psychiatry, GHU Paris Psychiatrie et Neurosciences, Service Hospitalo-Universitaire, Paris, France
| | - Christophe Gauld
- Department of Child Psychiatry, CHU de Lyon, F-69000 Lyon, France; Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS & Université Claude Bernard Lyon 1, F-69000 Lyon, France
| | - Alexander Balcerac
- Paris Brain Institute - Institut du Cerveau (ICM), UMR 7225 / UMRS 1127, Sorbonne University / CNRS / INSERM, Paris, France; Sorbonne University, Department of Neurology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Liane Schmidt
- Paris Brain Institute - Institut du Cerveau (ICM), UMR 7225 / UMRS 1127, Sorbonne University / CNRS / INSERM, Paris, France
| | - Stephane Mouchabac
- Paris Brain Institute - Institut du Cerveau (ICM), UMR 7225 / UMRS 1127, Sorbonne University / CNRS / INSERM, Paris, France; Sorbonne University, Department of Psychiatry, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Philippe Fossati
- Paris Brain Institute - Institut du Cerveau (ICM), UMR 7225 / UMRS 1127, Sorbonne University / CNRS / INSERM, Paris, France; Sorbonne University, Department of Philosophy, Science Norm Democracy Research Unit, UMR, 8011, Paris, France
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14
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Weapons of stress reduction: (R,S)-ketamine and its metabolites as prophylactics for the prevention of stress-induced psychiatric disorders. Neuropharmacology 2023; 224:109345. [PMID: 36427554 DOI: 10.1016/j.neuropharm.2022.109345] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022]
Abstract
Exposure to stress is one of the greatest contributing factors to developing a psychiatric disorder, particularly in susceptible populations. Enhancing resilience to stress could be a powerful intervention to reduce the incidence of psychiatric disease and reveal insight into the pathophysiology of psychiatric disorders. (R,S)-ketamine and its metabolites have recently been shown to exert protective effects when administered before or after a variety of stressors and may be effective, tractable prophylactic compounds against psychiatric disease. Drug dosing, sex, age, and strain in preclinical rodent studies, significantly influence the prophylactic effects of (R,S)-ketamine and related compounds. Due to the broad neurobiological actions of (R,S)-ketamine, a variety of mechanisms have been proposed to contribute to the resilience-enhancing effects of this drug, including altering various transcription factors across the genome, enhancing inhibitory connections from the prefrontal cortex, and increasing synaptic plasticity in the hippocampus. Promisingly, select data have shown that (R,S)-ketamine may be an effective prophylactic against psychiatric disorders, such as postpartum depression (PPD). Overall, this review will highlight a brief history of the prophylactic effects of (R,S)-ketamine, the potential mechanisms underlying its protective actions, and possible future directions for translating prophylactic compounds to the clinic. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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15
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Onisiforou A, Georgiou P, Zanos P. Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions. Pharmacol Biochem Behav 2023; 223:173531. [PMID: 36841543 DOI: 10.1016/j.pbb.2023.173531] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/08/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Major Depressive Disorder (MDD) is a serious neuropsychiatric disorder afflicting around 16-17 % of the global population and is accompanied by recurrent episodes of low mood, hopelessness and suicidal thoughts. Current pharmacological interventions take several weeks to even months for an improvement in depressive symptoms to emerge, with a significant percentage of individuals not responding to these medications at all, thus highlighting the need for rapid and effective next-generation treatments for MDD. Pre-clinical studies in animals have demonstrated that antagonists of the metabotropic glutamate receptor subtype 2/3 (mGlu2/3 receptor) exert rapid antidepressant-like effects, comparable to the actions of ketamine. Therefore, it is possible that mGlu2 or mGlu3 receptors to have a regulatory role on the unique antidepressant properties of ketamine, or that convergent intracellular mechanisms exist between mGlu2/3 receptor signaling and ketamine's effects. Here, we provide a comprehensive and critical evaluation of the literature on these convergent processes underlying the antidepressant action of mGlu2/3 receptor inhibitors and ketamine. Importantly, combining sub-threshold doses of mGlu2/3 receptor inhibitors with sub-antidepressant ketamine doses induce synergistic antidepressant-relevant behavioral effects. We review the evidence supporting these combinatorial effects since sub-effective dosages of mGlu2/3 receptor antagonists and ketamine could reduce the risk for the emergence of significant adverse events compared with taking normal dosages. Overall, deconvolution of ketamine's pharmacological targets will give critical insights to influence the development of next-generation antidepressant treatments with rapid actions.
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Affiliation(s)
- Anna Onisiforou
- Department of Psychology, University of Cyprus, Nicosia 2109, Cyprus
| | - Polymnia Georgiou
- Department of Biological Sciences, University of Cyprus, Nicosia 2109, Cyprus; Department of Psychology, University of Wisconsin Milwaukee, WI 53211, USA
| | - Panos Zanos
- Department of Psychology, University of Cyprus, Nicosia 2109, Cyprus.
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16
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Zhang K, Yao Y, Hashimoto K. Ketamine and its metabolites: Potential as novel treatments for depression. Neuropharmacology 2023; 222:109305. [PMID: 36354092 DOI: 10.1016/j.neuropharm.2022.109305] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/19/2022] [Accepted: 10/23/2022] [Indexed: 11/06/2022]
Abstract
Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor β1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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Affiliation(s)
- Kai Zhang
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China; Anhui Psychiatric Center, Anhui Medical University, Hefei, China.
| | - Yitan Yao
- Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, China; Anhui Psychiatric Center, Anhui Medical University, Hefei, China
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
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17
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Pray BA, Youssef Y, Alinari L. TBL1X: At the crossroads of transcriptional and posttranscriptional regulation. Exp Hematol 2022; 116:18-25. [PMID: 36206873 PMCID: PMC9929687 DOI: 10.1016/j.exphem.2022.09.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 02/02/2023]
Abstract
Over the past 2 decades, the adaptor protein transducin β-like 1 (TBL1X) and its homolog TBL1XR1 have been shown to be upregulated in solid tumors and hematologic malignancies, and their overexpression is associated with poor clinical outcomes. Moreover, dysregulation of the TBL1 family of proteins has been implicated as a key component of oncogenic prosurvival signaling, cancer progression, and metastasis. Herein, we discuss how TBL1X and TBL1XR1 are required for the regulation of major transcriptional programs through the silencing mediator for tetanoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (NCOR)/ B cell lymphoma 6 (BCL6) complex, Wnt/β catenin, and NF-κB signaling. We outline the utilization of tegavivint (Iterion Therapeutics), a first-in-class small molecule targeting the N-terminus domain of TBL1, as a novel therapeutic strategy in preclinical models of cancer and clinically. Although most published work has focused on the transcriptional role of TBL1X, we recently showed that in diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, genetic knockdown of TBL1X and treatment with tegavivint resulted in decreased expression of critical (onco)-proteins in a posttranscriptional/β-catenin-independent manner by promoting their proteasomal degradation through a Skp1/Cul1/F-box (SCF)/TBL1X supercomplex and potentially through the regulation of protein synthesis. However, given that TBL1X controls multiple oncogenic signaling pathways in cancer, treatment with tegavivint may ultimately result in drug resistance, providing the rationale for combination strategies. Although many questions related to TBL1X function remain to be answered in lymphoma and other diseases, these data provide a growing body of evidence that TBL1X is a promising therapeutic target in oncology.
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Affiliation(s)
- Betsy A Pray
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Youssef Youssef
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
| | - Lapo Alinari
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH.
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18
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Singla R, Mishra A, Cao R. The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model. Transl Psychiatry 2022; 12:355. [PMID: 36045116 PMCID: PMC9433414 DOI: 10.1038/s41398-022-02120-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 08/08/2022] [Accepted: 08/12/2022] [Indexed: 02/07/2023] Open
Abstract
Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called "clock genes/proteins", which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an "interaction triangle" model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).
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Affiliation(s)
- Rubal Singla
- grid.17635.360000000419368657Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812 USA
| | - Abhishek Mishra
- grid.17635.360000000419368657Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812 USA
| | - Ruifeng Cao
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA. .,Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
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19
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Xu S, Yao X, Li B, Cui R, Zhu C, Wang Y, Yang W. Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant. Front Pharmacol 2022; 12:740996. [PMID: 35872836 PMCID: PMC9301111 DOI: 10.3389/fphar.2021.740996] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/20/2021] [Indexed: 12/26/2022] Open
Abstract
Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.
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Affiliation(s)
- Songbai Xu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, China
| | - Xiaoxiao Yao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Cuilin Zhu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Cuilin Zhu, ; Yao Wang, ; Wei Yang,
| | - Yao Wang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Cuilin Zhu, ; Yao Wang, ; Wei Yang,
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Cuilin Zhu, ; Yao Wang, ; Wei Yang,
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20
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Harraz MM, Malla AP, Semenza ER, Shishikura M, Singh M, Hwang Y, Kang IG, Song YJ, Snowman AM, Cortés P, Karuppagounder SS, Dawson TM, Dawson VL, Snyder SH. A high-affinity cocaine binding site associated with the brain acid soluble protein 1. Proc Natl Acad Sci U S A 2022; 119:e2200545119. [PMID: 35412917 PMCID: PMC9169839 DOI: 10.1073/pnas.2200545119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/01/2022] [Indexed: 12/25/2022] Open
Abstract
Cocaine exerts its stimulant effect by inhibiting dopamine (DA) reuptake, leading to increased dopamine signaling. This action is thought to reflect the binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share cocaine’s behavioral actions. Further, recent reports show more potent actions of the drug, implying the existence of a high-affinity receptor for cocaine. We now report high-affinity binding of cocaine associated with the brain acid soluble protein 1 (BASP1) with a dissociation constant (Kd) of 7 nM. Knocking down BASP1 in the striatum inhibits [3H]cocaine binding to striatal synaptosomes. Depleting BASP1 in the nucleus accumbens but not the dorsal striatum diminishes locomotor stimulation in mice. Our findings imply that BASP1 is a pharmacologically relevant receptor for cocaine.
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Affiliation(s)
- Maged M. Harraz
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Adarsha P. Malla
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Evan R. Semenza
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Maria Shishikura
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Manisha Singh
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Yun Hwang
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - In Guk Kang
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Young Jun Song
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Adele M. Snowman
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Pedro Cortés
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Senthilkumar S. Karuppagounder
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Ted M. Dawson
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Valina L. Dawson
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | - Solomon H. Snyder
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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21
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Averill LA, Averill CL, Gueorguieva R, Fouda S, Sherif M, Ahn KH, Ranganathan M, D'Souza DC, Southwick SM, Sanacora G, Duman RS, Krystal JH, Abdallah CG. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. J Affect Disord 2022; 303:91-97. [PMID: 35101523 DOI: 10.1016/j.jad.2022.01.104] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/10/2022] [Accepted: 01/27/2022] [Indexed: 12/20/2022]
Abstract
Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.
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Affiliation(s)
- Lynnette A Averill
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Menninger Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA; US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
| | - Christopher L Averill
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Menninger Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA; US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Ralitza Gueorguieva
- Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA
| | - Samar Fouda
- US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Mohamed Sherif
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Carney Institute for Brain Science, Brown University, Providence, RI, USA
| | - Kyung-Heup Ahn
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Mohini Ranganathan
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Deepak Cyril D'Souza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Steven M Southwick
- US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Gerard Sanacora
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Ronald S Duman
- US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - John H Krystal
- US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Chadi G Abdallah
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Menninger Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA; US Department of Veterans Affairs, National Center for PTSD - Clinical Neuroscience Division, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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22
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Kang MJY, Hawken E, Vazquez GH. The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity. Front Psychiatry 2022; 13:860882. [PMID: 35546951 PMCID: PMC9082546 DOI: 10.3389/fpsyt.2022.860882] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/18/2022] [Indexed: 12/25/2022] Open
Abstract
The mechanism of action underlying ketamine's rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.
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Affiliation(s)
- Melody J Y Kang
- Center of Neuroscience Studies (CNS), Queen's University, Kingston, ON, Canada
| | - Emily Hawken
- Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada.,Providence Care Hospital, Kingston, ON, Canada
| | - Gustavo Hector Vazquez
- Center of Neuroscience Studies (CNS), Queen's University, Kingston, ON, Canada.,Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada.,Providence Care Hospital, Kingston, ON, Canada
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23
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Tang WQ, Liu Y, Ji CH, Gu JH, Chen YM, Huang J, Guan W, Xu DW, Jiang B. Virus-mediated decrease of LKB1 activity in the mPFC diminishes stress-induced depressive-like behaviors in mice. Biochem Pharmacol 2021; 197:114885. [PMID: 34968488 DOI: 10.1016/j.bcp.2021.114885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 11/30/2021] [Accepted: 12/06/2021] [Indexed: 01/01/2023]
Abstract
As a highly prevalent neuropsychiatric disorder worldwide, the pathophysiology of depression is not yet fully understood and based on multiple factors among which chronic stress is critical. Numerous previous studies have shown the role of central mammalian target of rapamycin complex 1 (mTORC1) signaling in depression. However, so far it remains elusive by which way chronic stress down-regulates the activity of central mTORC1. Liver kinase b1 (LKB1) has been demonstrated to regulate the activity of the mTORC1 signaling cascade by phosphorylating AMP activated protein kinase (AMPK). Here, this study aimed to explore whether LKB1 participates in depression by regulating the downstream AMPK-mTORC1 signaling, and various methods including mouse models of depression, western blotting and immunofluorescence were used together. Our results showed that chronic stress significantly enhanced the expression of both phosphorylated LKB1 and total LKB1 in the medial prefrontal cortex (mPFC) but not the hippocampus. Furthermore, genetic knockdown of LKB1 in the mPFC fully reversed not only the depressive-like behaviors induced by chronic stress in mice but also the effects of chronic stress on the activity of AMPK and the mTORC1 system. Taken together, this study preliminarily suggests that LKB1 in the mPFC could be a feasible target for antidepressants. This study also provides support for the potential use of LKB1 inhibition strategies against the chronic stress-related neuropsychiatric disorders.
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Affiliation(s)
- Wen-Qian Tang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Yue Liu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Chun-Hui Ji
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jiang-Hong Gu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Yan-Mei Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jie Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Da-Wei Xu
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, Jiangsu, China.
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
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24
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[Ketamine Augmented Psychotherapy (KAP) in mood disorder: User guide]. Encephale 2021; 48:304-312. [PMID: 34876279 DOI: 10.1016/j.encep.2021.08.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/30/2021] [Accepted: 08/20/2021] [Indexed: 01/02/2023]
Abstract
Ketamine, a non-competitive NMDA receptor antagonist, is used as a fast-acting antidepressant therapy in depressive disorders. This treatment provokes dissociative effects associating derealization and depersonalization, and a synaptogenic signaling cascade promoting brain plasticity. Despite several preliminary studies suggesting the usefulness of its combination with psychotherapy, administration of ketamine isn't generally combined with per- and post-infusion psychotherapy protocols in its clinical antidepressant use. However, the phenomenology of psychodysleptic experiences and the synaptogenic effect could potentiate cognitive and behavioral therapies (CBT). In this article, we purpose a practical protocol to Ketamine Augmented Psychotherapy (KAP) synthesizing contemporary data from the literature and our clinical experience. We detail proposals for clinical practice, and propose four important steps for the use of a psychodysleptic molecule for antidepressant purposes: preparation, administration, integration, and prolongation. Finally, we discuss the limits and prospects of this combination in the management of mood disorders.
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25
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Choudhury D, Autry AE, Tolias KF, Krishnan V. Ketamine: Neuroprotective or Neurotoxic? Front Neurosci 2021; 15:672526. [PMID: 34566558 PMCID: PMC8461018 DOI: 10.3389/fnins.2021.672526] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 07/12/2021] [Indexed: 12/20/2022] Open
Abstract
Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.
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Affiliation(s)
- Divya Choudhury
- Department of BioSciences, Rice University, Houston, TX, United States
| | - Anita E. Autry
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Kimberley F. Tolias
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Vaishnav Krishnan
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
- Department of Neurology, Baylor College of Medicine, Houston, TX, United States
- Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
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26
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Choi Y, Kim B, Ham S, Chung S, Maeng S, Kim HS, Im HI. Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis. PLoS One 2021; 16:e0256390. [PMID: 34437591 PMCID: PMC8389495 DOI: 10.1371/journal.pone.0256390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 08/05/2021] [Indexed: 12/14/2022] Open
Abstract
Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.
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Affiliation(s)
- Yunjung Choi
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Baeksun Kim
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
| | - Suji Ham
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
| | - Sooyoung Chung
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
| | - Sungho Maeng
- College of East-West Medical Science, Kyung Hee University, Yongin, South Korea
| | - Hye-Sun Kim
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea
- Department of Pharmacology, Seoul National University Bundang Hospital, Seongnam, Bundang-Gu, South Korea
| | - Heh-In Im
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
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27
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miR-129-5p Ameliorates Ischemic Brain Injury by Binding to SIAH1 and Activating the mTOR Signaling Pathway. J Mol Neurosci 2021; 71:1761-1771. [PMID: 34355355 DOI: 10.1007/s12031-021-01872-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/09/2021] [Indexed: 10/20/2022]
Abstract
Aberrant expression of microRNAs (miRNAs) has been linked with ischemic brain injury (IBI), but the mechanistic actions behind the associated miRNAs remain to be determined. Of note, miR-129-5p was revealed to be downregulated in the serum of patients with IBI. In silico prediction identified a putative target gene, siah E3 ubiquitin protein ligase 1 (SIAH1), of miR-129-5p. Accordingly, this study plans to clarify the functional relevance of the interplay of miR-129-5p and SIAH1 in IBI. IBI was modeled by exposing human hippocampal neuronal cells to oxygen-glucose deprivation (OGD) in vitro and by occluding the middle cerebral artery (MCAO) in a mouse model in vivo. Apoptosis of hippocampal neuronal cells was assessed by annexin V-FITC/PI staining and TUNEL staining. The area of cerebral infarction was measured using TTC staining, along with neurological scoring on modeled mice. Loss of hippocampal neuronal cells in the peri-infarct area was monitored using Nissl staining. Downregulated miR-129-5p expression was found in OGD-induced hippocampal neuronal cells and MCAO-treated mice. Mechanistically, miR-129-5p was validated to target and inhibit SIAH1 through the application of dual-luciferase reporter assay. Additionally, enforced miR-129-5p inhibited the apoptosis of OGD-induced cells and decreased the cerebral infarct area, neurological scores and apoptosis of hippocampal neuronal cells by downregulating SIAH1 and activating the mTOR signaling pathway. Taken together, the results of this study reveal the important role and underlying mechanism of miR-129-5p in IBI, providing a promising biomarker for preventive and therapeutic strategies.
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28
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Onaolapo AY, Onaolapo OJ. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule. World J Psychiatry 2021; 11:297-315. [PMID: 34327123 PMCID: PMC8311508 DOI: 10.5498/wjp.v11.i7.297] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/13/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
The versatility of glutamate as the brain’s foremost excitatory neurotransmitter and modulator of neurotransmission and function is considered common knowledge. Years of research have continued to uncover glutamate’s effects and roles in several neurological and neuropsychiatric disorders, including depression. It had been considered that a deeper understanding of the roles of glutamate in depression might open a new door to understanding the pathological basis of the disorder, improve the approach to patient management, and lead to the development of newer drugs that may benefit more patients. This review examines our current understanding of the roles of endogenous and exogenous sources of glutamate and the glutamatergic system in the aetiology, progression and management of depression. It also examines the relationships that link the gut-brain axis, glutamate and depression; as it emphasizes how the gut-brain axis could impact depression pathogenesis and management via changes in glutamate homeostasis. Finally, we consider what the likely future of glutamate-based therapies and glutamate-based therapeutic manipulations in depression are, and if with them, we are now on the final chapter of understanding the neurochemical milieu of depressive disorders.
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Affiliation(s)
- Adejoke Yetunde Onaolapo
- Behavioural Neuroscience Unit, Neurobiology Subdivision, Department of Anatomy, Ladoke Akintola University of Technology, Oyo State 234, Nigeria
| | - Olakunle James Onaolapo
- Behavioural Neuroscience Unit, Neuropharmacology Subdivision, Department of Pharmacology, Ladoke Akintola University of Technology, Oyo State 234, Nigeria
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29
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Zhang S, Lachance BB, Mattson MP, Jia X. Glucose metabolic crosstalk and regulation in brain function and diseases. Prog Neurobiol 2021; 204:102089. [PMID: 34118354 DOI: 10.1016/j.pneurobio.2021.102089] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 04/08/2021] [Accepted: 06/01/2021] [Indexed: 01/11/2023]
Abstract
Brain glucose metabolism, including glycolysis, the pentose phosphate pathway, and glycogen turnover, produces ATP for energetic support and provides the precursors for the synthesis of biological macromolecules. Although glucose metabolism in neurons and astrocytes has been extensively studied, the glucose metabolism of microglia and oligodendrocytes, and their interactions with neurons and astrocytes, remain critical to understand brain function. Brain regions with heterogeneous cell composition and cell-type-specific profiles of glucose metabolism suggest that metabolic networks within the brain are complex. Signal transduction proteins including those in the Wnt, GSK-3β, PI3K-AKT, and AMPK pathways are involved in regulating these networks. Additionally, glycolytic enzymes and metabolites, such as hexokinase 2, acetyl-CoA, and enolase 2, are implicated in the modulation of cellular function, microglial activation, glycation, and acetylation of biomolecules. Given these extensive networks, glucose metabolism dysfunction in the whole brain or specific cell types is strongly associated with neurologic pathology including ischemic brain injury and neurodegenerative disorders. This review characterizes the glucose metabolism networks of the brain based on molecular signaling and cellular and regional interactions, and elucidates glucose metabolism-based mechanisms of neurological diseases and therapeutic approaches that may ameliorate metabolic abnormalities in those diseases.
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Affiliation(s)
- Shuai Zhang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Brittany Bolduc Lachance
- Program in Trauma, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States
| | - Mark P Mattson
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, United States; Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, 21201, United States; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States.
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30
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Bevilacqua L, Charney A, Pierce CR, Richards SM, Jha MK, Glasgow A, Brallier J, Kirkwood K, Bagiella E, Charney DS, Murrough JW. Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial. J Psychopharmacol 2021; 35:124-127. [PMID: 33522376 DOI: 10.1177/0269881120985147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).
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Affiliation(s)
- Laura Bevilacqua
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Alex Charney
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Charlotte R Pierce
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Samantha M Richards
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Manish K Jha
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Andrew Glasgow
- Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, New York, USA
| | - Jess Brallier
- Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine, New York, USA
| | - Katherine Kirkwood
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Emilia Bagiella
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Dennis S Charney
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA.,Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA.,Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, USA
| | - James W Murrough
- Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, USA.,Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, USA
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31
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Zhong X, Ouyang C, Liang W, Dai C, Zhang W. (2R,6R)-Hydroxynorketamine Alleviates Electroconvulsive Shock-Induced Learning Impairment by Inhibiting Autophagy. Neuropsychiatr Dis Treat 2021; 17:297-304. [PMID: 33568909 PMCID: PMC7868300 DOI: 10.2147/ndt.s278422] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/11/2021] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Learning impairment after electroconvulsive therapy (ECT) is common. Ketamine, an anesthetic used for ECT, has been demonstrated to attenuate cognitive impairment after ECT. However, the mechanism by which ketamine occurs in this case is still unknown. We aimed to explore the role of ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] in the protection against learning impairment and investigate whether autophagy is involved in the protective effect. MATERIALS AND METHODS A rat depression model received electroconvulsive shock (ECS; simulated ECT in animal models) daily for 3 days. The Morris water maze was used to assess the spatial learning function of the rats. Western blotting was used to detect the expression of Beclin-1, light chain (LC)3-II/LC3-I, p62, mammalian target of rapamycin (mTOR), and p-mTOR in the hippocampus. RESULTS The escape latency for the maze in the ECS group was significantly longer than that in the sham ECS group (P=0.042). Meanwhile, the escape latency in the (2R,6R)-HNK+ECS group was significantly shorter than that in the ECS group (P=0.005). The LC3-II/LC3-I ratio and Beclin-1 expression level significantly increased, and the p62 expression level significantly decreased in the ECS group, compared with those in the sham ECS group (all P<0.001). The (2R,6R)-HNK+ECS group showed lower LC3-II/LC3-I ratio (P<0.001) and Beclin-1 expression level (P<0.001) and higher p62 (P<0.001) and p-mTOR expression levels (P=0.048) than did the ECS group. After small-molecule enhancer of rapamycin 28 (SMER28) administration, the role of (2R,6R)-HNK in protecting against learning impairment and inhibiting autophagy was abrogated, showing no difference in the escape latency; the difference in the LC3-II/LC3-I ratio and p62 expression level between the SMER28+(2R,6R)-HNK+ECS and ECS groups was not as significant as that between the (2R,6R)-HNK+ECS and ECS groups (P<0.05-0.01 vs P<0.001). CONCLUSION (2R,6R)-HNK yields cognitive protection by suppressing autophagy through the mTOR signaling pathway in the ECS-treated rat hippocampus.
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Affiliation(s)
- Xiaomei Zhong
- Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China
| | - Cong Ouyang
- Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China
| | - Wanyuan Liang
- Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China
| | - Cunying Dai
- Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China
| | - Weiru Zhang
- Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People's Republic of China
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32
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Gałuszko-Wȩgielnik M, Włodarczyk A, Cubała WJ, Wilkowska A, Górska N, Słupski J. Case Report: Repeated Series of Ketamine Infusions in Patients With Treatment-Resistant Depression: Presentation of Five Cases. Front Psychiatry 2021; 12:705190. [PMID: 34925081 PMCID: PMC8674554 DOI: 10.3389/fpsyt.2021.705190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 10/25/2021] [Indexed: 12/02/2022] Open
Abstract
Purpose: Approximately 30% of patients with major depressive disorder (MDD) are treatment resistant. There is an unquestionable need for new treatment strategies. Subanesthetic doses of intravenous (IV) ketamine have a rapid antidepressant effect in treatment-resistant depression (TRD). This paper describes the efficacy of repeated series of intravenous ketamine infusions as an add-on treatment in five TRD inpatients. Methods: Eligible patients aged 43-63 were given eight ketamine infusions as an add-on treatment for patients with MDD. The subjects have readministered the intervention due to worsening depressive symptoms. Results: Of the five inpatients given ketamine as a series of eight infusions, one underwent three, and four had two treatment series. Four patients achieved remission after first series and three after the second series of ketamine infusions. The adverse reactions were mild and transient with no sequelae. Limitations: Presented case series applies to short-term intervention with IV ketamine as an add-on therapy. The results cannot be generalized to the long-term maintenance treatment nor other ketamine formulations as well as different administration schedules and dosing. Conclusions: This case series showed efficacy and safety of the repeated series of IV ketamine treatment in TRD in MDD and bipolar disorder type I. The subsequent interventions were safe and observed adverse events were mild and transient. Interestingly, the IV ketamine treatment at successive administrations seems to alter the major depression severity of the next affective episode. There is a critical need for further research regarding IV ketamine treatment effectiveness and long-term safety in future studies.
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Affiliation(s)
| | - Adam Włodarczyk
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław Jerzy Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Alina Wilkowska
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Natalia Górska
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Jakub Słupski
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Tianeptine Enhances Energy-related Processes in the Hippocampal Non-synaptic Mitochondria in a Rat Model of Depression. Neuroscience 2020; 451:111-125. [DOI: 10.1016/j.neuroscience.2020.09.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022]
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Yao Y, Hong S, Ikeda T, Mori H, MacDougald OA, Nada S, Okada M, Inoki K. Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity. Mol Cell 2020; 80:437-451.e6. [PMID: 33157014 PMCID: PMC7665239 DOI: 10.1016/j.molcel.2020.10.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/22/2020] [Accepted: 10/02/2020] [Indexed: 01/02/2023]
Abstract
Amino-acid-induced lysosomal mechanistic target of rapamycin complex 1 (mTORC1) localization through the Rag GTPases is a critical step for its activation by Rheb GTPase. However, how the mTORC1 interacts with Rheb on the lysosome remains elusive. We report that amino acids enhance the polyubiquitination of Rheb (Ub-Rheb), which shows a strong binding preference for mTORC1 and supports its activation, while the Ub-Rheb is subjected to subsequent degradation. Mechanistically, we identified ATXN3 as a Ub-Rheb deubiquitinase whose lysosomal localization is blocked by active Rag heterodimer in response to amino acid stimulation. Consistently, cells lacking functional Rag heterodimer on the lysosome accumulate Ub-Rheb, and blockade of its degradation instigates robust lysosomal mTORC1 localization and its activation without the Ragulator-Rag system. Thus, polyubiquitination of Rheb is an important post-translational modification, which facilitates the binding of mTORC1 to Rheb on the lysosome and is another crosstalk between the amino acid and growth factor signaling for mTORC1 activation.
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Affiliation(s)
- Yao Yao
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA
| | - Sungki Hong
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA
| | - Takayuki Ikeda
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Hiroyuki Mori
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1137 E. Catherine St., Ann Arbor, MI 48109-5622, USA
| | - Ormond A MacDougald
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1137 E. Catherine St., Ann Arbor, MI 48109-5622, USA; Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5368, USA
| | - Shigeyuki Nada
- Department of Oncogene Research, the Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masato Okada
- Department of Oncogene Research, the Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Ken Inoki
- Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1137 E. Catherine St., Ann Arbor, MI 48109-5622, USA; Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5368, USA.
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Athira KV, Bandopadhyay S, Samudrala PK, Naidu VGM, Lahkar M, Chakravarty S. An Overview of the Heterogeneity of Major Depressive Disorder: Current Knowledge and Future Prospective. Curr Neuropharmacol 2020; 18:168-187. [PMID: 31573890 PMCID: PMC7327947 DOI: 10.2174/1570159x17666191001142934] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 08/05/2019] [Accepted: 09/27/2019] [Indexed: 02/08/2023] Open
Abstract
Major depressive disorder (MDD) is estimated to impose maximum debilitating effects on the society by 2030, with its critical effects on health, functioning, quality of life and concomitant high levels of morbidity and mortality. Yet, the disease is inadequately understood, diagnosed and treated. Moreover, with the recent drastic rise in the pace of life, stress has materialized as one of the most potent environmental factors for depression. In this scenario, it is important to understand the modern pathogenetic hypotheses and mechanisms, and possibly try to shift from the traditional approaches in depression therapy. These include the elaboration of pathophysiological changes in heterogeneous systems such as genetic, epigenetic, serotonergic, noradrenergic, gamma-aminobutyric acid, glutamatergic and endocannabinoid systems, neurotrophic factors, HPA axis, immune system as well as cellular stress mechanisms. These components interact with each other in a complex matrix and further elucidation of their mechanism and cascade pathways are needed. This might aid in the identification of MDD subtypes as well as the development of sophisticated biomarkers. Further, characterization might also aid in developing multitargeted therapies that hold much promise as compared to the conventional monoamine based treatment. New candidate pharmacons, refined psychotherapeutic modalities, advanced neuro-surgical and imaging techniques as well as the implementation of pharmacokinetic, pharmacogenetic prescribing guidelines constitute the emerging expanses of MDD treatment.
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Affiliation(s)
- Kaipuzha Venu Athira
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, 781125, Assam, India.,Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.,Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, Kerala, India
| | - Sikta Bandopadhyay
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India
| | - Pavan Kumar Samudrala
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, 781125, Assam, India
| | - V G M Naidu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, 781125, Assam, India
| | - Mangala Lahkar
- Department of Pharmacology, Gauhati Medical College, Guwahati, 781032, Assam, India
| | - Sumana Chakravarty
- Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India
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Wang JL, Wang Y, Gao TT, Liu L, Wang YJ, Guan W, Chen TT, Zhao J, Zhang Y, Jiang B. Venlafaxine protects against chronic stress-related behaviors in mice by activating the mTORC1 signaling cascade. J Affect Disord 2020; 276:525-536. [PMID: 32871684 DOI: 10.1016/j.jad.2020.07.096] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Recent studies have suggested the role of mammalian target of rapamycin complex 1 (mTORC1) in the pathophysiology of depression. Although venlafaxine was thought to be a serotonin and norepinephrine reuptake inhibitor (SNRI), its pharmacological mechanism remain elusive. In this study, the effects of venlafaxine on the mTORC1 system were studied in both chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models. METHOD First, we examined whether repeated venlafaxine treatment reversed the effects of CUMS and CSDS on the mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Second, several selective pharmacological inhibitors of the mTORC1 system, including rapamycin, LY294002 and U0126, were used together to determine whether the protective effects of venlafaxine against the CUMS and CSDS models were prevented by mTORC1 system blockade. Finally, genetic knockdown of mTORC1 by mTORC1-shRNA was further adopted to test whether mTORC1 was necessary for the anti-stress effects of venlafaxine in mice. RESULT Our results showed that the decreasing effects of CUMS and CSDS on the mTORC1 signaling cascade in the hippocampus and mPFC were restored by venlafaxine, and the use of rapamycin, LY294002, U0126 and mTORC1-shRNA fully abolished the anti-stress actions of venlafaxine in mice. CONCLUSION The mTORC1 system is involved in the pharmacological mechanism of venlafaxine.
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Affiliation(s)
- Jin-Liang Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Yuan Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Ting-Ting Gao
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Ling Liu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Ying-Jie Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Ting-Ting Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China
| | - Jie Zhao
- Department of Pharmacy, The Sixth People's Hospital of Nantong, Nantong 226011, Jiangsu, China
| | - Yin Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Provincial key laboratory of Inflammation and Molecular Drug Target, Jiangsu, China.
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Bartlett MJ, Flores AJ, Ye T, Smidt SI, Dollish HK, Stancati JA, Farrell DC, Parent KL, Doyle KP, Besselsen DG, Heien ML, Cowen SL, Steece-Collier K, Sherman SJ, Falk T. Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. Exp Neurol 2020; 333:113413. [PMID: 32717354 PMCID: PMC7518549 DOI: 10.1016/j.expneurol.2020.113413] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 02/08/2023]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.
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Affiliation(s)
- Mitchell J Bartlett
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA
| | - Andrew J Flores
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Physiological Sciences, The University of Arizona, Tucson, AZ 85724, USA
| | - Tony Ye
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA
| | - Saskia I Smidt
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA
| | - Hannah K Dollish
- Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ 85724, USA
| | - Jennifer A Stancati
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI 49503, USA
| | - Drew C Farrell
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
| | - Kate L Parent
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
| | - Kristian P Doyle
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Department of Immunobiology, The University of Arizona, Tucson, AZ 85724, USA
| | - David G Besselsen
- University Animal Care, The University of Arizona, Tucson, AZ 85724, USA
| | - Michael L Heien
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
| | - Stephen L Cowen
- Department of Psychology, The University of Arizona, Tucson, AZ 85724, USA
| | - Kathy Steece-Collier
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI 49503, USA
| | - Scott J Sherman
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA
| | - Torsten Falk
- Department of Neurology, The University of Arizona, Tucson, AZ 85724, USA; Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Physiological Sciences, The University of Arizona, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Neuroscience, The University of Arizona, Tucson, AZ 85724, USA.
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Korczak M, Kurowski P, Leśniak A, Grönbladh A, Filipowska A, Bujalska-Zadrożny M. GABA B receptor intracellular signaling: novel pathways for depressive disorder treatment? Eur J Pharmacol 2020; 885:173531. [PMID: 32871173 DOI: 10.1016/j.ejphar.2020.173531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 08/26/2020] [Accepted: 08/28/2020] [Indexed: 12/22/2022]
Abstract
Affecting over 320 million people around the world, depression has become a formidable challenge for modern medicine. In addition, an increasing number of studies cast doubt on the monoamine theory of depressive disorder and, worryingly, antidepressant medications only significantly benefit patients with severe depression. Thus, it is not surprising that researchers have shown an increased interest in new theories attempting to explain the pathogenesis of this disease. One example is the excitatory/inhibitory transmission imbalance theory. These abnormalities involve glutamate and γ-aminobutyric acid (GABA) signaling. Studies on GABAB receptors and their antagonists are particularly promising for the treatment of depressive disorders. In this paper, intracellular pathways controlled by GABAB receptors and their links to depression are described, including the impact of ketamine on GABAergic synaptic transmission.
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Affiliation(s)
- Maciej Korczak
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Kurowski
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland.
| | - Anna Leśniak
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
| | - Alfhild Grönbladh
- The Beijer Laboratory, Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, The Uppsala University, Uppsala, Sweden
| | - Anna Filipowska
- Department of Biosensors and Processing of Biomedical Signals, The Silesian University of Technology, Zabrze, Poland
| | - Magdalena Bujalska-Zadrożny
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, The Medical University of Warsaw, Warsaw, Poland
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Gladulich LFH, Xie J, Jensen KB, Kamei M, Paes-de-Carvalho R, Cossenza M, Proud CG. Bicuculline regulated protein synthesis is dependent on Homer1 and promotes its interaction with eEF2K through mTORC1-dependent phosphorylation. J Neurochem 2020; 157:1086-1101. [PMID: 32892352 DOI: 10.1111/jnc.15178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/29/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023]
Abstract
The regulation of protein synthesis is a vital and finely tuned process in cellular physiology. In neurons, this process is very precisely regulated, as which mRNAs undergo translation is highly dependent on context. One of the most prominent regulators of protein synthesis is the enzyme eukaryotic elongation factor kinase 2 (eEF2K) that regulates the elongation stage of protein synthesis. This kinase and its substrate, eukaryotic elongation factor 2 (eEF2) are important in processes such as neuronal development and synaptic plasticity. eEF2K is regulated by multiple mechanisms including Ca2+ -ions and the mTORC1 signaling pathway, both of which play key roles in neurological processes such as learning and memory. In such settings, the localized control of protein synthesis is of crucial importance. In this work, we sought to investigate how the localization of eEF2K is controlled and the impact of this on protein synthesis in neuronal cells. In this study, we used both SH-SY5Y neuroblastoma cells and mouse cortical neurons, and pharmacologically and/or genetic approaches to modify eEF2K function. We show that eEF2K activity and localization can be regulated by its binding partner Homer1b/c, a scaffolding protein known for its participation in calcium-regulated signaling pathways. Furthermore, our results indicate that this interaction is regulated by the mTORC1 pathway, through a known phosphorylation site in eEF2K (S396), and that it affects rates of localized protein synthesis at synapses depending on the presence or absence of this scaffolding protein.
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Affiliation(s)
- Luis F H Gladulich
- Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.,Lifelong Health, South Australia Health & Medical Research Institute (SAHMRI) Adelaide, SA, Australia
| | - Jianling Xie
- Lifelong Health, South Australia Health & Medical Research Institute (SAHMRI) Adelaide, SA, Australia
| | - Kirk B Jensen
- Lifelong Health, South Australia Health & Medical Research Institute (SAHMRI) Adelaide, SA, Australia
| | - Makoto Kamei
- Lifelong Health, South Australia Health & Medical Research Institute (SAHMRI) Adelaide, SA, Australia.,Center for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Roberto Paes-de-Carvalho
- Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.,Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niterói, Brazil
| | - Marcelo Cossenza
- Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.,Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil
| | - Christopher G Proud
- Lifelong Health, South Australia Health & Medical Research Institute (SAHMRI) Adelaide, SA, Australia
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Gupta G, Deval R, Mishra A, Upadhyay S, Singh PK, Rao VR. Re-testing reported significant SNPs related to suicide in a historical high -risk isolated population from north east India. Hereditas 2020; 157:31. [PMID: 32680568 PMCID: PMC7368720 DOI: 10.1186/s41065-020-00144-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 07/07/2020] [Indexed: 02/08/2023] Open
Abstract
Background Genetic diathesis of suicide is supported by family and twin studies. Few candidate gene pathways are known, but does not explain fully the complexity of suicide genetic risk. Recent investigations opting for Genome-Wide Association Studies (GWAS) resulted in finding additional targets, but replication remained a challenge. In this respect small isolated population approach in several complex disease phenotypes is found encouraging. The present study is an attempt to re-test some of the reported significant SNPs for suicide among a small historical high- risk isolated population from Northeast India. Methods Two hundred ten cases (inclusive of depressed, suicide attempter and depressed + suicide attempter) and 249 controls were considered in the present study which were evaluated for the psychiatric parameters. Sixteen reported significant SNPs for suicide behaviour were re-tested using association approach under various genetic models. Networking by GeneMANIA tool was used for function prediction of the associated genes. Results Seven SNPs (of 6 genes) remained significant in different genetic models. On networking genes with significant SNPs IL7, RHEB, CTNN3, KCNIP4, ARFGEF3 are found in interaction with already known candidate gene pathways while SNP rs1109089 (RHEB) gained further support from earlier expression studies. NUGGC gene is in complete isolation. Conclusions Small population approach in replicating significant SNPs is useful in complex phenotypes like suicide. This study explored the region-specific demographics of India by identifying vulnerable population for suicide via genetic association analysis in bringing into academic and administrative forum, the importance of suicide as a disease and its biological basis.
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Affiliation(s)
- Gaurav Gupta
- Department of Biotechnology, Invertis University, Bareilly (U.P), India.,Department of Genetics, Osmania University, Hyderabad, 500007, India
| | - Ravi Deval
- Department of Biotechnology, Invertis University, Bareilly (U.P), India
| | - Anshuman Mishra
- VBRI Innovation Centre, New Delhi, India.,Institute of Advanced Materials (IAAM), 59053, Ulrika, Sweden
| | - Shashank Upadhyay
- Department of Biotechnology, Invertis University, Bareilly (U.P), India
| | - Piyoosh Kumar Singh
- Department of Anthropology, Delhi University, Delhi, India.,Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
| | - V R Rao
- Department of Genetics, Osmania University, Hyderabad, 500007, India. .,Department of Anthropology, Delhi University, Delhi, India. .,Genome Foundation, Hyderabad, India.
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Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, Sherif M, Ahn KH, D'Souza DC, Formica R, Southwick SM, Duman RS, Sanacora G, Krystal JH. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 2020; 45:990-997. [PMID: 32092760 PMCID: PMC7162891 DOI: 10.1038/s41386-020-0644-9] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/08/2020] [Accepted: 02/12/2020] [Indexed: 02/08/2023]
Abstract
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
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Affiliation(s)
- Chadi G Abdallah
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA.
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA.
| | - Lynnette A Averill
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Ralitza Gueorguieva
- Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA
| | - Selin Goktas
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Prerana Purohit
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Mohini Ranganathan
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Mohamed Sherif
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Kyung-Heup Ahn
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Deepak Cyril D'Souza
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Richard Formica
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Steven M Southwick
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Ronald S Duman
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Gerard Sanacora
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - John H Krystal
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
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Patchouli alcohol protects against chronic unpredictable mild stress-induced depressant-like behavior through inhibiting excessive autophagy via activation of mTOR signaling pathway. Biomed Pharmacother 2020; 127:110115. [PMID: 32244196 DOI: 10.1016/j.biopha.2020.110115] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 12/28/2022] Open
Abstract
Patchouli alcohol (PA), a tricyclic sesquiterpene, is the major chemical component of patchouli oil. This study investigated the antidepressant-like effect and mechanism of PA in chronic unpredictable mild stress (CUMS). Our results showed that PA markedly attenuated CUMS-induced depressant-like behaviors, including an effective increase of sucrose preference and spontaneous exploratory capacity, as well as reduction of immobility time. In addition, PA markedly attenuated CUMS-induced mTOR, p70S6K, and 4E-BP-1 phosphorylation reduction in the hippocampus. Furthermore, PA reversed CUMS-induced increases in LC3-II and p62 levels and CUMS-induced decrease in PSD-95 and SYN-I levels. These results indicated that the antidepressant-like effect of PA was correlated with the activation of the mTOR signaling pathway. Moreover, behavioral experimental results showed that the antidepressant-like effect of PA was blocked by rapamycin (autophagy inducer and mTOR inhibitor) and chloroquine (autophagic flux inhibitor). These results suggest that PA exerted antidepressant-like effect in CUMS rats through inhibiting autophagy, repairing synapse, and restoring autophagic flux in the hippocampus by activating the mTOR signaling pathway. The results render PA a promising antidepressant agent worthy of further development into a pharmaceutical drug for the treatment of depression.
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Xu D, Wang C, Zhu X, Zhao W, Jiang B, Cui S, Sun Y, Cui Z. The antidepressant-like effects of fluvoxamine in mice involve the mTOR signaling in the hippocampus and prefrontal cortex. Psychiatry Res 2020; 285:112708. [PMID: 31810748 DOI: 10.1016/j.psychres.2019.112708] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/24/2019] [Accepted: 11/24/2019] [Indexed: 12/31/2022]
Abstract
Recent studies have suggested that activation of the mammalian target of rapamycin (mTOR) signaling may be related to antidepressant actions. Although thought as a selective serotonin reuptake inhibitor (SSRI), the antidepressant mechanisms of fluvoxamine remain elusive. Therefore, this study aims to evaluate whether mTOR underlies the antidepressant-like effects of fluvoxamine. Male C57BL/6 J mice were subjected to 8 weeks of chronic unpredictable mild stress (CUMS) with fluvoxamine administered during the last 2 weeks. Western blotting analyses were then used to assess the expression of the mTOR signaling cascade in the hippocampus and prefrontal cortex (PFC) among all groups. The selective inhibitor of mTOR, rapamycin, was further used. It was found that fluvoxamine treatment fully reversed the effects of CUMS on the mTOR signaling in the hippocampus and PFC, and the usage of rapamycin significantly prevented the antidepressant-like effects of fluvoxamine in the CUMS model of depression. Taken together, the mTOR system is involved in the antidepressant mechanisms of fluvoxamine.
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Affiliation(s)
- Dawei Xu
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China
| | - Chengniu Wang
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China; Institute of Reproductive Medicine, Medical College, Nantong University, Nantong 226001, People's Republic of China
| | - Xinhui Zhu
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China
| | - Wei Zhao
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, People's Republic of China
| | - Shengyu Cui
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China
| | - Yuyu Sun
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China.
| | - Zhiming Cui
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, People's Republic of China.
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Duman RS, Shinohara R, Fogaça MV, Hare B. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry 2019; 24:1816-1832. [PMID: 30894661 PMCID: PMC6754322 DOI: 10.1038/s41380-019-0400-x] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 11/09/2022]
Abstract
Efforts to develop efficacious antidepressant agents with novel mechanisms have been largely unsuccessful since the 1950's until the discovery of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid and sustained antidepressant actions even in treatment-resistant patients. This finding has ushered in a new era for the development of novel rapid-acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here, we review the current state of rapid-acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain-derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.
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Affiliation(s)
- Ronald S Duman
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
| | - Ryota Shinohara
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Manoela V Fogaça
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Brendan Hare
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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Kim JW, Monteggia LM. Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways. Behav Brain Res 2019; 380:112378. [PMID: 31760154 DOI: 10.1016/j.bbr.2019.112378] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 12/13/2022]
Abstract
Clinical findings show that a single subanesthetic dose of ketamine elicits rapid antidepressant effects. Accumulating data suggests that ketamine blocks the N-methyl-D-aspartate receptor and results in specific effects on intracellular signaling including increased brain-derived neurotrophic factor (BDNF) protein expression, which augments synaptic responses required for rapid antidepressant effects. To further investigate this potential mechanism for ketamine's antidepressant action, we examined the effect of increasing ketamine doses on intracellular signaling, synaptic plasticity, and rapid antidepressant effects. Given that ketamine is often used at 2.5-10 mg/kg to examine antidepressant effects and 20-50 mg/kg to model schizophrenia, we compared effects at 5, 20 and 50 mg/kg. We found that intraperitoneal (i.p.) injection of low dose (5 mg/kg) ketamine produces rapid antidepressant effects, which were not observed at 20 or 50 mg/kg. At 5 mg/kg ketamine significantly increased the level of BDNF, a protein necessary for the rapid antidepressant effects, while 20 and 50 mg/kg ketamine did not alter BDNF levels in the hippocampus. Low concentration ketamine also evoked the highest synaptic potentiation in the hippocampal CA1, while higher concentrations significantly decreased the synaptic effects. Our results suggest low dose ketamine produces antidepressant effects and has independent behavioral and synaptic effects compared to higher doses of ketamine that are used to model schizophrenia. These findings strengthen our knowledge on specific signaling associated with ketamine's rapid antidepressant effects.
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Affiliation(s)
- Ji-Woon Kim
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37240-7933, USA
| | - Lisa M Monteggia
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37240-7933, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37240-7933, USA.
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Ho MF, Zhang C, Zhang L, Li H, Weinshilboum RM. Ketamine and Active Ketamine Metabolites Regulate STAT3 and the Type I Interferon Pathway in Human Microglia: Molecular Mechanisms Linked to the Antidepressant Effects of Ketamine. Front Pharmacol 2019; 10:1302. [PMID: 31827434 PMCID: PMC6848891 DOI: 10.3389/fphar.2019.01302] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/11/2019] [Indexed: 11/13/2022] Open
Abstract
Inflammation is an important biological process which contributes to risk for depression, in part as a result of the production of proinflammatory cytokines and of alterations in glutamatergic neurotransmission. Ketamine has anti-inflammatory properties which might contribute to its antidepressant effects. This study was designed to clarify mechanisms of action for ketamine and its active metabolites, (2R,6R;2S,6S)-hydroxynorketamine (HNK), which also appear to play a major role in ketamine's rapid antidepressant effects. An HMC3 human microglial cell line was used as a model system to test a possible role for ketamine in immune response regulation that might contribute to its antidepressant effects. Our results highlight the fact that ketamine and its two active metabolites can regulate the type I interferon pathway mediated, at least partially, through signal transducer and activation of transcription 3 (STAT3) which plays a major role in the immune response. Specifically, STAT3 downstream genes that were modulated by either ketamine or its active metabolites were enriched in the "response to type I interferon" pathway. Our data also suggest that STAT3 might play a role in ketamine's antidepressant effects, mediated, at least in part, through eukaryotic elongation factor 2 (EEF2), resulting in the augmentation of brain-derived neurotropic factor (BDNF) expression and promoting the synthesis of synaptic proteins postsynaptic density protein 95 (PSD95) and synapsin I (SYN1).
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Affiliation(s)
- Ming-Fen Ho
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Cheng Zhang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Lingxin Zhang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Hu Li
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Richard M Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
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Nowacka A, Borczyk M. Ketamine applications beyond anesthesia - A literature review. Eur J Pharmacol 2019; 860:172547. [PMID: 31348905 DOI: 10.1016/j.ejphar.2019.172547] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 07/09/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2023]
Abstract
Ketamine's clinical use began in the 1970s. Physicians benefited from its safety and ability to induce short-term anesthesia and analgesia. The psychodysleptic effects caused by the drug called its further clinical use into question. Despite these unpleasant effects, ketamine is still applied in veterinary medicine, field medicine, and specialist anesthesia. Recent intensive research brought into light new possible applications of this drug. It began to be used in acute, chronic and cancer pain management. Most interesting reports come from research on the antidepressive and antisuicidal properties of ketamine giving hope for the creation of an effective treatment for major depressive disorder. Other reports highlight the possible use of ketamine in treating addiction, asthma and preventing cancer growth. Besides clinical use, the drug is also applied to in animal model of schizophrenia. It seems that nowadays, with numerous possible applications, the use of ketamine has returned; to its former glory. Nevertheless, the drug must be used with caution because still the mechanisms by which it executes its functions and long-term effects of its use are not fully known. This review aims to discuss the well-known and new promising applications of ketamine.
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Affiliation(s)
- Agata Nowacka
- Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Malgorzata Borczyk
- Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
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Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades. Acta Neuropsychiatr 2019; 31:143-150. [PMID: 30890202 DOI: 10.1017/neu.2018.39] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVES NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors. METHODS Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment. RESULTS We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL. CONCLUSION Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.
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Affiliation(s)
| | - Adam Kaplin
- Department of Psychiatry and Behavioral Sciences (Wang, Kaplin) and Department of Neurology and Neurosurgery (Kaplin), Johns Hopkins University School of Medicine, Baltimore; Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore (Wang)
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50
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Jiang Y, Su S, Zhang Y, Qian J, Liu P. Control of mTOR signaling by ubiquitin. Oncogene 2019; 38:3989-4001. [PMID: 30705402 PMCID: PMC6621562 DOI: 10.1038/s41388-019-0713-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 12/21/2022]
Abstract
The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.
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Affiliation(s)
- Yao Jiang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Siyuan Su
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yanqiong Zhang
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Jiayi Qian
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Pengda Liu
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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