Prolonged or repeated exposure to ketamine, a common anesthetic in pediatrics, has been shown to induce neurotoxicity and long-term neurocognitive deficits in the developing brain. Therefore, identification of potential therapeutic targets for preventing or alleviating such neurodegeneration and neuroapoptosis induced by ketamine is urgently needed. Remote ischemic preconditioning of the limb provides neuroprotection in different models of cerebral injury. Thus, the present study aimed to assess whether remote ischemic preconditioning could have a neuroprotective effect against neurotoxicity induced by ketamine. In our study, 96 newborn rats were assigned to one of four groups, including control, remote ischemic preconditioning, ketamine, and remote ischemic preconditioning plus ketamine. Ketamine was administered intraperitoneally in six doses of 20 mg/kg at 2-h intervals. Limb remote ischemic preconditioning comprised four ischemia (5 min)/reperfusion (5 min) cycles in the right hind limb using an elastic rubber band tourniquet. Histopathological characteristics of cerebral damage were assessed by H&E staining and transmission electron microscopy. TUNEL assay, immunohistochemical staining and immunoblot were employed to evaluate neural cell apoptosis. Learning and memory were evaluated using the Morris water maze. The results showed increased cleaved caspase-3 protein levels in the cerebral cortex and the hippocampal CA1 region, severe cell damage and DNA breakage, and decreased spatial learning and memory abilities in the ketamine group in comparison with controls. Notably, these changes were significantly reduced by remote ischemic preconditioning. These findings suggest that remote ischemic preconditioning ameliorates neuroapoptosis and neurocognitive impairment after repeated ketamine exposure in newborn rats.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Arvola O, Haapanen H, Herajarvi J, Anttila T, Puistola U, Karihtala P, Tuominen H, Anttila V, Juvonen T (2016) Remote ischemic preconditioning reduces cerebral oxidative stress following hypothermic circulatory arrest in a porcine model. Semin Thorac Cardiovasc Surg 28:92–102
Bakri MH, Ismail EA, Ali MS, Elsedfy GO, Sayed TA, Ibrahim A (2015) Behavioral and emotional effects of repeated general anesthesia in young children. Saudi J Anaesth 9:161–166
Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, Dissen GA, Creeley CE, Olney JW (2012) Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 116:372–384
Chen Q, Wu F, Peng X, Jiang M, Chen T, Wei D (2016) Limb remote ischemic preconditioning protects against cerebral ischemia through down-regulation of aquaporin-4. Int J Clin Exp Med 9:13878–13889
Dekaban AS (1978) Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4:345–356
Deng M, Hofacer RD, Jiang C, Joseph B, Hughes EA, Jia B, Danzer SC, Loepke AW (2014) Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions. Br J Anaesth 113:443–451
Dobbing J, Sands J (1979) Comparative aspects of the brain growth spurt. Early Hum Dev 3:79–83
Fan R, Yu T, Lin JL, Ren GD, Li Y, Liao XX, Huang ZT, Jiang CH (2016) Remote ischemic preconditioning improves post resuscitation cerebral function via overexpressing neuroglobin after cardiac arrest in rats. Brain Res 1648:345–355
Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO (2011) Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128:e1053–e1061
Hahn CD, Manlhiot C, Schmidt MR, Nielsen TT, Redington AN (2011) Remote ischemic per-conditioning: a novel therapy for acute stroke? Stroke 42:2960–2962
Hess DC, Hoda MN, Bhatia K (2013) Remote limb perconditioning [corrected] and postconditioning: will it translate into a promising treatment for acute stroke? Stroke 44:1191–1197
Hu X, Lu Y, Zhang Y, Li Y, Jiang L (2013) Remote ischemic preconditioning improves spatial learning and memory ability after focal cerebral ischemia-reperfusion in rats. Perfusion 28:546–551
Huang EP, Stevens CF (1998) The matter of mind: molecular control of memory. Essays Biochem 33:165–178
Huang L, Yang G (2015) Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood. Anesthesiology 122:821–831
Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882
Jin RL, Li WB, Li QJ, Zhang M, Xian XH, Sun XC, Zhao HG, Qi J (2006) The role of extracellular signal-regulated kinases in the neuroprotection of limb ischemic preconditioning. Neurosci Res 55:65–73
Komuro H, Rakic P (1993) Modulation of neuronal migration by NMDA receptors. Science (New York, NY) 260:95–97
Lei X, Guo Q, Zhang J (2012) Mechanistic insights into neurotoxicity induced by anesthetics in the developing brain. Int J Mol Sci 13:6772–6799
Li S, Hafeez A, Noorulla F, Geng X, Shao G, Ren C, Lu G, Zhao H, Ding Y, Ji X (2017) Preconditioning in neuroprotection: from hypoxia to ischemia. Prog Neurobiol 157:79–91
Liu JR, Liu Q, Li J, Baek C, Han XH, Athiraman U, Soriano SG (2012) Noxious stimulation attenuates ketamine-induced neuroapoptosis in the developing rat brain. Anesthesiology 117:64–71
Liu F, Patterson TA, Sadovova N, Zhang X, Liu S, Zou X, Hanig JP, Paule MG, Slikker W Jr, Wang C (2013) Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture. Toxicological sciences : an official journal of the Society of Toxicology 131:548–557
Liu ZJ, Chen C, Li XR, Ran YY, Xu T, Zhang Y, Geng XK, Zhang Y, Du HS, Leak RK, Ji XM, Hu XM (2016) Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther 22:43–52
Ma W, Cao YY, Qu S, Ma SS, Wang JZ, Deng LQ, Yuan WJ, Meng JH (2016) Remote ischemic preconditioning provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Eur Rev Med Pharmacol Sci 20:4972–4979
Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH, Ji X (2012) Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 79:1853–1861
Morrow BA, Roth RH, Redmond DE Jr, Sladek JR Jr, Elsworth JD (2007) Apoptotic natural cell death in developing primate dopamine midbrain neurons occurs during a restricted period in the second trimester of gestation. Exp Neurol 204:802–807
Muller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V, Rougon G, Kiss JZ (1996) PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 17:413–422
O’Farrell RA, Foley AG, Buggy DJ, Gallagher HC (2018) Neurotoxicity of inhalation anesthetics in the neonatal rat brain: effects on behavior and neurodegeneration in the piriform cortex. Anesthesiol Res Pract 2018:6376090
Obradovic AL, Atluri N, Dalla Massara L, Oklopcic A, Todorovic NS, Katta G, Osuru HP, Jevtovic-Todorovic V (2018) Early exposure to ketamine impairs axonal pruning in developing mouse Hippocampus. Mol Neurobiol 55:164–172
Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W Jr, Wang C (2011) Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 33:220–230
Reiprich P, Kilb W, Luhmann HJ (2005) Neonatal NMDA receptor blockade disturbs neuronal migration in rat somatosensory cortex in vivo. Cerebral cortex (New York, NY) 1991(15):349–358
Ren C, Wang P, Wang B, Li N, Li W, Zhang C, Jin K, Ji X (2015) Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke. Restor Neurol Neurosci 33:369–379
Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanic K, Welch TL, Olson MD, Hanson AC, Schroeder DR, Wilder RT, Warner DO (2012) Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 87:120–129
Straiko MM, Young C, Cattano D, Creeley CE, Wang H, Smith DJ, Johnson SA, Li ES, Olney JW (2009) Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 110:862–868
Stratmann G, Lee J, Sall JW, Lee BH, Alvi RS, Shih J, Rowe AM, Ramage TM, Chang FL, Alexander TG, Lempert DK, Lin N, Siu KH, Elphick SA, Wong A, Schnair CI, Vu AF, Chan JT, Zai H, Wong MK, Anthony AM, Barbour KC, Ben-Tzur D, Kazarian NE, Lee JY, Shen JR, Liu E, Behniwal GS, Lammers CR, Quinones Z, Aggarwal A, Cedars E, Yonelinas AP, Ghetti S (2014) Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 39:2275–2287
Vinten-Johansen J, Shi W (2013) The science and clinical translation of remote postconditioning. J Cardiovasc Med (Hagerstown) 14:206–213
Wang Y, Shen J, Xiong X, Xu Y, Zhang H, Huang C, Tian Y, Jiao C, Wang X, Li X (2014) Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy. PLoS One 9:e98834
Wang J, Han D, Sun M, Feng J (2016) A combination of remote ischemic Perconditioning and cerebral ischemic Postconditioning inhibits autophagy to attenuate plasma HMGB1 and induce neuroprotection against stroke in rat. Journal of molecular neuroscience : MN 58:424–431
Xia M, Ding Q, Zhang Z, Feng Q (2017) Remote limb ischemic preconditioning protects rats against cerebral ischemia via HIF-1alpha/AMPK/HSP70 pathway. Cell Mol Neurobiol 37:1105–1114
Xiao R, Yu D, Li X, Huang J, Jing S, Bao X, Yang T, Fan X (2017) Propofol exposure in early life induced developmental impairments in the mouse cerebellum. Front Cell Neurosci 11:373
Yan J, Huang Y, Lu Y, Chen J, Jiang H (2014a) Repeated administration of ketamine can induce hippocampal neurodegeneration and long-term cognitive impairment via the ROS/HIF-1alpha pathway in developing rats. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33:1715–1732
Yan J, Li YR, Zhang Y, Lu Y, Jiang H (2014b) Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: a prospective preliminary clinical study. J Child Neurol 29:1333–1338
Zhao H, Ren C, Chen X, Shen J (2012) From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia. Curr Drug Targets 13:173–187
Zheng X, Zhou J, Xia Y (2015) The role of TNF-alpha in regulating ketamine-induced hippocampal neurotoxicity. Archives of medical science : AMS 11:1296–1302
This work was supported by grants from the National Natural Science Foundation of China (81560502) and the Ningxia Natural Science Foundation (NZ15143 to Jinhai Meng and NZ16147 to Wan MA).
This study obtained approval from the animal care and use animal experimentation committee. All procedures complied with the guidelines of Ningxia Medical University institutional animal care.
Conflict of Interest
The authors declare that they have no conflicts of interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Liu, Y., Li, A.Q., Ma, W. et al. Limb Remote Ischemic Preconditioning Reduces Repeated Ketamine Exposure-Induced Adverse Effects in the Developing Brain of Rats. J Mol Neurosci 68, 58–65 (2019). https://doi.org/10.1007/s12031-019-01282-3
- Limb remote ischemic preconditioning
- Developing brain