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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

Sevoflurane Ameliorates Schizophrenia in a Mouse Model and Patients: A Pre-Clinical and Clinical Feasibility Study

Author(s): Tianyun Zhao, Ziwen Shi, Nongxi Ling, Jingwen Qin, Quancai Zhou, Lingzhi Wu, Yuansheng Wang, Chuansong Lin*, Daqing Ma* and Xingrong Song*

Volume 20, Issue 12, 2022

Published on: 08 June, 2022

Page: [2369 - 2380] Pages: 12

DOI: 10.2174/1570159X20666220310115846

Price: $65

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Abstract

Background: GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients.

Methods: Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2.

Results: MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01).

Conclusion: Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients’ symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.

Keywords: Low-concentration, sevoflurane, E/I balance, social deficits, early response, schizophrenia.

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[1]
Simeone, J.C.; Ward, A.J.; Rotella, P.; Collins, J.; Windisch, R. An evaluation of variation in published estimates of schizophrenia prevalence from 1990 horizontal line 2013: A systematic literature review. BMC Psychiatry, 2015, 15, 193.
[http://dx.doi.org/10.1186/s12888-015-0578-7] [PMID: 26263900]
[2]
Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 2015, 386(9995), 743-800.
[http://dx.doi.org/10.1016/S0140-6736(15)60692-4] [PMID: 26063472]
[3]
Howes, O.; McCutcheon, R.; Stone, J. Glutamate and dopamine in schizophrenia: An update for the 21st century. J. Psychopharmacol., 2015, 29(2), 97-115.
[http://dx.doi.org/10.1177/0269881114563634] [PMID: 25586400]
[4]
Stahl, S.M. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: Dopamine, serotonin, and glutamate. CNS Spectr., 2018, 23(3), 187-191.
[http://dx.doi.org/10.1017/S1092852918001013] [PMID: 29954475]
[5]
Carbon, M.; Correll, C.U. Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr., 2014, 19(Suppl 1), 38-52. quiz 35-7, 53
[http://dx.doi.org/10.1017/S1092852914000601] [PMID: 25403863]
[6]
Correll, C.U.; Rubio, J.M.; Inczedy-Farkas, G.; Birnbaum, M.L.; Kane, J.M.; Leucht, S. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry, 2017, 74(7), 675-684.
[http://dx.doi.org/10.1001/jamapsychiatry.2017.0624] [PMID: 28514486]
[7]
Lieberman, J.A. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J. Clin. Psychiatry, 2007, 68(2), e04.
[http://dx.doi.org/10.4088/JCP.0207e04] [PMID: 17335312]
[8]
Millan, M.J.; Fone, K.; Steckler, T.; Horan, W.P. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur. Neuropsychopharmacol., 2014, 24(5), 645-692.
[http://dx.doi.org/10.1016/j.euroneuro.2014.03.008] [PMID: 24820238]
[9]
2019 exceptional surveillance of psychosis and schizophrenia in adults: prevention and management (NICE guideline CG178); London 2019.
[10]
Olsen, R.W.; Sieghart, W. GABA A receptors: Subtypes provide diversity of function and pharmacology. Neuropharmacology, 2009, 56(1), 141-148.
[http://dx.doi.org/10.1016/j.neuropharm.2008.07.045] [PMID: 18760291]
[11]
Rudolph, U.; Knoflach, F. Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes. Nat. Rev. Drug Discov., 2011, 10(9), 685-697.
[http://dx.doi.org/10.1038/nrd3502] [PMID: 21799515]
[12]
Sohal, V.S.; Rubenstein, J.L.R. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol. Psychiatry, 2019, 24(9), 1248-1257.
[http://dx.doi.org/10.1038/s41380-019-0426-0] [PMID: 31089192]
[13]
Pitcher, G.M.; Kalia, L.V.; Ng, D.; Goodfellow, N.M.; Yee, K.T.; Lambe, E.K.; Salter, M.W. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat. Med., 2011, 17(4), 470-478.
[http://dx.doi.org/10.1038/nm.2315] [PMID: 21441918]
[14]
Jerath, A.; Panckhurst, J.; Parotto, M.; Lightfoot, N.; Wasowicz, M.; Ferguson, N.D.; Steel, A.; Beattie, W.S. Safety and efficacy of volatile anesthetic agents compared with standard intravenous midazolam/propofol sedation in ventilated critical care patients: A meta-analysis and systematic review of prospective trials. Anesth. Analg., 2017, 124(4), 1190-1199.
[http://dx.doi.org/10.1213/ANE.0000000000001634] [PMID: 27828800]
[15]
Sondekoppam, R.V.; Narsingani, K.H.; Schimmel, T.A.; McConnell, B.M.; Buro, K.; Özelsel, T.J. The impact of sevoflurane anesthesia on postoperative renal function: A systematic review and meta-analysis of randomized-controlled trials. Can. J. Anaesth., 2020, 67(11), 1595-1623.
[http://dx.doi.org/10.1007/s12630-020-01791-5] [PMID: 32812189]
[16]
MacIver, M.B. Anesthetic agent-specific effects on synaptic inhibition. Anesth. Analg., 2014, 119(3), 558-569.
[http://dx.doi.org/10.1213/ANE.0000000000000321] [PMID: 24977633]
[17]
Barnes, S.A.; Der-Avakian, A.; Young, J.W. Preclinical models to investigate mechanisms of negative symptoms in schizophrenia. Schizophr. Bull., 2017, 43(4), 706-711.
[http://dx.doi.org/10.1093/schbul/sbx065] [PMID: 28586462]
[18]
Leucht, S.; Davis, J.M.; Engel, R.R.; Kissling, W.; Kane, J.M. Definitions of response and remission in schizophrenia: Recommendations for their use and their presentation. Acta Psychiatr. Scand. Suppl., 2009, (438), 7-14.
[http://dx.doi.org/10.1111/j.1600-0447.2008.01308.x] [PMID: 19132961]
[19]
Kinon, B.J.; Chen, L.; Ascher-Svanum, H.; Stauffer, V.L.; Kollack-Walker, S.; Zhou, W.; Kapur, S.; Kane, J.M. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology, 2010, 35(2), 581-590.
[http://dx.doi.org/10.1038/npp.2009.164] [PMID: 19890258]
[20]
Chkhartishvili, E.; Maglakelidze, N.; Babilodze, M.; Chijavadze, E.; Nachkebia, N. Changes of open field behavior in animal model of depression. Georgian Med. News, 2011, 11(200), 107-112.
[PMID: 22201090]
[21]
Castanheira, L.; Ferreira, M.F.; Sebastião, A.M.; Telles-Correia, D. Anxiety assessment in pre-clinical tests and in clinical trials: A critical review. Curr. Top. Med. Chem., 2018, 18(19), 1656-1676.
[http://dx.doi.org/10.2174/1568026618666181115102518] [PMID: 30430939]
[22]
Sankoorikal, G.M.; Kaercher, K.A.; Boon, C.J.; Lee, J.K.; Brodkin, E.S. A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains. Biol. Psychiatry, 2006, 59(5), 415-423.
[http://dx.doi.org/10.1016/j.biopsych.2005.07.026] [PMID: 16199013]
[23]
Neill, J.C.; Barnes, S.; Cook, S.; Grayson, B.; Idris, N.F.; McLean, S.L.; Snigdha, S.; Rajagopal, L.; Harte, M.K. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacol. Ther., 2010, 128(3), 419-432.
[http://dx.doi.org/10.1016/j.pharmthera.2010.07.004] [PMID: 20705091]
[24]
Jackson, M.E.; Homayoun, H.; Moghaddam, B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl. Acad. Sci. USA, 2004, 101(22), 8467-8472.
[http://dx.doi.org/10.1073/pnas.0308455101] [PMID: 15159546]
[25]
Sanz-Clemente, A.; Nicoll, R.A.; Roche, K.W. Diversity in NMDA receptor composition: Many regulators, many consequences. Neuroscientist, 2013, 19(1), 62-75.
[http://dx.doi.org/10.1177/1073858411435129] [PMID: 22343826]
[26]
Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci., 2013, 14(6), 383-400.
[http://dx.doi.org/10.1038/nrn3504] [PMID: 23686171]
[27]
Luján, R.; Shigemoto, R.; López-Bendito, G. Glutamate and GABA receptor signalling in the developing brain. Neuroscience, 2005, 130(3), 567-580.
[http://dx.doi.org/10.1016/j.neuroscience.2004.09.042] [PMID: 15590141]
[28]
Bubeníková-Valesová, V.; Horácek, J.; Vrajová, M.; Höschl, C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci. Biobehav. Rev., 2008, 32(5), 1014-1023.
[http://dx.doi.org/10.1016/j.neubiorev.2008.03.012] [PMID: 18471877]
[29]
Nakazawa, K.; Sapkota, K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol. Ther., 2020, 205, 107426.
[http://dx.doi.org/10.1016/j.pharmthera.2019.107426] [PMID: 31629007]
[30]
Yamamoto, H.; Hagino, Y.; Kasai, S.; Ikeda, K. Specific roles of NMDA receptor subunits in mental disorders. Curr. Mol. Med., 2015, 15(3), 193-205.
[http://dx.doi.org/10.2174/1566524015666150330142807] [PMID: 25817860]
[31]
Geddes, A.E.; Huang, X.F.; Newell, K.A. Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2011, 35(4), 896-904.
[http://dx.doi.org/10.1016/j.pnpbp.2011.02.017] [PMID: 21371516]
[32]
Lorenz-Guertin, J.M.; Jacob, T.C. GABA type a receptor trafficking and the architecture of synaptic inhibition. Dev. Neurobiol., 2018, 78(3), 238-270.
[http://dx.doi.org/10.1002/dneu.22536] [PMID: 28901728]
[33]
McKernan, R.M.; Whiting, P.J. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci., 1996, 19(4), 139-143.
[http://dx.doi.org/10.1016/S0166-2236(96)80023-3] [PMID: 8658597]
[34]
Farrant, M.; Nusser, Z. Variations on an inhibitory theme: Phasic and tonic activation of GABA(A) receptors. Nat. Rev. Neurosci., 2005, 6(3), 215-229.
[http://dx.doi.org/10.1038/nrn1625] [PMID: 15738957]
[35]
Brohan, J.; Goudra, B.G. The role of GABA receptor agonists in anesthesia and sedation. CNS Drugs, 2017, 31(10), 845-856.
[http://dx.doi.org/10.1007/s40263-017-0463-7] [PMID: 29039138]
[36]
Packer, A.M.; Yuste, R. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: A canonical microcircuit for inhibition? J. Neurosci., 2011, 31(37), 13260-13271.
[http://dx.doi.org/10.1523/JNEUROSCI.3131-11.2011] [PMID: 21917809]
[37]
Benson, D.L.; Huntsman, M.M.; Jones, E.G. Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb. Cortex, 1994, 4(1), 40-51.
[http://dx.doi.org/10.1093/cercor/4.1.40] [PMID: 8180490]
[38]
Belforte, J.E.; Zsiros, V.; Sklar, E.R.; Jiang, Z.; Yu, G.; Li, Y.; Quinlan, E.M.; Nakazawa, K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat. Neurosci., 2010, 13(1), 76-83.
[http://dx.doi.org/10.1038/nn.2447] [PMID: 19915563]
[39]
Homayoun, H.; Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci., 2007, 27(43), 11496-11500.
[http://dx.doi.org/10.1523/JNEUROSCI.2213-07.2007] [PMID: 17959792]
[40]
Vutskits, L. Anaesthesia, neural activity, and brain development: Interneurones in the spotlight. Br. J. Anaesth., 2021, 126(6), 1084-1085.
[http://dx.doi.org/10.1016/j.bja.2021.03.002] [PMID: 33814118]
[41]
Chen, X.; Zhou, X.; Yang, L.; Miao, X.; Lu, D.H.; Yang, X.Y.; Zhou, Z.B.; Kang, W.B.; Chen, K.Y.; Zhou, L.H.; Feng, X. Neonatal exposure to low-dose (1.2%) sevoflurane increases rats’ hippocampal neurogenesis and synaptic plasticity in later life. Neurotox. Res., 2018, 34(2), 188-197.
[http://dx.doi.org/10.1007/s12640-018-9877-3] [PMID: 29427282]
[42]
Kolbitsch, C.; Lorenz, I.H.; Hörmann, C.; Schocke, M.; Kremser, C.; Zschiegner, F.; Löckinger, A.; Pfeiffer, K.P.; Felber, S.; Benzer, A. A subanesthetic concentration of sevoflurane increases regional cerebral blood flow and regional cerebral blood volume and decreases regional mean transit time and regional cerebrovascular resistance in volunteers. Anesth. Analg., 2000, 91(1), 156-162.
[http://dx.doi.org/10.1213/00000539-200007000-00029] [PMID: 10866904]
[43]
Kim, S.Y.; Kim, J.M.; Lee, J.H.; Song, B.M.; Koo, B.N. Efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery. Br. J. Anaesth., 2013, 111(2), 222-228.
[http://dx.doi.org/10.1093/bja/aet056] [PMID: 23524149]
[44]
Brosda, J. Jantschak, F.; Pertz, H.H. α2-Adrenoceptors are targets for antipsychotic drugs. Psychopharmacology (Berl.), 2014, 231(5), 801-812.
[http://dx.doi.org/10.1007/s00213-014-3459-8] [PMID: 24488407]
[45]
Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Stella, A.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nat. Rev. Neurosci., 2007, 8(10), 766-775.
[http://dx.doi.org/10.1038/nrn2214] [PMID: 17882254]
[46]
Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J.; Mattson, M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal., 2010, 13(11), 1763-1811.
[http://dx.doi.org/10.1089/ars.2009.3074] [PMID: 20446769]
[47]
Calabrese, V.; Cornelius, C.; Maiolino, L.; Luca, M.; Chiaramonte, R.; Toscano, M.A.; Serra, A. Oxidative stress, redox homeostasis and cellular stress response in Ménière’s disease: Role of vitagenes. Neurochem. Res., 2010, 35(12), 2208-2217.
[http://dx.doi.org/10.1007/s11064-010-0304-2] [PMID: 21042850]
[48]
Toda, N.; Toda, H.; Hatano, Y. Nitric oxide: Involvement in the effects of anesthetic agents. Anesthesiology, 2007, 107(5), 822-842.
[http://dx.doi.org/10.1097/01.anes.0000287213.98020.b6] [PMID: 18073558]
[49]
Fan, W.; Liu, Q.; Zhu, X.; Wu, Z.; Li, D.; Huang, F.; He, H. Regulatory effects of anesthetics on nitric oxide. Life Sci., 2016, 151, 76-85.
[http://dx.doi.org/10.1016/j.lfs.2016.02.094] [PMID: 26946305]
[50]
Correll, C.U. Current treatment options and emerging agents for schizophrenia. J. Clin. Psychiatry, 2020, 81(3), MS19053BR3C.
[http://dx.doi.org/10.4088/JCP.MS19053BR3C] [PMID: 32297721]
[51]
Martínez-Raga, J.; Amore, M.; Di Sciascio, G.; Florea, R.I.; Garriga, M.; Gonzalez, G.; Kahl, K.G.; Karlsson, P.A.; Kuhn, J.; Margariti, M.; Pacciardi, B.; Papageorgiou, K.; Pompili, M.; Rivollier, F.; Royuela, Á.; Safont, G.; Scharfetter, J.; Skagen, B.; Tajima-Pozo, K.; Vidailhet, P. 1st international experts’ meeting on agitation: Conclusions regarding the current and ideal management paradigm of agitation. Front. Psychiatry, 2018, 9, 54.
[http://dx.doi.org/10.3389/fpsyt.2018.00054] [PMID: 29535649]

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