
Effects of mid‑gestational sevoflurane and magnesium sulfate on maternal oxidative stress, inflammation and fetal brain histopathology
- Authors:
- Cagri Ozdemi̇r
- Berrin Isik
- Gulce Koca
- Mehmet Arda Inan
-
Affiliations: Department of Anesthesiology and Reanimation, Mamak State Hospital, 06270 Ankara, Turkey, Department of Anesthesiology and Reanimation, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey, Department of Medical Biochemistry, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey, Department of Medical Pathology, Faculty of Medicine, Gazi University, 06560 Ankara, Turkey - Published online on: May 16, 2024 https://doi.org/10.3892/etm.2024.12574
- Article Number: 286
-
Copyright: © Ozdemi̇r et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
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Ní Mhuireachtaigh R and O'Gorman DA: Anesthesia in pregnant patients for nonobstetric surgery. J Clin Anesth. 18:60–66. 2006.PubMed/NCBI View Article : Google Scholar | |
Osterman MJ and Martin JA: Primary cesarean delivery rates, by state: Results from the revised birth certificate, 2006-2012. Natl Vital Stat Rep. 63:1–11. 2014.PubMed/NCBI | |
United States Food and Drug Administration. FDA drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Updated 2016. Accessed Februry 10, 2017. | |
Krasowski MD and Harrison NL: The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations. Br J Pharmacol. 129:731–743. 2000.PubMed/NCBI View Article : Google Scholar | |
Eger EI, Liao M, Laster MJ, Won A, Popovich J, Raines DE, Solt K, Dutton RC, Cobos FV and Sonner JM: Contrasting roles of the N-methyl-D-aspartate receptor in the production of immobilization by conventional and aromatic anesthetics. Anesth Analg. 102:1397–1406. 2006.PubMed/NCBI View Article : Google Scholar | |
Lerner RA: A hypothesis about the endogenous analogue of general anesthesia. Proc Natl Acad Sci USA. 94:13375–13377. 1997.PubMed/NCBI View Article : Google Scholar | |
Zhou ZB, Yang XY, Tang Y, Zhou X, Zhou LH and Feng X: Subclinical concentrations of sevoflurane reduce oxidative stress but do not prevent hippocampal apoptosis. Mol Med Rep. 14:721–727. 2016.PubMed/NCBI View Article : Google Scholar | |
Shen X, Dong Y, Xu Z, Wang H, Miao C and Soriano SG: Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 118:502–515. 2013.PubMed/NCBI View Article : Google Scholar | |
Cui FH, Li J, Li KZ, Xie YG and Zhao XL: Effects of sevoflurane exposure during different stages of pregnancy on the brain development of rat offspring. J Anesth. 35:654–662. 2021.PubMed/NCBI View Article : Google Scholar | |
Zheng H, Dong Y, Xu Z, Crosby G, Culley DJ, Zhang Y and Xie Z: Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice. Anesthesiology. 118:516–526. 2013.PubMed/NCBI View Article : Google Scholar | |
Bilotta F, Gelb AW, Stazi E, Titi L, Paoloni FP and Rosa G: Pharmacological perioperative brain neuroprotection: A qualitative review of randomized clinical trials. Br J Anaesth. 110: (Suppl 1):S113–S120. 2013.PubMed/NCBI View Article : Google Scholar | |
Hudetz JA, Iqbal Z, Gandhi SD, Patterson KM, Byrne AJ, Hudetz AG, Pagel PS and Warltier DC: Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand. 53:864–872. 2009.PubMed/NCBI View Article : Google Scholar | |
Roach GW, Newman MF, Murkin JM, Martzke J, Ruskin A, Li J, Guo A, Wisniewski A and Mangano DT: Multicenter Study of Perioperative Ischemia (MsSPI). Ineffectiveness of burst suppression therapy in mitigating perioperative cerebrovascular dysfunction. Anesthesiology. 99:1255–1264. 1999.PubMed/NCBI View Article : Google Scholar | |
Han F, Xu L, Huang Y, Chen T, Zhou T and Yang L: Magnesium sulphate can alleviate oxidative stress and reduce inflammatory cytokines in rat placenta of intrahepatic cholestasis of pregnancy model. Arch Gynecol Obstet. 298:631–638. 2018.PubMed/NCBI View Article : Google Scholar | |
Khatib N, Ginsberg Y, Shalom-Paz E, Dabaja H, Gutzeit O, Zmora O, Millo Z, Ross MG and Beloosesky R: Fetal neuroprotective mechanism of maternal magnesium sulfate for late gestation inflammation: In a rodent model. J Matern Fetal Neonatal Med. 33:3732–3739. 2020.PubMed/NCBI View Article : Google Scholar | |
Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell D, Nelson Mansfield P, Machamer JE, et al: Magnesium sulfate for neuroprotection after traumatic brain injury: A randomised controlled trial. Lancet Neurol. 6:29–38. 2007.PubMed/NCBI View Article : Google Scholar | |
Hallak M, Hotra JW and Kupsky WJ: Magnesium sulfate protection of fetal rat brain from severe maternal hypoxia. Obstet Gynecol. 96:124–128. 2000.PubMed/NCBI View Article : Google Scholar | |
Zhang Y, Dong Y, Xu Z and Xie Z: Propofol and magnesium attenuate isoflurane-induced caspase-3 activation via inhibiting mitochondrial permeability transition pore. Med Gas Res. 2(20)2012.PubMed/NCBI View Article : Google Scholar | |
Beloosesky R, Khatib N, Ginsberg Y, Anabosy S, Shalom-Paz E, Dahis M, Ross MG and Weiner Z: Maternal magnesium sulfate fetal neuroprotective effects to the fetus: inhibition of neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells activation in a rodent model. Am J Obstet Gynecol. 215:382.e1–e6. 2016.PubMed/NCBI View Article : Google Scholar | |
Animal Experiments Center Ethics Committee. Legislation. Available from: https://hadmek.tarimorman.gov.tr/Sayfa/Detay/644. Accessed November 22, 2022. | |
Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M and Browne WJ: Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 18(e3000410)2020.PubMed/NCBI View Article : Google Scholar | |
Song R, Ling X, Peng M, Xue Z, Cang J and Fang F: Maternal Sevoflurane exposure causes abnormal development of fetal prefrontal cortex and induces cognitive dysfunction in offspring. Stem Cells Int. 2027(6158468)2017.PubMed/NCBI View Article : Google Scholar | |
Sameshima H, Ota A and Ikenoue T: Pretreatment with magnesium sulfate protects against hypoxic-ischemic brain injury but postasphyxial treatment worsens brain damage in seven-day-old rats. Am J Obstet Gynecol. 180:725–730. 1999.PubMed/NCBI View Article : Google Scholar | |
Cho GJ, Hong HR, Hong SC, Oh MJ and Kim HJ: The neuroprotective effect of magnesium sulfate in preterm fetal mice. J Perinatal Med. 45:537–543. 2015.PubMed/NCBI View Article : Google Scholar | |
Dong Y, Zhang G, Zhang B, Moir RD, Xia W, Marcantonio ER, Culley DJ, Crosby G, Tanzi RE and Xie Z: The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol. 66:620–631. 2009.PubMed/NCBI View Article : Google Scholar | |
Erel O: A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 12:1103–1111. 2005.PubMed/NCBI View Article : Google Scholar | |
Rubio CP and Cerón JJ: Spectrophotometric assays for evaluation of Reactive Oxygen Species (ROS) in serum: General concepts and applications in dogs and humans. BMC Vet Res. 17(226)2021.PubMed/NCBI View Article : Google Scholar | |
Blaylock M, Engelhardt T and Bissonnette B: Fundamentals of neuronal apoptosis relevant to pediatric anesthesia. Paediatr Anaesth. 20:383–395. 2010.PubMed/NCBI View Article : Google Scholar | |
Ikonomidou C: Triggers of apoptosis in the immature brain. Brain Dev. 31:488–492. 2009.PubMed/NCBI View Article : Google Scholar | |
Li X, Jiang X and Zhao P: Effects of pregnancy anesthesia on fetal nervous system. Front Pharmacol. 11(523514)2021.PubMed/NCBI View Article : Google Scholar | |
Lee S, Chung W, Park H, Park H, Yoon S, Park S, Park J, Heo JY, Ju X, Yoon SH, et al: Single and multiple sevoflurane exposures during pregnancy and offspring behavior in mice. Paediatr Anaesth. 27:742–751. 2017.PubMed/NCBI View Article : Google Scholar | |
Wu Z, Li X, Zhang Y, Tong D, Wang L and Zhao P: Effects of Sevoflurane exposure during mid-pregnancy on learning and memory in offspring rats: Beneficial effects of maternal exercise. Front Cell Neurosci. 12(122)2018.PubMed/NCBI View Article : Google Scholar | |
Andropoulos DB and Greene MF: Anesthesia and developing brains-implications of the FDA warning. N Engl J Med. 376:905–907. 2017.PubMed/NCBI View Article : Google Scholar | |
Palanisamy A: Maternal anesthesia and fetal neurodevelopment. Int J Obstet Anesth. 21:152–162. 2012.PubMed/NCBI View Article : Google Scholar | |
Workman AD, Charvet CJ, Clancy B, Darlington RB and Finlay BL: Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci. 33:7368–7383. 2013.PubMed/NCBI View Article : Google Scholar | |
Brioni JD, Varughese S, Ahmed R and Bein B: A clinical review of inhalation anesthesia with sevoflurane: From early research to emerging topics. J Anesth. 5:764–778. 2017.PubMed/NCBI View Article : Google Scholar | |
Zhou X, Li W, Chen X, Yang X, Zhou Z, Lu D and Feng X: Dose-dependent effects of sevoflurane exposure during early lifetime on apoptosis in hippocampus and neurocognitive outcomes in Sprague-Dawley rats. Int J Physiol Pathophysiol Pharmacol. 8:111–119. 2016.PubMed/NCBI | |
Wang S, Peretich K, Zhao Y, Liang G, Meng Q and Wei H: Anesthesia-induced neurodegeneration in fetal rat brains. Pediatr Res. 66:435–440. 2009.PubMed/NCBI View Article : Google Scholar | |
Hirotsu A, Iwata Y, Tatsumi K, Miyai Y, Matsuyama T and Tanaka T: Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development. Eur J Pharmacol. 863(172682)2019.PubMed/NCBI View Article : Google Scholar | |
Zhang Y, Li M, Cui E, Zhang H, Zhu X, Zhou J, Yan M and Sun J: Dexmedetomidine attenuates sevoflurane-induced neurocognitive impairment through α2-adrenoceptors. Mol Med Rep. 23(38)2021.PubMed/NCBI View Article : Google Scholar | |
Bergdolt L and Dunaevsky A: Brain changes in a maternal immune activation model of neurodevelopmental brain disorders. Prog Neurobiol. 175:1–19. 2019.PubMed/NCBI View Article : Google Scholar | |
Wan Y, Xu J, Ma D, Zeng Y, Cibelli M and Maze M: Postoperative impairment of cognitive function in rats: A possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology. 106:436–443. 2007.PubMed/NCBI View Article : Google Scholar | |
Fan CH, Peng B and Zhang FC: The postoperative effect of sevoflurane inhalational anesthesia on cognitive function and inflammatory response of pediatric patients. Eur Rev Med Pharmacol Sci. 22:3971–3975. 2018.PubMed/NCBI View Article : Google Scholar | |
Ginsberg Y, Khatib N, Weiner Z and Beloosesky R: Maternal inflammation, fetal brain implications and suggested neuroprotection: A summary of 10 years of research in animal models. Rambam Maimonides Med J. 8(e0028)2018.PubMed/NCBI View Article : Google Scholar | |
Hennessy E, Gormley S, Lopez-Rodriguez AB, Murray C, Murray C and Cunningham C: Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav Immun. 59:233–244. 2017.PubMed/NCBI View Article : Google Scholar | |
Pickering M, Cumiskey D and O'Connor JJ: Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 90:663–670. 2005.PubMed/NCBI View Article : Google Scholar | |
Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG and Feuerstein GZ: Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke. 28:1233–1244. 1997.PubMed/NCBI View Article : Google Scholar | |
Mayne M, Ni W, Yan HJ, Xue M, Johnston JB, Del Bigio MR, Peeling J and Power C: Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage. Stroke. 32:240–248. 2001.PubMed/NCBI View Article : Google Scholar | |
Nawashiro H, Martin D and Hallenbeck JM: Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J Cereb Blood Flow Metab. 17:229–232. 1997.PubMed/NCBI View Article : Google Scholar | |
Carpentier PA, Dingman AL and Palmer TD: Placental TNF-α signaling in illness-induced complications of pregnancy. Am J Pathol. 6:2802–2810. 2011.PubMed/NCBI View Article : Google Scholar | |
Zhao X, Bausano B, Pike BR, Newcomb-Fernandez JK, Wang KK, Shohami E, Ringger NC, DeFord SM, Anderson DK and Hayes RL: TNF-alpha stimulates caspase-3 activation and apoptotic cell death in primary septo-hippocampal cultures. J Neurosci Res. 64:121–131. 2001.PubMed/NCBI View Article : Google Scholar | |
Hemmer K, Fransen L, Vanderstichele H, Vanmechelen E and Heuschling P: An in vitro model for the study of microglia-induced neurodegeneration: Involvement of nitric oxide and tumor necrosis factor-alpha. Neurochem Int. 38:557–565. 2001.PubMed/NCBI View Article : Google Scholar | |
Robertson J, Beaulieu JM, Doroudchi MM, Durham HD, Julien JP and Mushynski WE: Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha. J Cell Biol. 155:217–226. 2001.PubMed/NCBI View Article : Google Scholar | |
Haddad JJ: Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation. Biochem Biophys Res Commun. 296:847–856. 2002.PubMed/NCBI View Article : Google Scholar | |
Hoek JB and Pastorino JG: Ethanol, oxidative stress, and cytokineinduced liver cell injury. Alcohol. 27:63–68. 2002.PubMed/NCBI View Article : Google Scholar | |
Wu Y, Song J, Wang Y, Wang X, Culmsee C and Zhu C: The potential role of ferroptosis in neonatal brain injury. Front Neurosci. 13(115)2019.PubMed/NCBI View Article : Google Scholar | |
Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA and Ganie SA: Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother. 74:101–110. 2015.PubMed/NCBI View Article : Google Scholar | |
Xu Z and Qian B: Sevoflurane anesthesia-mediated oxidative stress and cognitive impairment in hippocampal neurons of old rats can be ameliorated by expression of brain derived neurotrophic factor. Neurosci Lett. 721(134785)2020.PubMed/NCBI View Article : Google Scholar | |
Allaouchiche B, Debon R, Goudable J, Chassard D and Duflo F: Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg. 93:981–985. 2001.PubMed/NCBI View Article : Google Scholar | |
Tsuchiya M, Asada A, Kasahara E, Sato EF, Shindo M and Inoue M: Antioxidant protection of propofol and its recycling in erythrocyte membranes. Am J Respir Crit Care Med. 165:54–60. 2002.PubMed/NCBI View Article : Google Scholar | |
Sun Z, Satomoto M, Adachi YU, Kinoshita H and Makita K: Inhibiting NADPH oxidase protects against long-term memory impairment induced by neonatal sevoflurane exposure in mice. Br J Anaesth. 117:80–86. 2016.PubMed/NCBI View Article : Google Scholar | |
Liu B, Gu Y, Xiao H, Lei X, Liang W and Zhang J: Altered metabolomic profiles may be associated with sevoflurane-induced neurotoxicity in neonatal rats. Neurochem Res. 40:788–799. 2015.PubMed/NCBI View Article : Google Scholar | |
Xu G, Lu H, Dong Y, Shapoval D, Soriano SG, Liu X, Zhang Y and Xie Z: Coenzyme Q10 reduces sevoflurane-induced cognitive deficiency in young mice. Br J Anaesth. 119:481–449. 2017.PubMed/NCBI View Article : Google Scholar | |
Oppenheim RW: Cell death during development of the nervous system. Annu Rev Neurosci. 14:453–501. 1991.PubMed/NCBI View Article : Google Scholar | |
Wang Y, Li Y, Xing Q, Han XG, Dong X, Lu Y and Zhou M: Sevoflurane anesthesia in pregnant rats negatively affects nerve function in offspring potentially via inhibition of the Wnt/β-catenin pathway. Mol Med Rep. 15:2753–2759. 2017.PubMed/NCBI View Article : Google Scholar | |
Yu Z, Wang J, Wang H, Wang J, Cui J and Junzhang P: Effects of sevoflurane exposure during late pregnancy on brain development and beneficial effects of enriched environment on offspring cognition. Cell Mol Neurobiol. 40:1339–1352. 2020.PubMed/NCBI View Article : Google Scholar | |
Areias J, Sola C, Chastagnier Y, Pico J, Bouquier N, Dadure C, Perroy J and Szabo V: Whole-brain characterization of apoptosis after sevoflurane anesthesia reveals neuronal cell death patterns in the mouse neonatal neocortex. Sci Rep. 13(14763)2023.PubMed/NCBI View Article : Google Scholar | |
Satomoto M, Itoh H, Uchida A and Makita K: Resveratrol did not prevent sevoflurane-induced neuroapoptosis in the neonatal mice brain. Masui. 62:1184–1187. 2013.PubMed/NCBI | |
Wang Y, Yin S, Xue H, Yang Y, Zhang N and Zhao P: Mid-gestational sevoflurane exposure inhibits fetal neural stem cell proliferation and impairs postnatal learning and memory function in a dose-dependent manner. Dev Biol. 435:185–197. 2018.PubMed/NCBI View Article : Google Scholar | |
Bercker S, Bert B, Bittigau P, Felderhoff-Müser U, Bührer C, Ikonomidou C, Weise M, Kaisers UX and Kerner T: Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res. 16:140–147. 2009.PubMed/NCBI View Article : Google Scholar | |
Jia M, Liu WX and Yang JJ, Xu N, Xie ZM, Ju LS, Ji MH, Martynyuk AE and Yang JJ: Role of histone acetylation in long-term neurobehavioral effects of neonatal Exposure to sevoflurane in rats. Neurobiol Dis. 91:209–220. 2016.PubMed/NCBI View Article : Google Scholar | |
Wang SQ, Fang F, Xue ZG, Cang J and Zhang XG: Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss. Eur Rev Med Pharmacol Sci. 17:941–950. 2013.PubMed/NCBI | |
Costantine MM and Drever N: Antenatal exposure to magnesium sulfate and neuroprotection in preterm infants. Obstet Gynecol Clin North Am. 38:351–366. 2011.PubMed/NCBI View Article : Google Scholar | |
Lamhot VB, Khatib N, Ginsberg Y, Anunu R, Richter-Levin G, Weiner Z, Ross MG, Divon MY, Hallak M and Beloosesky R: Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring. Am J Obstet Gynecol. 213:851.e1–e8. 2015.PubMed/NCBI View Article : Google Scholar | |
Zhu X, Yao Y, Guo M, Li J, Yang P, Xu H and Lin D: Sevoflurane increases intracellular calcium to induce mitochondrial injury and neuroapoptosis. Toxicol Lett. 336:11–20. 2021.PubMed/NCBI View Article : Google Scholar | |
Gao F, Ding B, Zhou L, Gao X, Guo H and Xu H: Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-κB pathway. J Surg Res. 184:944–950. 2013.PubMed/NCBI View Article : Google Scholar | |
Andretta A, Schieferdecker MEM, Petterle RR, Dos Santos Paiva E and Boguszewski CL: Relations between serum magnesium and calcium levels and body composition and metabolic parameters in women with fibromyalgia. Adv Rheumatol Lond Engl. 60(18)2020.PubMed/NCBI View Article : Google Scholar | |
Pan K and Garaschuk O: The role of intracellular calcium-store-mediated calcium signals in in vivo sensor and effector functions of microglia. J Physiol. 601:4203–4215. 2022.PubMed/NCBI View Article : Google Scholar | |
Woodburn SC, Bollinger JL and Wohleb ES: The semantics of microglia activation: Neuroinflammation, homeostasis, and stress. J Neuroinflamm. 18(258)2021.PubMed/NCBI View Article : Google Scholar | |
Khatib N, Ginsberg Y, Ben David C, Ross MG, Vitner D, Zipori Y, Zamora O, Weiner Z and Beloosesky R: Magnesium sulphate neuroprotection mechanism is placental mediated by inhibition of inflammation, apoptosis and oxidative stress. Placenta. 127:29–36. 2022.PubMed/NCBI View Article : Google Scholar | |
Mohammadi H, Shamshirian A, Eslami S, Shamshirian D and Ebrahimzadeh MA: Magnesium sulfate attenuates lethality and oxidative damage induced by different models of hypoxia in mice. Biomed Res Int. 2020(2624734)2020.PubMed/NCBI View Article : Google Scholar | |
Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A and Wei H: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology. 109:243–250. 2008.PubMed/NCBI View Article : Google Scholar | |
Dribben WH, Creeley CE, Wang HH, Smith DJ, Farber NB and Olney JW: High dose magnesium sulfate exposure induces apoptotic cell death in the developing neonatal mouse brain. Neonatology. 96:23–32. 2009.PubMed/NCBI View Article : Google Scholar | |
Wang Y, Yin SW, Zhang N and Zhao P: High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring. Neural Regen Res. 9:1575–1584. 2018.PubMed/NCBI View Article : Google Scholar | |
Li D, Liu L, Li L, Li X, Huang B, Zhou C, Zhang Z, Wang C, Dong P, Zhang X, et al: Sevoflurane induces exaggerated and persistent cognitive decline in a type II diabetic rat model by aggregating hippocampal inflammation. Front Pharmacol. 8(886)2017.PubMed/NCBI View Article : Google Scholar |