Skip to main content
SpringerLink
Log in

Appraisal of the Neuroprotective Effect of Dexmedetomidine: A Meta-Analysis

  • Chapter
  • First Online:
Advances in Molecular Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1408))

  • 629 Accesses

Abstract

Dexmedetomidine is an adrenergic receptor agonist that has been regarded as neuroprotective in several studies without an objective measure to it. Thus, the aim of this meta-analysis was to analyze and quantify the current evidence for the neuroprotective effects of dexmedetomidine in animals. The search was performed by querying the National Library of Medicine. Studies were included based on their language, significancy of their results, and complete availability of data on animal characteristics and interventions. Risk of bias was assessed using SYRCLE’s risk of bias tool and certainty was assessed using the ARRIVE Guidelines 2.0. Synthesis was performed by calculating pooled standardized mean difference and presented in forest plots and tables. The number of eligible records included per outcome is the following: 22 for IL-1β, 13 for IL-6, 19 for apoptosis, 7 for oxidative stress, 7 for Escape Latency, and 4 for Platform Crossings. At the cellular level, dexmedetomidine was found protective against production of IL-1β (standardized mean difference (SMD) =  − 4.3 [− 4.8; − 3.7]) and IL-6 (SMD =  − 5.6 [− 6.7; − 4.6]), apoptosis (measured through TUNEL, SMD =  − 6.0 [− 6.8; − 4.6]), and oxidative stress (measured as MDA production, SMD =  − 2.0 [− 2.4; − 1.4]) exclusively in the central nervous system. At the organism level, dexmedetomidine improved behavioral outcomes measuring escape latency (SMD = − 2.4 [− 3.3; − 1.6]) and number of platform crossings (SMD = 9.1 [− 6.8; − 11.5]). No eligible study had high risk of bias and certainty was satisfactory for reproducibility in all cases. This meta-analysis highlights the complexity of adrenergic stimulation and sheds light into the mechanisms potentiated by dexmedetomidine, which could be exploited for improving current neuroprotective formulations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AR:

Adrenergic receptor

ARRIVE:

Animal Research: Reporting of In Vivo Experiments

cAMP:

Cyclic adenosine monophosphate

CI:

Confidence interval

CNS:

Central nervous system

DAG:

Diacylglycerol

DRG:

Dorsal root ganglion

GIRKs:

G protein-coupled inwardly-rectifying K+ channels

MDA:

Malondialdehyde

NMDAR:

NMDA-type glutamatergic receptors

OXPHOS:

Oxidative phosphorylation

OSP:

Outlier, significance, and precision

PKA:

Protein kinase A

PLC:

Phospholipase C

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PKC:

Protein kinase C

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analyses

ROS:

Reactive oxygen species

SMD:

Standardized mean difference

SYRCLE:

SYstematic Review Centre for Laboratory animal Experimentation

TUNEL:

Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling

References

  1. Song SS, Lyden PD (2012) Overview of Therapeutic Hypothermia. Curr Treat Option Ne 14(6):541–548

    Article  Google Scholar 

  2. Black J, Furney S, Graf H, Nolte A (2009) Philosophical foundations of health education. In: Black J (ed)

    Google Scholar 

  3. Chen Y, Zhou Z, Min W (2018) Mitochondria, oxidative stress and innate immunity. Front Physiol 9:1487

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yagami T, Yamamoto Y, Koma H (2019) Pathophysiological roles of intracellular proteases in neuronal development and neurological diseases. Mol Neurobiol 56(5):3090–3112

    Article  CAS  PubMed  Google Scholar 

  5. Beamer E, Gölöncsér F, Horváth G, Bekő K, Otrokocsi L, Koványi B et al (2016) Purinergic mechanisms in neuroinflammation: an update from molecules to behavior. Neuropharmacology 104:94–104

    Article  CAS  PubMed  Google Scholar 

  6. Yang C, Hawkins KE, Doré S, Candelario-Jalil E (2019) Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol-Cell Physiol 316(2):C135–C153

    Article  CAS  PubMed  Google Scholar 

  7. Tauber SC, Djukic M, Gossner J, Eiffert H, Brück W, Nau R (2021) Sepsis-associated encephalopathy and septic encephalitis: an update. Expert Rev Anti-infe 19(2):215–231

    Article  CAS  Google Scholar 

  8. Kim JG, Sung HJ, Ok SH, Kwon SC, Cheon KS, Kim HJ et al (2011) Calcium sensitization involved in dexmedetomidine-induced contraction of isolated rat aorta. Can J Physiol Pharm 89(9):681–689

    Article  CAS  Google Scholar 

  9. Talley EM, Rosin DL, Lee A, Guyenet PG, Lynch KR (1996) Distribution of α2A-adrenergic receptor-like immunoreactivity in the rat central nervous system. J Comp Neurol 372(1):111–134

    Article  CAS  PubMed  Google Scholar 

  10. Rosin DL, Talley EM, Lee A, Stornetta RL, Gaylinn BD, Guyenet PG et al (1996) Distribution of α2C-adrenergic receptor-like immunoreactivity in the rat central nervous system. J Comp Neurol 372(1):135–165

    Article  CAS  PubMed  Google Scholar 

  11. MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting—homing in on α2-adrenoceptor-subtype function. Trends Pharmacol Sci 18(6):211–219

    Article  CAS  PubMed  Google Scholar 

  12. Scholz J, Finnerup NB, Attal N, Aziz Q, Baron R, Bennett MI et al (2019) The IASP classification of chronic pain for ICD-11. Pain 160(1):53–59

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hunter JC, Fontana DJ, Hedley LR, Jasper JR, Lewis R, Link RE et al (1997) Assessment of the role of α2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Brit J Pharmacol 122(7):1339–1344

    Article  CAS  Google Scholar 

  14. Baron R (2009) Sensory nerves. Handb Exp Pharmacol 194:3–30

    Article  CAS  Google Scholar 

  15. Maze M, Virtanen R, Daunt D, Banks SJM, Stover EP, Feldman D (1991) Effects of dexmedetomidine, a novel imidazole sedative-anesthetic agent, on adrenal steroidogenesis: in vivo and in vitro studies. Anesthesia Analgesia 73(2):204

    Google Scholar 

  16. Gertler R, Brown HC, Mitchell DH, Silvius EN (2001) Dexmedetomidine: a novel sedative-analgesic agent. Bayl Univ Medical Cent Proc 14(1):13–21

    Article  CAS  Google Scholar 

  17. Motiejunaite J, Amar L, Vidal-Petiot E (2021) Adrenergic receptors and cardiovascular effects of catecholamines. Ann D’endocrinologie 82(3–4):193–197

    Article  Google Scholar 

  18. Lüscher C, Slesinger PA (2010) Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 11(5):301–315

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zamponi GW, Currie KPM (2013) Regulation of CaV2 calcium channels by G protein coupled receptors. Biochimica Et Biophysica Acta Bba - Biomembr 1828(7):1629–1643

    Article  CAS  Google Scholar 

  20. Rocca GJD, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ (1997) Ras-dependent mitogen-activated protein kinase activation by g protein-coupled receptors convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. J Biol Chem 272(31):19125–19132

    Article  CAS  PubMed  Google Scholar 

  21. Dorn GW, Oswald KJ, McCluskey TS, Kuhel DG, Liggett SB (1997) α2A-Adrenergic receptor stimulated calcium release is transduced by Gi-associated Gβγ-mediated activation of phospholipase C. Biochemistry 36(21):6415–6423

    Google Scholar 

  22. Putney JW (1999) TRP, inositol 1,4,5-trisphosphate receptors, and capacitative calcium entry. Proc National Acad Sci 96(26):14669–14671

    Article  CAS  Google Scholar 

  23. Huang J, Jiang Q (2019) Dexmedetomidine protects against neurological dysfunction in a mouse intracerebral hemorrhage model by inhibiting mitochondrial dysfunction-derived oxidative stress. J Stroke Cerebrovasc Dis 28(5):1281–1289

    Article  PubMed  Google Scholar 

  24. Tian M, Wang W, Wang K, Jin P, Lenahan C, Wang Y et al (2021) Dexmedetomidine alleviates cognitive impairment by reducing blood-brain barrier interruption and neuroinflammation via regulating Th1/Th2/Th17 polarization in an experimental sepsis model of mice. Int Immunopharmacol 101(Pt B):108332

    Article  CAS  PubMed  Google Scholar 

  25. Xue H, Wu Z, Xu Y, Gao Q, Zhang Y, Li C et al (2021) Dexmedetomidine post-conditioning ameliorates long-term neurological outcomes after neonatal hypoxic ischemia: the role of autophagy. Life Sci 270:118980

    Article  CAS  PubMed  Google Scholar 

  26. Gao Y, Zhang Y, Dong Y, Wu X, Liu H (2020) Dexmedetomidine mediates neuroglobin up-regulation and alleviates the hypoxia/reoxygenation injury by inhibiting neuronal apoptosis in developing rats. Front Pharmacol 11:555532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen Y, Li L, Zhang J, Cui H, Wang J, Wang C et al (2021) Dexmedetomidine alleviates lipopolysaccharide-induced hippocampal neuronal apoptosis via inhibiting the p38 MAPK/c-Myc/CLIC4 signaling pathway in rats. Mol Neurobiol 58(11):5533–5547

    Article  CAS  PubMed  Google Scholar 

  28. Lv H, Li Y, Cheng Q, Chen J, Chen W (2021) Neuroprotective effects against cerebral ischemic injury exerted by dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 axis. Mol Neurobiol 58(5):1990–2004

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Zhang X, Zhang B, He G, Zhou L, Xie Y (2017) Dexmedetomidine reduces the neuronal apoptosis related to cardiopulmonary bypass by inhibiting activation of the JAK2–STAT3 pathway. Drug Des Dev Ther 11:2787–2799

    Article  CAS  Google Scholar 

  30. Liu P, Chen T, Tan F, Tian J, Zheng L, Deng Y et al (2020) Dexmedetomidine alleviated neuropathic pain in dorsal root ganglion neurons by inhibition of anaerobic glycolysis activity and enhancement of ROS tolerance. Bioscience Rep 40(5):BSR20191994

    Google Scholar 

  31. Qiu L, Ge L, Hu Q (2020) Dexmedetomidine protects SK-N-SH nerve cells from oxidative injury by maintaining iron homeostasis. Biological Pharm Bulletin 43(3):424–431

    Article  CAS  Google Scholar 

  32. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. Bmc Med Res Methodol 5(1):13

    Article  PubMed  PubMed Central  Google Scholar 

  34. The Jackson Laboratory. Body weight information for C57BL/6J. Available from: https://www.jax.org/jax-mice-and-services/strain-data-sheet-pages/body-weight-chart-000664

  35. Shin HJ, Cho YM, Shin HJ, Kim HD, Choi KM, Kim MG et al (2017) Comparison of commonly used ICR stocks and the characterization of Korl:ICR. Laboratory Animal Res 33(1):8–14

    Article  Google Scholar 

  36. ENVIGO. CD-1 mice growth curve. Available from: https://www.envigo.com/model/hsd-icr-cd-1

  37. Nistiar F, Racz O, Lukacinova A, Hubkova B, Novakova J, Lovasova E et al (2012) Age dependency on some physiological and biochemical parameters of male wistar rats in controlled environment. J Environ Sci Heal Part 47(9):1224–1233

    Article  CAS  Google Scholar 

  38. Taconic. Sprague dawley rat model. Available from: https://www.taconic.com/pdfs/sprague-dawley-rat.pdf

  39. Zhang Y, Tan SL, Du J, Chen Y, Jia J, Feng JG et al (2021) Dexmedetomidine alleviates neuroinflammation, restores sleep disorders and neurobehavioral abnormalities in rats with minimal hepatic encephalopathy. Int Immunopharmacol 96:107795

    Article  CAS  PubMed  Google Scholar 

  40. Wang Z, Zhou W, Dong H, Ma X, He Z (2018) Dexmedetomidine pretreatment inhibits cerebral ischemia/reperfusion-induced neuroinflammation via activation of AMPK. Mol Med Rep 18(4):3957–3964

    CAS  PubMed  Google Scholar 

  41. Hwang L, Ko IG, Jin JJ, Kim SH, Kim CJ, Chang B et al (2019) Dexmedetomidine ameliorates memory impairment in sleep-deprived mice. Anim Cells Syst 23(6):371–379

    Article  CAS  Google Scholar 

  42. Wang N, Wang M (2019) Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activation of the PI3K/Akt/mTOR pathway. Bmc Anesthesiol 19(1):134

    Article  PubMed  PubMed Central  Google Scholar 

  43. Çınar S, Tümkaya L, Mercantepe T, Saral S, Rakıcı S, Yılmaz A et al (2021) Can dexmedetomidine be effective in the protection of radiotherapy-induced brain damage in the rat? Neurotox Res 39(4):1338–1351

    Article  PubMed  Google Scholar 

  44. Sun D, Wang J, Liu X, Fan Y, Yang M, Zhang J (2020) Dexmedetomidine attenuates endoplasmic reticulum stress-induced apoptosis and improves neuronal function after traumatic brain injury in mice. Brain Res 1732:146682

    Article  CAS  PubMed  Google Scholar 

  45. Chiu KM, Lin TY, Lee MY, Lu CW, Wang MJ, Wang SJ (2019) Dexmedetomidine protects neurons from kainic acid-induced excitotoxicity by activating BDNF signaling. Neurochem Int 129:104493

    Article  CAS  PubMed  Google Scholar 

  46. Hwang L, Choi IY, Kim SE, Ko IG, Shin MS, Kim CJ et al (2013) Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med 31(5):1047–1056

    Article  CAS  PubMed  Google Scholar 

  47. Ning Q, Liu Z, Wang X, Zhang R, Zhang J, Yang M et al (2017) Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice. Neurol Res 39(4):357–366

    Article  CAS  PubMed  Google Scholar 

  48. Ayoglu H, Gul S, Hanci V, Bahadir B, Bektas S, Mungan AG et al (2010) The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model. J Clin Neurosci 17(6):770–773

    Article  CAS  PubMed  Google Scholar 

  49. Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Évid Based Ment Heal 22(4):153

    Article  Google Scholar 

  50. Harrer M, Cuijpers P, Furukawa T, Ebert DD, Dmetar: companion R package for the guide “doing meta-analysis in R”. Available from: http://dmetar.protectlab.org/

  51. Fodor LA, Coteț CD, Cuijpers P, Szamoskozi Ștefan, David D, Cristea IA (2018) The effectiveness of virtual reality based interventions for symptoms of anxiety and depression: a meta-analysis. Sci Rep 8(1):10323

    Google Scholar 

  52. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2008) Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 61(10):991–996

    Article  PubMed  Google Scholar 

  53. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. Bmc Med Res Methodol 14(1):43

    Article  PubMed  PubMed Central  Google Scholar 

  54. Du Sert NP, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ et al (2020) Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. Plos Biol 18(7):e3000411

    Google Scholar 

  55. Zhu YJ, Peng K, Meng XW, Ji FH (2016) Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model. Brain Res 1644:1–8

    Article  CAS  PubMed  Google Scholar 

  56. Feng X, Ma W, Zhu J, Jiao W, Wang Y (2021) Dexmedetomidine alleviates early brain injury following traumatic brain injury by inhibiting autophagy and neuroinflammation through the ROS/Nrf2 signaling pathway. Mol Med Rep 24(3):661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kii N, Sawada A, Yoshikawa Y, Tachibana S, Yamakage M (2022) Dexmedetomidine ameliorates perioperative neurocognitive disorders by suppressing monocyte-derived macrophages in mice with preexisting traumatic brain injury. Anesthesia Analgesia 134(4):869–880

    Article  CAS  PubMed  Google Scholar 

  58. Wang YL, Zhang Y, Cai DS (2021) Dexmedetomidine ameliorates postoperative cognitive dysfunction via the MicroRNA-381-mediated EGR1/p53 axis. Mol Neurobiol 58(10):5052–5066

    Article  CAS  PubMed  Google Scholar 

  59. Li F, Wang X, Zhang Z, Zhang X, Gao P (2019) Dexmedetomidine attenuates neuroinflammatory-induced apoptosis after traumatic brain injury via Nrf2 signaling pathway. Ann Clin Transl Neur 6(9):1825–1835

    Article  CAS  Google Scholar 

  60. Mei B, Li J, Zuo Z (2021) Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central α2A adrenoceptor. Brain Behav Immun 91:296–314

    Article  CAS  PubMed  Google Scholar 

  61. Wang D, Xu X, Wu YG, Lyu L, Zhou ZW, Zhang JN (2018) Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms. Neural Regen Res 13(5):819–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li R, Lai IK, Pan JZ, Zhang P, Maze M (2020) Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to prevent lipopolysaccharide-induced cognitive decline in mice. Anesthesiology 133(2):393–407

    Article  CAS  PubMed  Google Scholar 

  63. Sun YB, Zhao H, Mu DL, Zhang W, Cui J, Wu L et al (2019) Dexmedetomidine inhibits astrocyte pyroptosis and subsequently protects the brain in in vitro and in vivo models of sepsis. Cell Death Dis 10(3):167

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang L, Xiao F, Zhang J, Wang X, Ying J, Wei G et al (2021) Dexmedetomidine mitigated NLRP3-mediated neuroinflammation via the ubiquitin-autophagy pathway to improve perioperative neurocognitive disorder in mice. Front Pharmacol 12:646265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hu J, Vacas S, Feng X, Lutrin D, Uchida Y, Lai IK et al (2018) Dexmedetomidine prevents cognitive decline by enhancing resolution of high mobility group box 1 protein–induced inflammation through a vagomimetic action in mice. Anesthesiology 128(5):921–931

    Article  CAS  PubMed  Google Scholar 

  66. Xu KL, Liu XQ, Yao YL, Ye MR, Han YG, Zhang T et al (2018) Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway. Biochem Bioph Res Commun 495(1):421–426

    Article  CAS  Google Scholar 

  67. Guo B, Chen C, Yang L, Zhu R (2021) Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response. Bioengineered 12(1):7920–7928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang WG, Wang L, Jiao ZH, Xue B, Xu ZW (2018) Locomotor activity of rats with SCI is improved by dexmedetomidine by targeting the expression of inflammatory factors. Mol Med Rep 18(1):415–420

    CAS  PubMed  Google Scholar 

  69. Li P, Shen T, Luo X, Yang J, Luo Z, Tan Y et al (2021) Modulation of microglial phenotypes by dexmedetomidine through TREM2 reduces neuroinflammation in heatstroke. Sci Rep 11(1):13345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chen L, Cao J, Cao D, Wang M, Xiang H, Yang Y et al (2019) Protective effect of dexmedetomidine against diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury: an in vivo and in vitro study. Life Sci 235:116553

    Article  CAS  PubMed  Google Scholar 

  71. Karakaya D, Cakir-Aktas C, Uzun S, Soylemezoglu F, Mut M (2022) Tailored therapeutic doses of dexmedetomidine in evolving neuroinflammation after traumatic brain injury. Neurocrit Care 36(3):802–814

    Article  CAS  PubMed  Google Scholar 

  72. Lu Y, Lin B, Zhong J (2017) The therapeutic effect of dexmedetomidine on rat diabetic neuropathy pain and the mechanism. Biological Pharm Bulletin 40(9):b17-00224

    Article  Google Scholar 

  73. Zhang W, Yu T, Cui X, Yu H, Li X (2020) Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA-101 expression and the E2F2–TLR4–NF-κB axis. Exp Physiol 105(9):1588–1597

    Article  CAS  PubMed  Google Scholar 

  74. Minaei A, Haghdoost-Yazdi H (2019) Dexmedetomidine attenuates the induction and reverses the progress of 6-hydroxydopamine- induced parkinsonism; involvement of KATP channels, alpha 2 adrenoceptors and anti-inflammatory mechanisms. Toxicol Appl Pharm 382:114743

    Article  CAS  Google Scholar 

  75. Zhang X, Yan F, Feng J, Qian H, Cheng Z, Yang Q et al (2018) Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-κB pathway. PLoS ONE 13(5):e0196897

    Article  PubMed  PubMed Central  Google Scholar 

  76. Shan W, Liao X, Tang Y, Liu J (2021) Dexmedetomidine alleviates inflammation in neuropathic pain by suppressing NLRP3 via Nrf2 activation. Exp Ther Med 22(4):1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Xu H, Zhao B, She Y, Song X (2018) Dexmedetomidine ameliorates lidocaine-induced spinal neurotoxicity via inhibiting glutamate release and the PKC pathway. Neurotoxicology 69:77–83

    Article  CAS  PubMed  Google Scholar 

  78. Zhao L, Zhai M, Yang X, Guo H, Cao Y, Wang D et al (2019) Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia-reperfusion injury by targeting the CNPY2-endoplasmic reticulum stress signalling. J Cell Mol Med 23(12):8173–8183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim E, Kim HC, Lee S, Ryu HG, Park YH, Kim JH et al (2017) Dexmedetomidine confers neuroprotection against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the TLR-4/NF-κB pathway. Neurosci Lett 649:20–27

    Article  CAS  PubMed  Google Scholar 

  80. Shen M, Wang S, Wen X, Han XR, Wang YJ, Zhou XM et al (2017) Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother 95:885–893

    Article  CAS  PubMed  Google Scholar 

  81. Wang SL, Duan L, Xia B, Liu Z, Wang Y, Wang GM (2017) Dexmedetomidine preconditioning plays a neuroprotective role and suppresses TLR4/NF-κB pathways model of cerebral ischemia reperfusion. Biomed Pharmacother 93:1337–1342

    Article  CAS  PubMed  Google Scholar 

  82. Kan MC, Wang WP, Yao GD, Li JT, Xie T, Wang W et al (2013) Anticonvulsant effect of dexmedetomidine in a rat model of self-sustaining status epilepticus with prolonged amygdala stimulation. Neurosci Lett 543:17–21

    Google Scholar 

  83. Yuan F, Fu H, Sun K, Wu S, Dong T (2017) Effect of dexmedetomidine on cerebral ischemia-reperfusion rats by activating mitochondrial ATP-sensitive potassium channel. Metab Brain Dis 32(2):539–546

    Article  CAS  PubMed  Google Scholar 

  84. Li M, Jin Z, Zhan J, Wang Y, Chen K (2022) Dexmedetomidine improved one-lung ventilation-induced cognitive dysfunction in rats. Bmc Anesthesiol 22(1):115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhao S, Cheng WJ, Liu X, Li Z, Li HZ, Shi N et al (2022) Effects of dexmedetomidine and oxycodone on neurocognitive and inflammatory response after tourniquet-induced ischemia-reperfusion injury. Neurochem Res 47(2):461–469

    Article  CAS  PubMed  Google Scholar 

  86. Deng F, Cai L, Zhou B, Zhou Z, Xu G (2020) Whole transcriptome sequencing reveals dexmedetomidine-improves postoperative cognitive dysfunction in rats via modulating lncRNA. 3 Biotech 10(5):202

    Google Scholar 

  87. Liaquat Z, Xu X, Zilundu PLM, Fu R, Zhou L (2021) The current role of dexmedetomidine as neuroprotective agent: an updated review. Brain Sci 11(7):846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hoorn CE, Hoeks SE, Essink H, Tibboel D, Graaff JC (2019) A systematic review and narrative synthesis on the histological and neurobehavioral long-term effects of dexmedetomidine. Pediatr Anesth 29(2):125–136

    Article  Google Scholar 

  89. Zhai Y, Zhu Y, Liu J, Xie K, Yu J, Yu L et al (2020) Dexmedetomidine post-conditioning alleviates cerebral ischemia-reperfusion injury in rats by inhibiting high mobility group protein B1 group (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. Med Sci Monit Int Medical J Exp Clin Res 26:e918617-1–e918617-11

    Google Scholar 

  90. Alharbi KS, Afzal M, Alzarea SI, Khan SA, Alomar FA, Kazmi I (2022) Rosinidin protects streptozotocin-induced memory impairment-activated neurotoxicity by suppressing oxidative stress and inflammatory mediators in rats. Medicina 58(8):993

    Article  PubMed  PubMed Central  Google Scholar 

  91. Johansson K, Cebula M, Rengby O, Dreij K, Carlström KE, Sigmundsson K et al (2017) Cross talk in HEK293 cells between Nrf2, HIF, and NF-κB activities upon challenges with redox therapeutics characterized with single-cell resolution. Antioxid Redox Sign 26(6):229–246

    Article  CAS  Google Scholar 

  92. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H et al (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7(1):11624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol Sci 34(6):340–346

    Article  CAS  PubMed  Google Scholar 

  94. Wang N, Nie H, Zhang Y, Han H, Wang S, Liu W et al (2022) Dexmedetomidine exerts cerebral protective effects against cerebral ischemic injury by promoting the polarization of M2 microglia via the Nrf2/HO-1/NLRP3 pathway. Inflamm Res 71(1):93–106

    Article  CAS  PubMed  Google Scholar 

  95. Shao G (2022) Dexmedetomidine inhibits cerebral nerve cell apoptosis after cerebral hemorrhage in rats via the Nrf2/HO-1/NQO1 signaling pathway. Eur Rev Med Pharmaco 26(13):4574–4582

    CAS  Google Scholar 

  96. Feng P, Zhang A, Su M, Cai H, Wang X, Zhang Y (2021) Dexmedetomidine inhibits apoptosis of astrocytes induced by oxygen-glucose deprivation via targeting JAK/STAT3 signal pathway. Brain Res 1750:147141

    Article  CAS  PubMed  Google Scholar 

  97. Liu H, Li J, Jiang L, He J, Zhang H, Wang K (2022) Dexmedetomidine pretreatment alleviates cerebral ischemia/reperfusion injury by inhibiting neuroinflammation through the JAK2/STAT3 pathway. Braz J Med Biol Res 55:e12145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lv J, Wei Y, Chen Y, Zhang X, Gong Z, Jiang Y et al (2017) Dexmedetomidine attenuates propofol-induce neuroapoptosis partly via the activation of the PI3k/Akt/GSK3β pathway in the hippocampus of neonatal rats. Environ Toxicol Phar 52:121–128

    Article  CAS  Google Scholar 

  99. Cheng X, Hu J, Wang Y, Ye H, Li X, Gao Q et al (2018) Effects of dexmedetomidine postconditioning on myocardial ischemia/reperfusion injury in diabetic rats: role of the PI3K/Akt-dependent signaling pathway. J Diabetes Res 2018:3071959

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zhang J, Zhang H, Zhao L, Zhao Z, Liu Y (2021) Effect and mechanism of lidocaine pretreatment combined with dexmedetomidine on oxidative stress in patients with intracranial aneurysm clipping. J Healthc Eng 2021:4293900

    PubMed  PubMed Central  Google Scholar 

  101. Sun X, Kang F, Shen Y, Shen Y, Li J (2021) Dexmedetomidine and phosphocreatine post-treatment provides protection against focal cerebral ischemia-reperfusion injury in rats. Acta Histochem Cytoc 54(4):105–113

    Article  CAS  Google Scholar 

  102. Garthe A, Kempermann G (2013) An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci-switz 7:63

    Google Scholar 

  103. Alam A, Hana Z, Jin Z, Suen KC, Ma D (2018) Surgery, neuroinflammation and cognitive impairment. EBioMedicine 37:547–556

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fang S, Chen Y, Yao P, Li Y, Yang Y, Xu G (2018) Dexmedetomidine alleviates postoperative cognitive dysfunction in aged rats probably via silent information regulator 1 pathway. Nan Fang Yi Ke Da Xue Xue Bao J South Medical Univ 38(9):1071–1075

    CAS  Google Scholar 

  105. Lei B, Lv L, Hu S, Tang Y, Zhong Y (2022) Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity. Proc National Acad Sci 119(15):e2116844119

    Article  CAS  Google Scholar 

  106. Lv L, Liu Y, Xie J, Wu Y, Zhao J, Li Q et al (2019) Interplay between α2-chimaerin and Rac1 activity determines dynamic maintenance of long-term memory. Nat Commun 10(1):5313

    Article  PubMed  PubMed Central  Google Scholar 

  107. Liu Y, Lv L, Wang L, Zhong Y (2018) Social isolation induces Rac1-dependent forgetting of social memory. Cell Rep 25(2):288-295.e3

    Article  CAS  PubMed  Google Scholar 

  108. Davis RL, Zhong Y (2017) The biology of forgetting—a perspective. Neuron 95(3):490–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Haditsch U, Leone DP, Farinelli M, Chrostek-Grashoff A, Brakebusch C, Mansuy IM et al (2009) A central role for the small GTPase Rac1 in hippocampal plasticity and spatial learning and memory. Mol Cell Neurosci 41(4):409–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang H, Zablah YB, Zhang H, Liu A, Gugustea R, Lee D et al (2022) Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity. Front Aging Neurosci. 14:914491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Coffey ET (2014) Nuclear and cytosolic JNK signalling in neurons. Nat Rev Neurosci 15(5):285–299

    Article  CAS  PubMed  Google Scholar 

  112. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C et al (2003) The NMDA receptor Is coupled to the ERK pathway by a direct Interaction between NR2B and RasGRF1. Neuron 40(4):775–784

    Article  CAS  PubMed  Google Scholar 

  113. Schmitt JM, Guire ES, Saneyoshi T, Soderling TR (2005) Calmodulin-Dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. J Neurosci 25(5):1281–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sun XY, Tuo QZ, Liuyang ZY, Xie AJ, Feng XL, Yan X et al (2016) Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation. Cell Death Dis 7(11):e2449–e2449

    Article  PubMed  PubMed Central  Google Scholar 

  115. Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N (2006) NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc National Acad Sci 103(8):2892–2897

    Article  CAS  Google Scholar 

  116. Xie CW (2004) Calcium-regulated signaling pathways. Neuromol Med 6(1):53–64

    Article  CAS  Google Scholar 

  117. Banerjee M, Shenoy RR (2021) Emphasizing roles of BDNF promoters and inducers in Alzheimer’s disease for improving impaired cognition and memory. J Basic Clin Physiol Pharmacol 0(0):000010151520210182

    Google Scholar 

  118. Zhu Y, Li S, Liu J, Wen Q, Yu J, Yu L et al (2019) Role of JNK signaling pathway in dexmedetomidine post-conditioning-induced reduction of the inflammatory response and autophagy effect of focal cerebral ischemia reperfusion injury in rats. Inflammation 42(6):2181–2191

    Article  CAS  PubMed  Google Scholar 

  119. Li G, Cao F, Jin Y, Wang Y, Wang D, Zhou L (2021) Role of NR2B/ERK signaling in the neuroprotective effect of dexmedetomidine against sevoflurane induced neurological dysfunction in the developing rat brain. Acta Neurobiol Exp 81(3):271–278

    Article  Google Scholar 

  120. Dong Y, Hong W, Tang Z, Gao Y, Wu X, Liu H (2020) Dexmedetomidine attenuates neurotoxicity in developing rats induced by sevoflurane through upregulating BDNF-TrkB-CREB and downregulating ProBDNF-P75NRT-RhoA signaling pathway. Mediat Inflamm 2020:5458061

    Article  Google Scholar 

Download references

Statements and Declarations

Funding

This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT [Grant numbers 3220565 (SG), 1201039 (FS), 11170840 (CE), 1191300 (CR)]; Millennium Science Initiative Program—ICN09_016/ICN 2021_045: Millennium Institute on Immunology and Immunotherapy (ICN09_016/ICN 2021_045; former P09/016-F) (FS, CR); The Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD) is supported by the Iniciativa Científica Milenio ANID, Chile (FS); Ministry of Education, Science and Technological Development of the Republic of Serbia (grant number 451-03-9/2021-14/200015) (JFS).

Disclosure of Interests

All authors declare they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Author Contribution

SG, CA, YP, and DA extracted and analyzed the data. SG, CE, CR, JFS, and FS, collectively contributed to manuscript drafting. All authors read and approved the final manuscript.

Acknowledgements

None.

Author information

Authors and Affiliations

  1. Laboratory of Integrative Physiopathology, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile

    Sebastian Gatica, Cristobal Aravena, Yolanda Prado, Diego Aravena, Claudia A. Riedel & Felipe Simon

  2. Millennium Institute on Immunology and Immunotherapy, Santiago, Chile

    Sebastian Gatica, Cristobal Aravena, Yolanda Prado, Diego Aravena, Claudia A. Riedel & Felipe Simon

  3. Laboratory of Molecular Biology, Nanomedicine and Genomics, Faculty of Medicine, University of Atacama, Copiapo, Chile

    Cesar Echeverría

  4. Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia

    Juan F. Santibanez

  5. Integrative Center for Biology and Applied Chemistry (CIBQA), Bernardo O’Higgins University, Santiago, Chile

    Juan F. Santibanez

  6. Millennium Nucleus of Ion Channel-Associated Diseases, Universidad de Chile, Santiago, Chile

    Felipe Simon

  7. Laboratory of Neurobiology, Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile

    Jimmy Stehberg

Authors
  1. Sebastian Gatica
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristobal Aravena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yolanda Prado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diego Aravena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cesar Echeverría
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juan F. Santibanez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claudia A. Riedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jimmy Stehberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Felipe Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sebastian Gatica or Felipe Simon .

Editor information

Editors and Affiliations

  1. Universidad Andres Bello, Santiago, Chile

    Felipe Simon

  2. Spanish National Research Council, Madrid, Spain

    Carmelo Bernabeu

1 Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1193 kb)

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gatica, S. et al. (2023). Appraisal of the Neuroprotective Effect of Dexmedetomidine: A Meta-Analysis. In: Simon, F., Bernabeu, C. (eds) Advances in Molecular Pathology. Advances in Experimental Medicine and Biology, vol 1408. Springer, Cham. https://doi.org/10.1007/978-3-031-26163-3_9

Download citation

Publish with us

Policies and ethics

Search

Navigation