Cognitive Impairments Induced by Repeated Sevoflurane Exposure During Pre-adolescence in Adult Male and Female Rats: Involvement of Biochemical, Histological and Neuroplasticity Approaches
Journal of Cellular & Molecular Anesthesia,
Vol. 8 No. 4 (2023),
6 November 2023
,
Page 231-245
https://doi.org/10.22037/jcma.v8i4.41777
Abstract
Background: In some therapeutic interventions, repeated exposure to pre-adolescence anesthesia is necessary. According to research, exposure to general anesthetics during pre-adolescence can lead to cell death, cognitive and behavioral problems, and neurobehavioral difficulties as an adult. The current study aimed to provide detailed morphological and functional evaluations of the long-term impacts of repeated sevoflurane exposure in male and female rats.
Materials and Methods: Seventy-two pre-adolescent rats were randomly divided into male and female control and inhaled sevoflurane groups (concentration of 2%) daily for 15 days. Animals received care for 20-30 days. The influence of repeated exposure to sevoflurane on cognitive functions was tested using the Morris Water Maze, novel object, and social interaction tests. As a measure of oxidative stress, superoxide dismutase (SOD) and glutathione levels were measured. Toluidine blue stain was utilized to evaluate the number of dark neurons in the hippocampus. Effects of sevoflurane on synaptic plasticity were compared in the performant pathway of the CA1 of the hippocampus.
Results: Repeated sevoflurane exposure in pre-adolescence led to behavioral disorders in male and female adult rats; there was no significant difference in levels of superoxide dismutase and glutathione. We found a significant quantifiable increase in dark neurons. Electrophysiological recordings indicated impaired long-term potentiation and pair-pulse in adult animals that received repeat sevoflurane exposure.
Conclusion: According to our findings, repeated exposure to sevoflurane during pre-adolescence can cause changes in the hippocampus and neuroplasticity in the adult brain. Results from this study may provide a new perspective on how repeated exposure to anesthesia can lead to toxic effects in pre-adolescent rats.
Keywords:
- Sevoflurane, Anesthesia, Pre-adolescence, Cognitive problems, neurobehavioral problems, Cell damage
How to Cite
1.
Fahanik Babaei J, Jafarian M, Adeli S, Barzegar Behrooz A, Pestehei SK. Cognitive Impairments Induced by Repeated Sevoflurane Exposure During Pre-adolescence in Adult Male and Female Rats: Involvement of Biochemical, Histological and Neuroplasticity Approaches. J Cell Mol Anesth [Internet]. 2023 Apr. 23 [cited 2025 Jan. 14];8(4):231-45. Available from: https://journals.sbmu.ac.ir/jcma/article/view/41777
References
1. Lunardi N, Ori C, Erisir A, Jevtovic-Todorovic V. General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox Res. 2010;17(2):179-88.
2. Lee BH, Chan JT, Hazarika O, Vutskits L, Sall JW. Early exposure to volatile anesthetics impairs long-term associative learning and recognition memory. PLoS One. 2014;9(8):e105340.
3. DiMaggio C, Sun LS, Ing C, Li G. Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis. J Neurosurg Anesthesiol. 2012;24(4):376-81.
4. Jevtovic-Todorovic V. Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children? Mol Neurobiol. 2013;48(2):288-93.
5. Rogan MT, Staubli UV, LeDoux JE. Fear conditioning induces associative long-term potentiation in the amygdala. Nature. 1997;390(6660):604-7.
6. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science. 2006;313(5790):1093-7.
7. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology. 1994;80(4):814-24.
8. Jevtovic-Todorovic V, Brambrick A. General Anesthesia and Young Brain: What is New? J Neurosurg Anesthesiol. 2018;30(3):217-22.
9. Liu XS, Xue QS, Zeng QW, Li Q, Liu J, Feng XM, et al. Sevoflurane impairs memory consolidation in rats, possibly through inhibiting phosphorylation of glycogen synthase kinase-3beta in the hippocampus. Neurobiol Learn Mem. 2010;94(4):461-7.
10. Shen FY, Song YC, Guo F, Xu ZD, Li Q, Zhang B, et al. Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats. Front Psychiatry. 2018;9:332.
11. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876-82.
12. Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology. 2015;122(1):87-95.
13. Odeh D, Orsolic N, Adrovic E, Gacina L, Peric P, Odeh S, et al. Effects of Volatile Anaesthetics and Iron Dextran on Chronic Inflammation and Antioxidant Defense System in Rats. Antioxidants (Basel). 2022;11(4).
14. Spear LP. Adolescent brain development and animal models. Ann N Y Acad Sci. 2004;1021:23-6.
15. Spear LP, Brake SC. Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol. 1983;16(2):83-109.
16. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93-110.
17. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.
18. Su D, Zhao Y, Wang B, Li W, Xiao J, Chen J, et al. Repeated but not single isoflurane exposure improved the spatial memory of young adult mice. Acta Anaesthesiol Scand. 2011;55(4):468-73.
19. Jiang S, Miao B, Chen Y. Prolonged duration of isoflurane anesthesia impairs spatial recognition memory through the activation of JNK1/2 in the hippocampus of mice. Neuroreport. 2017;28(7):386-90.
20. Linsenmeier RA, Beckmann L, Dmitriev AV. Intravenous ketamine for long term anesthesia in rats. Heliyon. 2020;6(12):e05686.
21. Wang Y, Yin SW, Zhang N, Zhao P. High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring. Neural Regen Res. 2018;13(9):1575-84.
22. Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res. 2002;133(2):115-26.
23. Feinberg I. Cortical pruning and the development of schizophrenia. Schizophr Bull. 1990;16(4):567-70.
24. Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res. 1979;163(2):195-205.
25. Faust TE, Gunner G, Schafer DP. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci. 2021;22(11):657-73.
26. Huang L, Yang G. Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood. Anesthesiology. 2015;122(4):821-31.
27. Nishikawa K, Harrison NL. The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: effects of TM2 mutations in the alpha and beta subunits. Anesthesiology. 2003;99(3):678-84.
28. Alkire MT, Nathan SV, McReynolds JR. Memory enhancing effect of low-dose sevoflurane does not occur in basolateral amygdala-lesioned rats. Anesthesiology. 2005;103(6):1167-73.
29. Wu Z, Li X, Zhang Y, Tong D, Wang L, Zhao P. Effects of Sevoflurane Exposure During Mid-Pregnancy on Learning and Memory in Offspring Rats: Beneficial Effects of Maternal Exercise. Front Cell Neurosci. 2018;12:122.
30. Li H, Dai CL, Gu JH, Peng S, Li J, Yu Q, et al. Intranasal Administration of Insulin Reduces Chronic Behavioral Abnormality and Neuronal Apoptosis Induced by General Anesthesia in Neonatal Mice. Front Neurosci. 2019;13:706.
31. Shen X, Liu Y, Xu S, Zhao Q, Guo X, Shen R, et al. Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. Neurotoxicology. 2013;39:45-56.
32. Yonezaki K, Uchimoto K, Miyazaki T, Asakura A, Kobayashi A, Takase K, et al. Postanesthetic effects of isoflurane on behavioral phenotypes of adult male C57BL/6J mice. PLoS One. 2015;10(3):e0122118.
33. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-91.
34. Deans AR, Lewis SE, Huala E, Anzaldo SS, Ashburner M, Balhoff JP, et al. Finding our way through phenotypes. PLoS Biol. 2015;13(1):e1002033.
35. Allaouchiche B, Debon R, Goudable J, Chassard D, Duflo F. Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg. 2001;93(4):981-5.
36. Zhou ZB, Yang XY, Tang Y, Zhou X, Zhou LH, Feng X. Subclinical concentrations of sevoflurane reduce oxidative stress but do not prevent hippocampal apoptosis. Mol Med Rep. 2016;14(1):721-7.
37. Yilmaz Dogru H, Benli I, Dogru S. The oxidative/anti-oxidative effects of sevoflurane on reproductive system of females: An experimental study. Turk J Obstet Gynecol. 2017;14(4):228-32.
38. Komuro H, Rakic P. Modulation of neuronal migration by NMDA receptors. Science. 1993;260(5104):95-7.
39. Koyama R, Tao K, Sasaki T, Ichikawa J, Miyamoto D, Muramatsu R, et al. GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat Med. 2012;18(8):1271-8.
40. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51.
41. Lau CG, Takeuchi K, Rodenas-Ruano A, Takayasu Y, Murphy J, Bennett MV, et al. Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans. 2009;37(Pt 6):1369-74.
42. Lohmann C, Kessels HW. The developmental stages of synaptic plasticity. J Physiol. 2014;592(1):13-31.
43. Guo Y, Chen Q, Wu B, Sun L. Isovitexin restores sevoflurane‑induced cognitive dysfunction by mediating autophagy through activation of the PGC‑1alpha/FNDC5 signaling pathway. Acta Neurobiol Exp (Wars). 2022;82(3):373-9.
44. Yonamine R, Satoh Y, Kodama M, Araki Y, Kazama T. Coadministration of hydrogen gas as part of the carrier gas mixture suppresses neuronal apoptosis and subsequent behavioral deficits caused by neonatal exposure to sevoflurane in mice. Anesthesiology. 2013;118(1):105-13.
45. Aksenov DP, Miller MJ, Dixon CJ, Wyrwicz AM. The effect of sevoflurane and isoflurane anesthesia on single unit and local field potentials. Exp Brain Res. 2019;237(6):1521-9.
2. Lee BH, Chan JT, Hazarika O, Vutskits L, Sall JW. Early exposure to volatile anesthetics impairs long-term associative learning and recognition memory. PLoS One. 2014;9(8):e105340.
3. DiMaggio C, Sun LS, Ing C, Li G. Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis. J Neurosurg Anesthesiol. 2012;24(4):376-81.
4. Jevtovic-Todorovic V. Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children? Mol Neurobiol. 2013;48(2):288-93.
5. Rogan MT, Staubli UV, LeDoux JE. Fear conditioning induces associative long-term potentiation in the amygdala. Nature. 1997;390(6660):604-7.
6. Whitlock JR, Heynen AJ, Shuler MG, Bear MF. Learning induces long-term potentiation in the hippocampus. Science. 2006;313(5790):1093-7.
7. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology. 1994;80(4):814-24.
8. Jevtovic-Todorovic V, Brambrick A. General Anesthesia and Young Brain: What is New? J Neurosurg Anesthesiol. 2018;30(3):217-22.
9. Liu XS, Xue QS, Zeng QW, Li Q, Liu J, Feng XM, et al. Sevoflurane impairs memory consolidation in rats, possibly through inhibiting phosphorylation of glycogen synthase kinase-3beta in the hippocampus. Neurobiol Learn Mem. 2010;94(4):461-7.
10. Shen FY, Song YC, Guo F, Xu ZD, Li Q, Zhang B, et al. Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats. Front Psychiatry. 2018;9:332.
11. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876-82.
12. Amrock LG, Starner ML, Murphy KL, Baxter MG. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology. 2015;122(1):87-95.
13. Odeh D, Orsolic N, Adrovic E, Gacina L, Peric P, Odeh S, et al. Effects of Volatile Anaesthetics and Iron Dextran on Chronic Inflammation and Antioxidant Defense System in Rats. Antioxidants (Basel). 2022;11(4).
14. Spear LP. Adolescent brain development and animal models. Ann N Y Acad Sci. 2004;1021:23-6.
15. Spear LP, Brake SC. Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol. 1983;16(2):83-109.
16. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93-110.
17. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.
18. Su D, Zhao Y, Wang B, Li W, Xiao J, Chen J, et al. Repeated but not single isoflurane exposure improved the spatial memory of young adult mice. Acta Anaesthesiol Scand. 2011;55(4):468-73.
19. Jiang S, Miao B, Chen Y. Prolonged duration of isoflurane anesthesia impairs spatial recognition memory through the activation of JNK1/2 in the hippocampus of mice. Neuroreport. 2017;28(7):386-90.
20. Linsenmeier RA, Beckmann L, Dmitriev AV. Intravenous ketamine for long term anesthesia in rats. Heliyon. 2020;6(12):e05686.
21. Wang Y, Yin SW, Zhang N, Zhao P. High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring. Neural Regen Res. 2018;13(9):1575-84.
22. Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res. 2002;133(2):115-26.
23. Feinberg I. Cortical pruning and the development of schizophrenia. Schizophr Bull. 1990;16(4):567-70.
24. Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res. 1979;163(2):195-205.
25. Faust TE, Gunner G, Schafer DP. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci. 2021;22(11):657-73.
26. Huang L, Yang G. Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood. Anesthesiology. 2015;122(4):821-31.
27. Nishikawa K, Harrison NL. The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: effects of TM2 mutations in the alpha and beta subunits. Anesthesiology. 2003;99(3):678-84.
28. Alkire MT, Nathan SV, McReynolds JR. Memory enhancing effect of low-dose sevoflurane does not occur in basolateral amygdala-lesioned rats. Anesthesiology. 2005;103(6):1167-73.
29. Wu Z, Li X, Zhang Y, Tong D, Wang L, Zhao P. Effects of Sevoflurane Exposure During Mid-Pregnancy on Learning and Memory in Offspring Rats: Beneficial Effects of Maternal Exercise. Front Cell Neurosci. 2018;12:122.
30. Li H, Dai CL, Gu JH, Peng S, Li J, Yu Q, et al. Intranasal Administration of Insulin Reduces Chronic Behavioral Abnormality and Neuronal Apoptosis Induced by General Anesthesia in Neonatal Mice. Front Neurosci. 2019;13:706.
31. Shen X, Liu Y, Xu S, Zhao Q, Guo X, Shen R, et al. Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. Neurotoxicology. 2013;39:45-56.
32. Yonezaki K, Uchimoto K, Miyazaki T, Asakura A, Kobayashi A, Takase K, et al. Postanesthetic effects of isoflurane on behavioral phenotypes of adult male C57BL/6J mice. PLoS One. 2015;10(3):e0122118.
33. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-91.
34. Deans AR, Lewis SE, Huala E, Anzaldo SS, Ashburner M, Balhoff JP, et al. Finding our way through phenotypes. PLoS Biol. 2015;13(1):e1002033.
35. Allaouchiche B, Debon R, Goudable J, Chassard D, Duflo F. Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg. 2001;93(4):981-5.
36. Zhou ZB, Yang XY, Tang Y, Zhou X, Zhou LH, Feng X. Subclinical concentrations of sevoflurane reduce oxidative stress but do not prevent hippocampal apoptosis. Mol Med Rep. 2016;14(1):721-7.
37. Yilmaz Dogru H, Benli I, Dogru S. The oxidative/anti-oxidative effects of sevoflurane on reproductive system of females: An experimental study. Turk J Obstet Gynecol. 2017;14(4):228-32.
38. Komuro H, Rakic P. Modulation of neuronal migration by NMDA receptors. Science. 1993;260(5104):95-7.
39. Koyama R, Tao K, Sasaki T, Ichikawa J, Miyamoto D, Muramatsu R, et al. GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat Med. 2012;18(8):1271-8.
40. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51.
41. Lau CG, Takeuchi K, Rodenas-Ruano A, Takayasu Y, Murphy J, Bennett MV, et al. Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans. 2009;37(Pt 6):1369-74.
42. Lohmann C, Kessels HW. The developmental stages of synaptic plasticity. J Physiol. 2014;592(1):13-31.
43. Guo Y, Chen Q, Wu B, Sun L. Isovitexin restores sevoflurane‑induced cognitive dysfunction by mediating autophagy through activation of the PGC‑1alpha/FNDC5 signaling pathway. Acta Neurobiol Exp (Wars). 2022;82(3):373-9.
44. Yonamine R, Satoh Y, Kodama M, Araki Y, Kazama T. Coadministration of hydrogen gas as part of the carrier gas mixture suppresses neuronal apoptosis and subsequent behavioral deficits caused by neonatal exposure to sevoflurane in mice. Anesthesiology. 2013;118(1):105-13.
45. Aksenov DP, Miller MJ, Dixon CJ, Wyrwicz AM. The effect of sevoflurane and isoflurane anesthesia on single unit and local field potentials. Exp Brain Res. 2019;237(6):1521-9.
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