25 October 2022 : Review article
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
Background
The Effects of Dexmedetomidine on Inflammatory Cytokines Associated with PND
The Effects of Dexmedetomidine on Inflammatory Mediators Associated with PND
The Effects of Dexmedetomidine on Oxidative Stress Associated with PND
The Effects of Dexmedetomidine on Neuronal Apoptosis Associated with PND
The Effects of Dexmedetomidine on Blood–Brain Barrier Integrity During PND
The Effects of Dexmedetomidine on Proteins Associated with Alzheimer’s Disease
Future Developments
Conclusions
References
Table 1 Summary of the mechanisms underlying the effects of dexmedetomidine on PND.
| Study | Subjects (size) | Object | Target or pathway (DEX dosage and time point after treatment) | PND type (DEX dosage and time point after treatment) |
|---|---|---|---|---|
| Chen W, 2015 []23 | Aged surgical patients (148) | Serum | IL-6↓, TNFa↓ (0.2 μg·kg·h, 1 day) | POCD↓ (0.2 μg·kg·h, 1 day) |
| Li XT, 2018 []24 | Elderly patients (60) | Serum | IL-6↓, S100β↓, IL-10↓(0.3 μg·kg·h and 0.6 μg·kg·h, 1 day, 3 days, and 7 days) | POCD↓ (0.3 μg·kg·h and 0.6 μg·kg·h, 1 day, 3 days, and 7 days) |
| Xu HY, 2017 []25 | Elderly patients (96) | Serum | IL-6↓, CRP↓ (0.5 μg·kg·h, 1 day and 3 days) | POCD↓ (0.5 μg·kg·h, within 1 week) |
| Li Z, 2021 []26 | Elderly patients (120) | Serum | Aβ↓ (0.6 μg·kg·h and 0.8 μg·kg·h, 7 days)IL-1β↓, IL-6↓ and TNF-α↓ (0.6 μg·kg·h and 0.8 μg·kg·h, 3 days) | POCD↓ (0.6 μg·kg·h and 0.8 μg·kg·h, 1 day, 3 days, and 7 days) |
| Zhao W, 2020 []27 | Elderly patients (416) | POCD↓ (200 ug and 400 ug, 1–3 days and 7 days)POD↓ (200 ug and 400 ug, 1–3 days) | ||
| Gong Z, 2018 []30 | Patients undergoing extracorporeal coronary artery bypass surgery (80) | POCD↓ (0.2 μg·kg·h, within 1 week) | ||
| Naguib AN, 2013 []31 | Children undergoing surgical repair of congenital heart disease(48) | Serum | IL-6↓, IL-10↓ (0.5 μg·kg·h, 1 day) | |
| Zhang Y, 2018 []35 | Sprague-Dawley aged rats, 18–20 months old, weight 400–550 g (90) | Cerebrospinal fluidBrain tissue | Aβ↓, p-Tau↓, PSD95↑ in hippocampus and prefrontal cortex (50 μg/kg, after operation)Aβ↓, p-Tau↑, PSD95↓ in cerebrospinal fluid (50 μg/kg, after operation) | POCD↓ (50 ug/kg, 31 to 35 days after operation) |
| Endesfelder S, 2017 []36 | 6-day old Wistar rats (80) | Brain tissue | Transcription factors (SOX2, Tbr1/2, Prox1)↑, regulators of neuronal plasticity (Nrp1, Nrg1, Syp, and Sema3a/f)↑ (1 μg/kg and 5 μg/kg, 24 h)Transcription factors (SOX2, Tbr1/2, Prox1)↓, regulators of neuronal plasticity (Nrp1, Nrg1, Syp, and Sema3a/f)↓ (10 μg/kg, 24 h) | |
| Li Y, 2015 []37 | Elderly patients (120) | Serum | IL-1β↓, IL-6↓, CRP↓ (0.4 μg·kg·h, 6 h and 1 day) | POCD↓ (0.4 μg·kg·h, 1 day) |
| Chen N, 2019 []43 | Male Sprague Dawley rats, aged 18 months, weight 400–500 g (80) | Hippocampus | IL-1β↓, TNF-α↓, NF-κB↓, activation of microglia↓ (10 μg/kg and 30 μg/kg, 1 day and 3 days) | POCD↓ (10 μg/kg and 30 μg/kg, 1 day and 3 days) |
| Qian XL, 2015 []44 | BALB/c mice (20–22 month old, weight 60–70 g) | Hippocampus | IL-1β↓, TNF-α↓, Bax↓, caspase-3↓ (15 μg/kg and 25 μg/kg, 1 day and 3 days) | POCD↓ (15 μg/kg and 25 μg/kg, 1 day and 3 days) |
| Zhu YS, 2019 []46 | Male Sprague Dawley rats, aged 18 months, weight 500–600 g (75) | Hippocampus | IL-1β↓, TNF-α↓ (12 μg/kg, 1 day and 3 days) | POCD↓ (12 μg/kg, 1 day, 3 days, and 7 days) |
| Bao Y, 2019 []48 | BV2 cells | NF-κB↓, miR-340↑, TNF-α↓, IL-6↓, IL-1β↓, IL-2↓, IL-12↓, MCP-1↓, IL-10↑ (20 μg/mL, 24 h) | ||
| Zhou XY, 2020 []55 | BV2 cells, Male elderly C57BL/6 mice (15 months old, weight 30–45 g) | Bv2 cellsHippocampus | TNF-α↓, IL-1β↓, IL-6↓, TLR4↓, NF-κB↓ in BV2 cells (0.1 μg/mL, 24 h)TNF-α↓, IL-1β↓, IL-6↓, TLR4↓, NF-κB↓ in BV2 cells in hippocampus (25 mg/kg, 24 h) | POCD↓ (25 μg/kg, 1 day, 3 days, and 7 days) |
| Bao F, 2019 []61 | HT22 cell line | HIF-α/PKM2 pathway↓, PI3K-AKT pathway↑ (200 μM, 24 h) | ||
| Xiao Y, 2018 []62 | Male Sprague Dawley rats at 7 days of age and weighing 10–15 g | Hippocampus | PSD95↑, PI3K/AKT pathway↑, propofol-induced neuronal damages↓ (25 μg/kg, 25 μg/kg and 75 μg/kg, 9 weeks old)propofol-induced neuronal apoptosis in the hippocampus↓ (75 μg/kg, 9 weeks old) | Propofol-induced neurological function impairment↓ (25 μg/kg, 25 μg/kg and 75 μg/kg, 9 weeks old) |
| Wang Y, 2016 []Lv J, 2017 []63 | Male postnatal day 7 Sprague Dawley rats weighing 12–16 g | Hippocampus | Bax/Bcl-2↓, caspase-3↓, PI3K/AKT/GSK-3β pathway↑ (75 μg/kg, 7 days) | Propofol-induced cognitive deficits↓ (75 μg/kg, 33 days) |
| Li Y, 2014 []64 | 7-day-old Sprague-Dawley rat pups weighting 14–18 g | Hippocampus | Caspase-3↓, Bcl-xL/Bad↑, AKT↑, hippocampal neuroapoptosis↓ (50 μg/kg, 75 μg/kg, and 3 doses of 25 μg/kg, 2 h) | |
| Xing N, 2020 []66 | 7-day-old Sprague-Dawley rats weighting 14–18 g (105) | Hippocampus | PSD95↑, caspase 3↓, Bax↓, miR-34a↓, aPI3K-Akt pathway↑, (25 μg/kg, 50 μg/kg, 75 μg/kg, 2 h)Propofol-induced hippocampal neurons injury↓, (from 0.01–100 μmol/L, best: 1 μmol/L, 3 h↑ | |
| Peng M, 2019 []67 | Male Sprague-Dawley rats weighing 200–240 g | Hippocampus | Cerebral ischemic injuries↓, GLT-1↑, Phospho-AKT/AKT↑ (1 μg/kg, 2–24 h) | |
| Wang N, 2019 []68 | Sprague-Dawley (SD) rats, weighing 150–200 g (50) | Hippocampus | IL-6↓, IL-8↓, TNF-α↓, PI3K/AKT/mTOR pathway↑ (4 μg/kg, after surgery) | |
| Xiong B, 2016 []69 | 18 month-old male Sprague-Dawley rats, weighing 500–600 g (90) | Hippocampus | Fas↓, caspase-8↓, and caspase-9↓, Bcl-2↑, hippocampal apoptosis↓ (3 μg/kg and 12 μg/kg, 1 day, 3 days and 7 days) | POCD↓ (3 μg/kg and 12 μg/kg, 1 day, 3 days and 7 days) |
| Li H, 2018 []74 | The human microglia clone 3 (HMC3) cell line | IL-1β↓, IL-18↓ (10 μM, 24 h)c-Fos↓, NLRP3↓ (0.1 μM, 1 μM, 10 μM, 24 h) | ||
| Zhu YS, 2019 []75 | Specific-pathogen free 18-month-old male Sprague-Dawley rats weighing 500–600 g (75) | Hippocampus | TNF-α↓, IL-1β↓, GABABR1↓, GABABR2↓, cAMP↑, PKA↑, p-CREB↑, BDNF↑ (12 μg/kg, 1 day and 3 days) | |
| Sun W, 2020 []76 | Male NIH Swiss mice, aged 9 weeks and weighing 20–24 g (64) | Hippocampus | miR-129↑, YAP1/JAG1 pathway↑ (24 h) | Cognitive impairment↓ (24 h) |
| Wang YL, 2021 []77 | C57BL/6J aged 18 weeks mice | Hippocampus | miR-381↑, EGR1/p53 pathway↓, hippocampal neuron apoptosis↓ (5 μg/kg, 14 days) | POCD↓ (5 μg/kg, 14 days) |
| Wang WX, 2018 []78 | Male Sprague-Dawley rats weighing 500–600 g | PlasmaHippocampus | IL-1β↓ and TNF-α↓ in plasma (3 μg/kg and 12 μg/kg, 24 h)IL-6↓, TNF-α↓, p38-MAPK↓, Phosphorylated CREB↑, PKA↑ and BDNF↑ in the hippocampus (3 μg/kg and 12 μg/kg, 24 h) | Long-term spatial memory↑ (3 μg/kg and 12 μg/kg, within 1 week) |
| Anjum N, 2015 []86 | ASA I–II patients, scheduled for laparoscopic cholecystectomy (45) | POCD↓ (0.5 μg·kg·h, 30 min) | ||
| Deiner S, 2017 []87 | Elderly patients undergoing major elective noncardiac surgery (404) | POD- (0.5 μg·kg·h, hospital stay or 5 days)POCD- (0.5 μg·kg·h, 3 months and 6 months) | ||
| Turan A, 2020 []88 | Patients undergoing cardiac surgery with cardiopulmonary bypass (794) | POD- (0.1 μg·kg·h, 0.2 μg·kg·h, 5 days) | ||
| ↓ – inhibit or decrease; ↑ – enhance or increase; ‘−‘ – no effects; N/A – not available. DEX – dexmedetomidine; PND – postoperative neurocognitive disorders; POCD – postoperative cognitive dysfunction; POD – postoperative delirium; IL – interleukin; TNF-α – tumor necrosis factor-α; S100β – S100 calcium binding protein B; CRP – C-reaction protein; Aβ – amyloid β-protein; p-Tau – phosphorylated microtubule associated protein Tau; PSD95 – postsynaptic density protein; SOX2 – SRY-Box transcription factor 2; Tbr1/2 – T-Box brain transcription factor 1; Prox1 – Prospero Homeobox 1; Nrp1 – Neuropilin 1; Nrg1 – Neuregulin 1; Syp – Synaptophysin; Sema3a/f – semaphorin 3A; NF-κB – nuclear factor kappa-B; Bax – B-cell lymphoma 2 associated x; MCP-1 – monocyte chemoattractant protein-1; HIF-α – hypoxia inducible factor 1 subunit alpha; PKM2 – pyruvate kinase isozyme type M2; PI3K – phosphoinositide-3 kinase; AKT – protein kinase B; Fas – fas cell surface death receptor; c-Fos – fos proto-oncogene; Bcl-2 – B-cell lymphoma 2; GSK-3β – glycogen synthase kinase-3β; Bcl-xL – B-cell lymphoma extra large; Bad – Bcl-2-associated death promoter; mTOR – mammalian target of rapamycin; GLT-1 – major glutamate transporter; GABABR1 – γ-Aminobutyric acid B receptor 1; GABABR2 – γ-Aminobutyric acid B receptor 2; cAMP – cathelicidin antimicrobial peptide; PKA – protein kinase A; CREB – responsive element binding protein; p-CREB – phosphorylated CREB; BDNF – brain derived neurotrophic factor; YAP1 – Yes-associated protein 1; JAG1 – Jagged 1; MAPK – mitogen-activated protein kinase; ASA – American Society of Anesthesiologist. | ||||