Logo Medical Science Monitor

Call: +1.631.470.9640
Mon - Fri 10:00 am - 02:00 pm EST

Contact Us

Logo Medical Science Monitor Logo Medical Science Monitor Logo Medical Science Monitor

25 October 2022: Review Articles  

A Review of the Biological Mechanisms of Dexmedetomidine for Postoperative Neurocognitive Disorders

Shanshan Yu1AEF, Yashu Leng1EF, Yaqi Wang1F, Guoqing Zhao12AEFG*

DOI: 10.12659/MSM.937862

Med Sci Monit 2022; 28:e937862

Abstract

ABSTRACT: Postoperative neurocognitive disorders are common neurological complications following surgery that are generally characterized by varying degrees of cognitive impairment. Postoperative neurocognitive disorders can exhibit as short-term postoperative delirium and/or long-term postoperative cognitive dysfunction. In addition, postoperative neurocognitive disorders may result in poor outcomes in patients, and are a leading cause of postoperative morbidity and mortality, particularly in elderly patients. Recently, there has been a heightened interest in mechanisms and clinical treatments for postoperative neurocognitive disorders. Though some influencing factors and mechanisms of postoperative neurocognitive disorders have been revealed, they remain troublesome problems in clinical departments. Dexmedetomidine is a commonly used anesthetic adjuvant that may help improve postoperative cognitive impairment, especially the conditions of a postoperative acute event (postoperative delirium, within 1 week after operation) and delayed neurocognitive recovery (postoperative cognitive dysfunction, up to 30 days). In the recent literature, dexmedetomidine has been shown to exert positive effects on cognitive impairment in clinical and animal studies, especially for postoperative neurocognitive disorders. However, not all clinical findings support this efficacy. Though some mechanisms of dexmedetomidine on postoperative neurocognitive disorders have been proposed, such as signaling pathways associated with inflammation and apoptosis, this evidence is fragmentary and disputed in the literature. Therefore, this article aims to review the potential biological mechanisms underlying dexmedetomidine’s effects on postoperative neurocognitive disorders, providing a reference for future studies.

Keywords: Cognitive neuroscience, Dexmedetomidine, neurogenic inflammation, Postoperative Cognitive Complications

Background

Postoperative neurocognitive disorders (PND) are frequent neurological complications following surgery [1–3]. PND can have short-term, long-term, and even permanent effects on patient memory, attention, information processing, language understanding, and integration of social ability [1–3]. PND can be defined as an overarching term for cognitive impairment or any change identified in the perioperative or postoperative period, and can include short-term postoperative delirium (POD) and long-term postoperative cognitive dysfunction (POCD) [1–3]. POCD is a condition characterized by neurocognitive deficits that appear after surgery and that may persist for weeks or months after the inciting event [4]. POD is an acute cognitive impairment or dementia seen within 1 week after surgery [5,6].

In addition, PND is associated with increased mortality, premature exit from employment, and negative socioeconomic consequences, particularly in elderly patients [7]. Prominent risk factors for PND include increased age, baseline cognitive impairment, and low education level [1,8]. Furthermore, type of surgery, operation duration, anesthetic agents, anesthesia modality, and unique attributes of the patient can contribute to PND [1]. A history of cerebral infarction, low SpO2 during induction of anesthesia, and long operative duration are risk factors for the development of PND in elderly patients undergoing laparoscopic surgery [9]. PND results from a complex process involving multiple pathological mechanisms caused by various factors. Although its mechanism remains unclear, stress response and inflammation are the most studied potential mechanisms [10,11]. Neuroinflammation plays a key role in the pathogenesis of PND [10]. Surgery can trigger neuroinflammation and induce POCD [12]. The inflammatory factors or cells induced by surgery in the peripheral blood penetrate the brain and affect the central nervous system (CNS) [13]. These inflammatory factors can activate microglial cells to produce an exaggerated immune response, leading to the release of a large number of inflammatory factors [14], including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, peripheral immune cells that enter the brain can amplify the inflammatory response [15]. Accumulated inflammatory mediators cause reversible or irreversible damage to brain tissue, leading to degeneration of neurites and, as a consequence, cognitive dysfunction [15].

Dexmedetomidine is a highly selective α2-adrenaline receptor agonist that can exert sedative, analgesic, and anxiolytic effects. It inhibits sympathetic activity through inhibiting central sympathetic outflow by blocking the α receptors in the brainstem, thereby inhibiting the release of norepinephrine [16]. It is a sedative commonly used in the peri-operative period. Dexmedetomidine decreases the need for opioids and benzodiazepines, both of which are probable causes of PND [17]. Patients sedated with dexmedetomidine can retain a near-normal natural sleep architecture and be easily awakened from sedation [18]. Studies have shown that dexmedetomidine has a positive effect on the protection of postoperative cognitive function and neuroprotective actions against brain ischemia [19].

Preclinical and clinical studies have reported the neuroprotective effects of dexmedetomidine. Dexmedetomidine was superior to placebo and other agents (such as ketamine, lidocaine, and dexamethasone) in improving PND after both cardiac and non-cardiac surgeries [20,21]. Perioperative administration of dexmedetomidine significantly improved postoperative neurocognitive function compared with saline and control anesthetic agents (mainly midazolam) in a dose-dependent manner [22–30]. Dexmedetomidine can be used for pre-induction sedation, intraoperative infusion, and postoperative analgesia. The underlying mechanisms of the influence of dexmedetomidine on PND may involve multiple stress signal transduction pathways as well as the inhibition of the inflammatory response [31–37]. Therefore, this article aims to review the potential biological mechanisms underlying the protective effect of dexmedetomidine against PND, providing a reference for future studies (Table 1).

The Effects of Dexmedetomidine on Inflammatory Cytokines Associated with PND

Inflammation is an inevitable response following surgical trauma, that can trigger cognitive function impairment [38]. Several studies have shown that peripheral inflammatory mediators [such as IL-1β, TNF-α, and interleukin-6 (IL-6)] can affect the brain through the vagus nerve pathway, directly through the blood-brain barrier or periventricular area, via production of inflammatory mediators by microglial cells, and via neural inflammatory reactions; all ultimately leading to neurodegenerative changes and cognitive function impairment [39–43]. Higher levels of IL-6 will increase neuronal damage [40]. Release of TNFα during the perioperative systemic inflammatory response is suspected to increase blood-brain barrier permeability, promoting neuroinflammation, delirium, and subsequent POCD [41]. Elderly patients are more prone to postoperative cognitive impairment, possibly because of a more severe central inflammatory reaction following peripheral immune system activation [42,43].

Dexmedetomidine can decrease the expression levels of IL-1β, TNF-α, nuclear factor kappa-B (NF-κB), B-cell lymphoma-2-associated X protein (Bax), and caspase-3 in the rat hippocampus, all of which serve to inhibit hippocampal inflammation and neuron apoptosis, and thereby protect postoperative cognitive dysfunction [43,44]. Dexmedetomidine combined with etomidate has been shown to inhibit the expression of IL-17A in rats [45]. Additionally, dexmedetomidine can alleviate PND in elderly patients by reducing plasma TNF-α and IL-6 concentrations [46].

The Effects of Dexmedetomidine on Inflammatory Mediators Associated with PND

NF-κB is an important regulator of inflammation and immune response [47]. It is primarily involved in cellular stress reactions, cytokine expression, and apoptotic regulation in inflammatory cascades. Dexmedetomidine exerts anti-inflammatory effects by inducing mir-340 overexpression and reducing NF-κB levels [48]. Toll-like receptors (TLRs) can recognize pathogen-related molecules and transmit signals into the cell, activate NF-κB, promote the transcriptional synthesis of inflammatory factors (such as TNF-α, IL-1, and IL-6), and initiate the inflammatory response to fight infection [49]. TLR4 is involved in the inflammatory response, and NF-κB is an important transcription factor downstream of the TLR4 gene [50]. TLR4 regulates the transcription of multiple pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, by promoting activation of the NF-κB pathway [51]. Therefore, the TLR4/NF-κB signaling pathway is essential in the inflammatory response. Lipopolysaccharide (LPS) is a TLR4 ligand that can activate microglia to produce pro-inflammatory cytokines, thereby inducing cognitive impairment [52,53]. Therefore, LPS-induced inflammation is a commonly used model for the study of PND [54]. Pretreatment with dexmedetomidine can improve LPS-induced PND in aged mice by inhibiting the TLR4/NF-κB pathway in the hippocampus [55].

The Effects of Dexmedetomidine on Oxidative Stress Associated with PND

The stress reaction during the perioperative period includes 3 aspects: psychological stress, anesthetic stress, and surgical trauma stress. Glucocorticoid receptors are present in the frontal cortex, especially the hippocampus, which is the region most frequently selected for investigation of the mechanism by which dexmedetomidine impacts postoperative cognitive impairment [56]. Oxidative stress plays an essential role in neuronal damage and cognitive dysfunction [57].

The phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) pathway plays an important role in neuronal damage associated with PND [58–60]. Dexmedetomidine can protect hippocampal neuronal HT22 cells against apoptosis caused by isoflurane through the PI3K/AKT pathway [61]. Besides, dexmedetomidine can attenuates propofol and isoflurane-induced neuroapoptosis and juvenile cognitive deficits via the activation of the PI3K/AKT pathway in the hippocampi of young rats [62–68].

The Effects of Dexmedetomidine on Neuronal Apoptosis Associated with PND

Apoptosis of hippocampal neurons also contributes to PND [69]. In PND mice, the expression of the fas cell surface death receptor (Fas), caspase-8, and caspase-9 proteins were upregulated, and B-cell lymphoma-2 (Bcl-2) was downregulated, which exerted anti-apoptosis effects. Overexpression of relaxin-3 in trauma and emergency states is responsible for neuronal apoptosis and brain damage [70,71]. Dexmedetomidine can reduce relaxin-3, Fas, caspase-8, and caspase-9, and increase Bcl-2 in the CA1 region of the hippocampus in aged rats [69].

NLRP3 plays a critical role in the initiation of inflammation in microglia [72]. Activated NLRP3 triggers the cleavage of pro-caspase-1 into caspase-1, which induces the release of IL-1 and IL-18 [73]. The transcription factor fos proto-oncogene (c-Fos) can bind to the promoter region of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) gene and positively regulate the expression of its downstream target caspase-1. Dexmedetomidine reduces PND in elderly rats by inhibiting the activation of c-Fos [74]. Besides, dexmedetomidine can alleviate PND by upregulating the cathelicidin antimicrobial peptide (cAMP)-protein kinase A (PKA)-cAMP responsive element binding protein (CREB) signaling pathway to attenuate surgical trauma-induced hippocampal inflammation through inhibiting the gamma aminobutyric acid-B receptor [75].

The miR-129/Yes-associated protein 1(YAP1)/Jagged 1(JAG1) and miR-381/early growth response 1 (EGR1)/p53 pathways are associated with hippocampal neuronal apoptosis, and can alleviate DNA damage, neuroinflammation, and cognitive impairment. Dexmedetomidine can activate these pathways and thereby improve PND [76,77].

Surgery and isoflurane anesthesia reduce doublecortin (DCX)-positive neurons and brain-derived neurotrophic factor (BDNF) expression, which may give rise to neurogenesis. Dexmedetomidine can prevent PND and promote neurogenesis through upregulation of BDNF and p-CREB/CREB, factors which are related to the neuronal apoptotic pathway cAMP/PKA-CREB [78].

The Effects of Dexmedetomidine on Blood–Brain Barrier Integrity During PND

The blood-brain barrier (BBB), a protective barrier between plasma and neurons, can be damaged by surgical trauma-induced systemic inflammation. Such damage is associated with cognitive dysfunction. The major facilitator superfamily domain-containing protein 2 (Mfsd2a) is regulated by pericytes to promote BBB integrity [79]. Mfsd2a-deficient mice demonstrate neurological abnormalities, including ataxia [80]. Further, lipid and brain development are associated with functional maintenance. Dexmedetomidine stabilizes BBB integrity by increasing Mfsd2a expression and reducing the incidence of cognitive dysfunction after surgical trauma [81].

The Effects of Dexmedetomidine on Proteins Associated with Alzheimer’s Disease

Polymerization of the amyloid beta 42 (Aβ) protein increases intracellular calcium concentration, induces apoptosis and neurotoxicity, and mediates neuronal cell death through microtubule-associated protein Tau (Tau) phosphorylation [82]. Postsynaptic density protein (PSD95) is critically involved in synapse formation [35, 83–85]. Dexmedetomidine, which is used in aged rats during cardiopulmonary bypass, can affect the expression of Aβ, p-Tau, and PSD95 proteins in cerebrospinal fluid, hippocampus, and prefrontal cortex, and thereby protect neurological function [35]. Dexmedetomidine reduces the incidence of PND in patients receiving orthotopic liver transplantation, and its mechanism of action may be attributed to decreased Aβ and Tau levels [85].

Future Developments

Though some studies have observed protective effects of dexmedetomidine on PND, the results are controversial. Intraoperative application of dexmedetomidine may cause a delay in recovery from anesthesia [86]. A multicenter study has shown that dexmedetomidine had no better effects on PND than placebo groups in non-cardiac surgery [87]. Furthermore, perioperative use of dexmedetomidine has no benefit in cardiac surgery in terms of the postoperative complications of delirium and atrial fibrillation [88]. Thus, dexmedetomidine should not be infused to reduce atrial fibrillation or delirium in patients undergoing cardiac surgery. Besides, in the literature, cognitive function was assessed mostly on the first, third, and seventh postoperative days, and only a few studies evaluated aspects of long-term prognosis. More studies are needed that involve long-term followup and robust cognitive evaluation to confirm or refute long-term improvement (>1 week) from dexmedetomidine.

Conclusions

Early diagnosis and supportive treatment are important to improve PND outcomes. The mechanisms underlying PND involve many factors, including inflammation and stress reactions. The underlying mechanisms of dexmedetomidine on PND may involve multiple stress signal transduction pathways and inhibition of the inflammatory response. Furthermore, the neurotoxic effects of general anesthetic agents, cerebral hypoperfusion, and sleep disturbances are also associated with the development of cognitive impairment in the postoperative period. Especially in elderly patients, long-term sleep disturbance can lead to significant impairment of cognitive function. Whether these mechanisms are involved in dexmedetomidine-induced amelioration of postoperative period cognitive impairment remains to be further investigated. Although most clinical and animal experiments support the ameliorative effects of dexmedetomidine on PND, these effects are controversial, and specific mechanisms must be further investigated.

References

1. Olotu C, Postoperative neurocognitive disorders: Curr Opin Anaesthesiol, 2020; 33(1); 101-8

2. Subramaniyan S, Terrando N, Neuroinflammation and perioperative neurocognitive disorders: Anesth Analg, 2019; 128(4); 781-88

3. Tasbihgou SR, Absalom AR, Postoperative neurocognitive disorders: Korean J Anesthesiol, 2021; 74(1); 15-22

4. Carr ZJ, Cios TJ, Potter KF, Does dexmedetomidine ameliorate postoperative cognitive dysfunction? A brief review of the recent literature: Curr Neurol Neurosci Rep, 2018; 18(10); 64

5. Oh ST, Park JY, Postoperative delirium: Korean J Anesthesiol, 2019; 72(1); 4-12

6. Vlisides P, Avidan M, Recent advances in preventing and managing postoperative delirium: F1000Res, 2019; 8; F1000 F aculty Rev-607

7. Deiner S, Silverstein JH, Postoperative delirium and cognitive dysfunction: Br J Anaesth, 2009; 103; i41-i46

8. Evered LA, Silbert BS, Postoperative cognitive dysfunction and noncardiac surgery: Anesth Analg, 2018; 127; 496-505

9. Fan Y, Liu X, Wu S, The risk factors for cognitive dysfunction in elderly patients after laparoscopic surgery: A retrospective analysis: Medicine (Baltimore), 2021; 100; e23977

10. Hovens IB, Schoemaker RG, Zee EAVD, Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning: Brain Behav Immun, 2014; 38; 202-10

11. Safavynia Seyed A, Goldstein Peter A, Fan Y, Liu X, Wu S, The role of neuroinflammation in postoperative cognitive dysfunction: Moving from hypothesis to treatment: Psychiatry, 2018; 9; 752

12. Chu JMT, Xiong W, Linghu KG, Extract attenuates postoperative cognitive dysfunction, systemic inflammation, and neuroinflammation: Exp Neurobiol, 2018; 27; 564-73

13. Podjaski C, Alvarez JI, Bourbonniere L, Netrin 1 regulates blood-brain barrier function and neuroinflammation: Brain, 2015; 138; 1598-612

14. Hoogland IC, Houbolt C, van Westerloo DJ, Systemic inflammation and microglial activation: Systematic review of animal experiments: J Neuroinflammation, 2015; 12; 114

15. Gyoneva S, Davalos D, Biswas D, Systemic inflammation regulates microglial responses to tissue damage in vivo: Glia, 2014; 62; 1345-60

16. Weerink MAS, Struys MMRF, Hannivoort LN, Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine: Clin Pharmacokinet, 2017; 56; 893-913

17. Ueki M, Kawasaki T, Habe K, The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass: Anaesthesia, 2014; 69; 693-700

18. Hall JE, Uhrich TD, Barney JA, Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions: Anesth Analg, 2000; 90; 699-705

19. Deiner S, Luo X, Lin HM, Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: A randomized clinical trial: JAMA Surg, 2017; 152; e171505

20. Li LQ, Wang C, Fang MD, Effects of dexamethasone on post-operative cognitive dysfunction and delirium in adults following general anaesthesia: A meta-analysis of randomized controlled trials: BMC Anesthesiol, 2019; 19(1); 113

21. Li M, Yang Y, Ma Y, Pharmacological agents that prevent postoperative cognitive dysfunction in patients with general anesthesia: A network meta-analysis: Am J Ther, 2020; 28(4); e420-e33

22. Yang W, Kong LS, Zhu XX, Effect of dexmedetomidine on postoperative cognitive dysfunction and inflammation in patients after general anaesthesia: A PRISMA-compliant systematic review and meta-analysis: Medicine (Baltimore), 2019; 98(18); e15383

23. Chen W, Liu B, Zhang F, The effects of dexmedetomidine on post-operative cognitive dysfunction and inflammatory factors in senile patients: Int J Clin Exp Med, 2015; 8; 4601-5

24. Li XT, Jiang XM, Zheng ZYEffect of dexmedetomidine on inflammatory factors level and cognitive function after femoral head replacement in elderly patients: Zhongguo Gu Shang, 2018; 31; 1091-95 [in Chinese]

25. Xu HY, Fu GH, Wu GS, Effect of dexmedetomidine-induced anesthesia on the postoperative cognitive function of elder patients after laparoscopic ovarian cystectomy: Saudi J Biol Sci, 2017; 24; 1771-75

26. Li Z, Li H, Yao SEffects of dexmedetomidine doses on postoperative cognitive dysfunction and serum β-amyloid and cytokine levels in elderly patients after spine surgery: A randomized controlled trial: Nan Fang Yi Ke Da Xue Xue Bao, 2021; 41; 600-6 [in Chinese]

27. Zhao W, Hu Y, Chen H, The effect and optimal dosage of dexmedetomidine plus sufentanil for postoperative analgesia in elderly patients with postoperative delirium and early postoperative cognitive dysfunction: A single-center, prospective, randomized, double-blind, controlled trial: Front Neurosci, 2020; 14; 549516

28. Govêia CS, Miranda DB, Oliveira LVB, Dexmedetomidine reduces postoperative cognitive and behavioral dysfunction in adults submitted to general anesthesia for non-cardiac surgery: Meta-analysis of randomized clinical trials: Braz J Anesthesiol, 2021; 71; 413-20

29. Evered L, Scott DA, Silbert B, Postoperative cognitive dysfunction is independent of type of surgery and anesthetic: Anesth Analg, 2011; 112; 1179-85

30. Gong Z, Li J, Zhong Y, Effects of dexmedetomidine on postoperative cognitive function in patients undergoing coronary artery bypass grafting: Exp Ther Med, 2018; 16; 4685-89

31. Naguib AN, Tobias JD, Hall MW, The role of different anesthetic techniques in altering the stress response during cardiac surgery in children: A prospective, double-blinded, and randomized study: Pediatr Crit Care Med, 2013; 14; 481-90

32. Neema PK, Dexmedetomidine in pediatric cardiac anesthesia: Ann Card Anaesth, 2012; 15; 177-79

33. Huang J, Dinh M, Kuchle N, Anesthetic management for combined mitral valve replacement and aortic valve repair in a patient with osteogenesis imperfecta: Ann Card Anaesth, 2011; 14; 115-18

34. Leino K, Hynynen M, Jalonen J, Renal effects of dexmedetomidine during coronary artery bypass surgery: A randomized placebo-controlled study: BMC Anesthesiol, 2011; 11; 9

35. Zhang Y, Lin Y, Liu Q, The effect of dexmedetomidine on cognitive function and protein expression of Aβ, p-Tau, and PSD95 after extracorporeal circulation operation in aged rats: Biomed Res Int, 2018; 2018; 4014021

36. Endesfelder S, Makki H, von Haefen C, Neuroprotective effects of dexmedetomidine against hyperoxia-induced injury in the developing rat brain: PLoS One, 2017; 12; e0171498

37. Li Y, He R, Chen S, Effect of dexmedetomidine on early postoperative cognitive dysfunction and peri-operative inflammation in elderly patients undergoing laparoscopic cholecystectomy: Exp Ther Med, 2015; 10(5); 1635-42

38. Ji MH, He X, Shen JC, Aging-related neural disruption might predispose to postoperative cognitive impairment following surgical trauma: J Alzheimers Dis, 2021; 81; 1685-99

39. Dunne SS, Coffey JC, Konje S, Biomarkers in delirium: A systematic review: J Psychosom Res, 2021; 147; 110530

40. Quan C, Chen J, Luo Y, BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery: Brain Behav, 2019; 9; e01238

41. Carr ZJ, Cios TJ, Potter KF, Swick JT, Does dexmedetomidine ameliorate postoperative cognitive dysfunction? A brief review of the recent literature: Curr Neurol Neurosci Rep, 2018; 18(10); 64

42. Miller-Rhodes P, Kong C, Baht GS, The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders: J Neuroinflammation, 2019; 1; 193

43. Chen N, Chen X, Xie J, Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation: Mol Med Rep, 2019; 20; 2119-26

44. Qian XL, Zhang W, Liu MZ, Dexmedetomidine improves early postoperative cognitive dysfunction in aged mice: Eur J Pharmacol, 2015; 746; 206-212

45. Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H, IL-17 enhancement of the IL-6 signaling cascade in astrocytes: J Immunol, 2010; 184; 4898-906

46. Zhu YS, Xiong YF, Luo FQ, Dexmedetomidine protects rats from postoperative cognitive dysfunction via regulating the GABAB R-mediated cAMP-PKA-CREB signaling pathway: Neuropathology, 2019; 39; 30-38

47. Kalogeris T, Baines CP, Krenz M, Cell biology of ischemia/reperfusion injury: Int Rev Cell Mol Biol, 2012; 298; 229-317

48. Bao Y, Zhu Y, He G, Dexmedetomidine attenuates neuroinflammation in LPS-stimulated BV2 microglia cells through upregulation of miR-340: Drug Des Devel Ther, 2019; 13; 3465-75

49. Hua F, Ma J, Ha T, Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion: J Neuroimmunol, 2007; 190; 101-11

50. Vilahur G, Badimon L, Ischemia/reperfusion activates myocardial innate immune response: The key role of the toll-like receptor: Front Physiol, 2014; 5; 496

51. Cortez M, Carmo LS, Rogero MM, A high-fat diet increases IL-1, IL-6, and TNF-α production by increasing NF-κB and attenuating PPAR-γ expression in bone marrow mesenchymal stem cells: Inflammation, 2013; 36; 379-86

52. Mrak RE, Griffin WS, Glia and their cytokines in progression of neurodegeneration: Neurobiol Aging, 2005; 26; 349-54

53. Choi DY, Lee JW, Lin G, Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-κB signaling pathway: Neurochem Int, 2012; 60; 68-77

54. Zhao WX, Zhang JH, Cao JB, Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity: J Neuroinflammation, 2017; 14; 17

55. Zhou XY, Liu J, Xu ZP, Dexmedetomidine ameliorates postoperative cognitive dysfunction by inhibiting Toll-like receptor 4 signaling in aged mice: Kaohsiung J Med Sci, 2020; 36; 721-31

56. Qiu LL, Luo D, Zhang H, Nox-2-mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice: Front Aging Neurosci, 2016; 8; 234

57. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats: Toxicol Appl Pharmacol, 2017; 333; 43-50

58. Yang LH, Xu YC, Zhang W, Neuroprotective effect of CTRP3 overexpression against sevoflurane anesthesia-induced cognitive dysfunction in aged rats through activating AMPK/SIRT1 and PI3K/AKT signaling pathways: Eur Rev Med Pharmacol Sci, 2020; 24; 5091-100

59. Zhou S, Fang Z, Wang G, Wu S, Gap junctional intercellular communication dysfunction mediates the cognitive impairment induced by cerebral ischemia-reperfusion injury: PI3K/AKT pathway involved: Am J Transl Res, 2017; 9; 5442-51

60. Zhang BJ, Yuan CX, Effects of ADAM2 silencing on isoflurane-induced cognitive dysfunction via the P13K/AKT signaling pathway in immature rats: Biomed Pharmacother, 2019; 109; 217-25

61. Bao F, Kang X, Xie Q, Wu J, HIF-α/PKM2 and PI3K-AKT pathways involved in the protection by dexmedetomidine against isoflurane or bupivacaine-induced apoptosis in hippocampal neuronal HT22 cells: Exp Ther Med, 2019; 17(1); 63-70

62. Xiao Y, Zhou L, Tu Y, Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/AKT signaling pathway: Neuropsychiatr Dis Treat, 2018; 14; 2191-206

63. Wang Y, Wu C, Han B, Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/AKT/Gsk-3β signaling disruption, and juvenile cognitive deficits in neonatal rats: Mol Med Rep, 2016; 14(1); 769-75

64. Li Y, Zeng M, Chen W, Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/AKT pathway in the hippocampus of neonatal rats: PLoS One, 2014; 9(4); e93639

65. Lv J, Wei Y, Chen Y, Dexmedetomidine attenuates propofol-induce neuroapoptosis partly via the activation of the PI3k/AKT/GSK3β pathway in the hippocampus of neonatal rats: Environ Toxicol Pharmacol, 2017; 52; 121-28

66. Xing N, Xing F, Li Y, Dexmedetomidine improves propofol-induced neuronal injury in rat hippocampus with the involvement of miR-34a and the PI3K/AKT signaling pathway: Life Sci, 2020; 247; 117359

67. Peng M, Ling X, Song R, Upregulation of GLT-1 via PI3K/AKT pathway contributes to neuroprotection induced by dexmedetomidine: Front Neurol, 2019; 10; 1041

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

69. Xiong B, Shi Q, Fang H, Dexmedetomidine alleviates postoperative cognitive dysfunction by inhibiting neuron excitation in aged rats: Am J Transl Res, 2016; 8; 70-80

70. Pfeilschifter J, Rob P, Mülsch A, Interleukin 1 beta and tumour necrosis factor alpha induce a macrophage-type of nitric oxide synthase in rat renal mesangial cells: Eur J Biochem, 1992; 203; 251-55

71. Ma S, Olucha-Bordonau FE, Hossain MA, Modulation of hippocampal theta oscillations and spatial memory by relaxin-3 neurons of the nucleus incertus: Learn Mem, 2009; 16; 730-42

72. Freeman LC, Ting JP, The pathogenic role of the inflammasome in neurodegenerative diseases: J Neurochem, 2016; 136; 29-38

73. Chavarría-Smith J, Vance RE, The NLRP1 inflammasomes: Immunol Rev, 2015; 265; 22-34

74. Li H, Zhang X, Chen M, Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades: EXCLI J, 2018; 17; 302-11

75. Zhu YS, Xiong YF, Luo FQ, Dexmedetomidine protects rats from postoperative cognitive dysfunction via regulating the GABAB R-mediated cAMP-PKA-CREB signaling pathway: Neuropathology, 2019; 39; 30-38

76. Sun W, Zhao J, Li C, Dexmedetomidine provides protection against hippocampal neuron apoptosis and cognitive impairment in mice with Alzheimer’s disease by mediating the miR-129/YAP1/JAG1 axis: Mol Neurobiol, 2020; 57; 5044-55

77. Wang YL, Zhang Y, Cai DS, Dexmedetomidine ameliorates postoperative cognitive dysfunction via the microRNA-381-mediated EGR1/p53 axis: Mol Neurobiol, 2021; 58(10); 5052-66

78. Wang WX, Wu Q, Liang SS, Dexmedetomidine promotes the recovery of neurogenesis in aged mouse with postoperative cognitive dysfunction: Neurosci Lett, 2018; 677; 110-16

79. Ben-Zvi A, Lacoste B, Kur E, Mfsd2a is critical for the formation and function of the blood-brain barrier: Nature, 2014; 509; 507-11

80. Berger JH, Charron MJ, Silver DL, Major facilitator superfamily domain-containing protein 2a (MFSD2A) has roles in body growth, motor function, and lipid metabolism: PLoS One, 2012; 7; e50629

81. Zhang XP, Liu YR, Chai M, High-fat treatment prevents postoperative cognitive dysfunction in a hyperlipidemia model by protecting the blood-brain barrier via Mfsd2a-related signaling: Mol Med Rep, 2019; 20; 4226-34

82. Shao H, Zhang Y, Dong Y, Chronic treatment with anesthetic propofol improves cognitive function and attenuates caspase activation in both aged and Alzheimer’s disease transgenic mice: J Alzheimers Dis, 2014; 41; 499-513

83. Wang J, Lu W, Chen L, Serine 707 of APPL1 is critical for the synaptic NMDA receptor-mediated AKT phosphorylation signaling pathway: Neurosci Bull, 2016; 32; 323-30

84. Planagumà J, Leypoldt F, Mannara F, Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice: Brain, 2015; 138; 94-109

85. Xu G, Li LL, Sun ZT, Effects of dexmedetomidine on postoperative cognitive dysfunction and serum levels of b-amyloid and neuronal microtubule-associated protein in orthotopic liver transplantation patients: Ann Transplant, 2016; 21; 508-15

86. Anjum N, Tabish H, Debdas S, Effects of dexmedetomidine and clonidine as propofol adjuvants on intra-operative hemodynamics and recovery profiles in patients undergoing laparoscopic cholecystectomy: A prospective randomized comparative study: Avicenna J Med, 2015; 5; 67-73

87. Deiner S, Luo X, Lin HM, Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: A randomized clinical trial: JAMA Surg, 2017; 152; e171505

88. Turan A, Duncan A, Leung S, Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): A randomised placebo-controlled trial: Lancet, 2020; 396; 177-85

SARS-CoV-2/COVID-19

24 November 2022 : Clinical Research  

A Prospective Questionnaire-Based Study to Evaluate Factors Affecting the Decision to Receive COVID-19 Vacc...

Med Sci Monit In Press; DOI: 10.12659/MSM.938665  

01 November 2022 : Clinical Research  

Questionnaire-Based Study of 81 Patients in Poland to Evaluate the Course of Inflammatory Bowel Disease and...

Med Sci Monit 2022; 28:e938243

03 October 2022 : Clinical Research  

Effect of Vitamin D Concentration on Course of COVID-19

Med Sci Monit 2022; 28:e937741

In Press

25 Nov 2022 : Clinical Research  

Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels

Med Sci Monit In Press; DOI: 10.12659/MSM.937990  

24 Nov 2022 : Clinical Research  

Effect of Positive End-Expiratory Pressure (PEEP) Titration in Elderly Patients Undergoing Lobectomy

Med Sci Monit In Press; DOI: 10.12659/MSM.938225  

24 Nov 2022 : Clinical Research  

A Prospective Questionnaire-Based Study to Evaluate Factors Affecting the Decision to Receive COVID-19 Vacc...

Med Sci Monit In Press; DOI: 10.12659/MSM.938665  

22 Nov 2022 : Clinical Research  

Preoperative Biologics Exposure Predisposes Ulcerative Colitis Patients to a Distinct Delayed Postoperative...

Med Sci Monit In Press; DOI: 10.12659/MSM.938412  

Most Viewed Current Articles

30 Dec 2021 : Clinical Research  

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis o...

DOI :10.12659/MSM.935379

Med Sci Monit 2021; 27:e935379

13 Nov 2021 : Clinical Research  

Acceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...

DOI :10.12659/MSM.932788

Med Sci Monit 2021; 27:e932788

01 Nov 2020 : Review article  

Long-Term Respiratory and Neurological Sequelae of COVID-19

DOI :10.12659/MSM.928996

Med Sci Monit 2020; 26:e928996

08 Mar 2022 : Review article  

A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Man...

DOI :10.12659/MSM.936292

Med Sci Monit 2022; 28:e936292

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750