The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model.
Ayoglu Hilal,Gul Sanser,Hanci Volkan,Bahadir Burak,Bektas Sibel,Mungan Ayca Gorkem,Turan Isil Ozkocak,Acikgoz Bektas
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
We investigated the effect of two different doses of dexmedetomidine on vasospasm in a rat model of subarachnoid haemorrhage (SAH). SAH was induced by injecting 0.3 mL blood into the cisterna magna in all rat groups except the control (Group C). At 1 hour and 24 hours after SAH, 5 microg/kg dexmedetomidine was given to group D5, and 10 microg/kg dexmedetomidine was given to group D10. No medication was administered to the haemorrhage group (Group H). Malondialdehyde (MDA) and paraoxonase (PON) levels were measured at 48 hours after SAH. Mean wall thickness (MWT), mean luminal diameter (MLD), and proliferating cell nuclear antigen (PCNA) expression of the basilar artery were evaluated. MDA levels and MWT were lower in the dexmedetomidine groups. The lowest MDA levels and MWT were found in Group D10. The MLD was lowest in Group H. PCNA expression was observed only in Group D10. We concluded that dexmedetomidine reduces oxidative stress and vasospasm following SAH in a dose-dependent manner.
10.1016/j.jocn.2009.10.012
The neuroprotective effect of dexmedetomidine in the hippocampus of rabbits after subarachnoid hemorrhage.
Cosar Murat,Eser Olcay,Fidan Huseyin,Sahin Onder,Buyukbas Sadik,Ela Yuksel,Yagmurca Murat,Ozen Oguz A
Surgical neurology
BACKGROUND:Subarachnoid hemorrhage is a serious condition, often accompanied by cerebral vasospasm, which may lead to brain ischemia and neurologic deterioration. We evaluated if dexmedetomidine has neuroprotective effects in the hippocampus of vasospastic SAH rabbits or not. MATERIALS AND METHODS:Eighteen New Zealand rabbits were taken. An experimental SAH model was formed by injecting 0.9 mL of autologous arterial blood per 1 kg of body weight to the cisterna magna of 12 rabbits. Craniotomy was performed in the control group (n = 6) except performing experimental SAH. Rabbits in the SAH-alone (n = 6) group were infused with 5 mL.kg(-1).h(-1) 0.9% sodium chloride, and rabbits (n = 6) in the SAH-dexmedetomidine group were infused with 5 microg.kg(-1).h(-1) dexmedetomidine for 2 hours, 48 hours after SAH was established. Rabbits of all groups were sacrificed via penthotal 24 hours after dexmedetomidine administration. Brains were removed immediately, and hippocampal tissues were blocked from the right hemisphere for histopathologic study. In addition to this, hippocampal tissues of left hemispheres were dissected for biochemical analyses to evaluate MDA levels, activity of XO, and SOD. RESULTS:The histopathologic study showed that dexmedetomidine may have a neuroprotective effect in SAH-induced hippocampal injuries. The biochemical parameters support the neuroprotective effect of dexmedetomidine (P < .05). CONCLUSION:Our study showed that dexmedetomidine may have a neuroprotective effect in the hippocampus of vasospastic SAH rabbits.
10.1016/j.surneu.2007.08.020
Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage.
British journal of anaesthesia
BACKGROUND:Dexmedetomidine, a sedative agent, provides neuroprotection when administered during or before brain ischaemia. This study was designed to determine whether dexmedetomidine post-treatment induces neuroprotection against subarachnoid haemorrhage (SAH) and the mechanisms for this effect. METHODS:Subarachnoid haemorrhage was induced by endovascular perforation to the junction of the right middle and anterior cerebral arteries in adult rats. Dexmedetomidine was applied immediately or 2 h after onset of SAH. Neurological outcome was evaluated 2 days after SAH. Right frontal cortex area 1 was harvested 24 h after SAH for western blotting. RESULTS:Subarachnoid haemorrhage reduced neurological scores and increased brain oedema and blood-brain barrier permeability. These effects were attenuated by dexmedetomidine post-treatment. Neuroprotection by dexmedetomidine was abolished by PD98095, an inhibitor of extracellular signal-regulated kinase (ERK) activation. Phospho-ERK, the activated form of ERK, was increased by dexmedetomidine; this activation was inhibited by PD98095. CONCLUSIONS:Dexmedetomidine post-treatment provides neuroprotection against SAH. This effect appears to be mediated by ERK.
10.1093/bja/aev549
Dexmedetomidine Inhibits Gasdermin D-Induced Pyroptosis the PI3K/AKT/GSK3β Pathway to Attenuate Neuroinflammation in Early Brain Injury After Subarachnoid Hemorrhage in Rats.
Frontiers in cellular neuroscience
Subarachnoid hemorrhage (SAH) is one kind of life-threatening stroke, which leads to severe brain damage. Pyroptosis plays a critical role in early brain injury (EBI) after SAH. Previous reports suggest that SAH-induced brain edema, cell apoptosis, and neuronal injury could be suppressed by dexmedetomidine (Dex). In this study, we used a rat model of SAH to investigate the effect of Dex on pyroptosis in EBI after SAH and to determine the mechanisms involved. Pyroptosis was found in microglia in EBI after SAH. Dex significantly alleviated microglia pyroptosis reducing pyroptosis executioner GSDMD and inhibited the release of proinflammatory cytokines induced by SAH. Furthermore, the reduction of GSDMD by Dex was abolished by the PI3K inhibitor LY294002. In conclusion, our data demonstrated that Dex reduces microglia pyroptosis in EBI after SAH the activation of the PI3K/AKT/GSK3β pathway.
10.3389/fncel.2022.899484
Dexmedetomidine attenuated early brain injury in rats with subarachnoid haemorrhage by suppressing the inflammatory response: The TLR4/NF-κB pathway and the NLRP3 inflammasome may be involved in the mechanism.
Yin Dongpei,Zhou Shuai,Xu Xin,Gao Weiwei,Li Fei,Ma Yuyang,Sun Dongdong,Wu Yingang,Guo Qi,Liu Huimin,Han Lulu,Wang Zengguang,Wang Yi,Zhang Jianning
Brain research
Early brain injury (EBI) plays a pivotal role in the prognosis of patients with subarachnoid haemorrhage (SAH). Dexmedetomidine (DEX), a highly selective α receptor agonist, is reported to exert multiple protective effects in many neurological diseases. This study was designed to investigate whether DEX had neuroprotective functions in EBI after SAH, and to explore the possible mechanisms. The SAH model was established by an endovascular perforation in adult male Sprague-Dawley (SD) rats. DEX (25 µg/kg) or vehicle was administered intraperitoneally 2 h after SAH. Neurological deficits, brain oedema, inflammation, BBB damage, and cell apoptosis at 24 h after SAH were evaluated. Additionally, the expression of components of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome were also assessed. We demonstrated that DEX treatment improved neurological scores, alleviated brain oedema, reduced the permeability of the blood-brain barrier (BBB), and up-regulated the expression of tight junction proteins. DEX treatment could reduce the neutrophil infiltration, microglial activation, and pro-inflammatory factor release. In addition, DEX alleviated cell apoptosis at 24 h after SAH. Notably, DEX could also suppress the activation of the TLR4/NF-κB pathway and the NLRP3 inflammasome. These findings suggested that treatment with DEX after SAH attenuated SAH-induced EBI, partially through the suppression of the TLR4/NF-κB pathway and the NLRP3 inflammasome.
10.1016/j.brainres.2018.05.040
Role of Dexmedetomidine in Aneurysmal Subarachnoid Hemorrhage: A Comprehensive Scoping Review.
Journal of neurosurgical anesthesiology
Dexmedetomidine (DEX), an α2-adrenergic agonist, has been widely used for anesthesia, pain control, and intensive care unit sedation. Besides sleep-like sedation, DEX has many other beneficial effects, such as anti-inflammation, antioxidation, and anticell death. Subarachnoid hemorrhage (SAH), a severe and potentially fatal form of stroke, is a complex disease that is divided into 2 phases: early brain injury and delayed cerebral ischemia. In each phase, several pathologic changes are involved, including disturbed intracranial homeostasis, metabolic failure, blood-brain barrier damage, vasospasm, microthrombosis, and cortical spreading depolarization. DEX has been shown to have an effect on these SAH-related pathologic processes. Research shows that DEX could serve as a protective therapy for patients with SAH due to its ability to maintain stable intracerebral homeostasis, balance coagulation-fibrinolysis, repair a damaged blood-brain barrier as well as prevent vasospasm and suppress cortical spreading depolarization by anti-inflammatory, antioxidative, antiapoptotic, and vasoconstriction-dilation effects. In this scoping review, we critically assess the existing data on the potential protective effect of DEX after SAH. So far, only 1 retrospective clinical trial assessing the effect of DEX on clinical outcomes after SAH has been performed. Hence, more trials are still needed as well as translational research bringing results from bench to bedside.
10.1097/ANA.0000000000000728
Association between dexmedetomidine use and neurological outcomes in aneurysmal subarachnoid hemorrhage patients: A retrospective observational study.
Okazaki Tomoya,Hifumi Toru,Kawakita Kenya,Shishido Hajime,Ogawa Daisuke,Okauchi Masanobu,Shindo Atsushi,Kawanishi Masahiko,Miyake Keisuke,Tamiya Takashi,Kuroda Yasuhiro
Journal of critical care
PURPOSE:Recent studies in animal subarachnoid hemorrhage (SAH) models have reported that dexmedetomidine (DEX) use demonstrates significantly better neurological outcomes. This study aimed to evaluate whether DEX use is associated with favorable neurological outcomes (FO) in SAH patients. MATERIALS AND METHODS:We retrospectively reviewed all SAH patients between 2009 and 2017. We calculated the total dosage of DEX administered for the first 24h after admission. All patients were classified into no use, low dosage, and standard dosage group. Multivariate analysis was performed to clarify the association between DEX use and FO (modified Ranking Scale score of 0-2 at hospital discharge). RESULTS:There were 161 patients with 55.3% of FO. On univariate analysis, there were significant differences with regard to age, Hunt and Kosnik (H&K) grade, and DEX use. Multivariate analysis showed that age, H&K grade, and low dosage DEX (rather than no use) (odds ratio (OR) 3.17; 95% confidence interval (CI), 1.24-8.53; p=0.02) were significantly associated with FO. However, standard dosage DEX was not a significant factor (OR, 0.75; 95% CI, 0.25-2.16; p=0.59). CONCLUSIONS:Low dosage DEX during the first 24h after admission was associated with FO in SAH patients.
10.1016/j.jcrc.2017.10.034
Effect of Dexmedetomidine on Cerebral Vasospasm and Associated Biomarkers in a Rat Subarachnoid Hemorrhage Model.
Song Young,Lim Beom Jin,Kim Do-Hyeong,Ju Jin Woo,Han Dong Woo
Journal of neurosurgical anesthesiology
BACKGROUND:The α2 adrenergic agonist dexmedetomidine (DEX) has huge potential for protecting against cerebral vasospasm, a leading cause of death and disability after subarachnoid hemorrhage (SAH). Biomarker assays for SAH have recently emerged as tools for predicting vasospasm and outcomes. We investigated the effects of DEX on vasospasm and assessed relevant biomarkers in a rat SAH model. METHODS:Male Wistar rats were randomly assigned to sham (n=10), vehicle (n=10), SAH (n=10), or SAH+ DEX (n=10) groups. The SAH and SAH+DEX groups received 0.3 mL injections of autologous blood into the cisterna magna, followed by intraperitoneal injections of normal saline or 10 μg/kg DEX. Forty-eight hours later, neurological deficits as well as the basilar artery (BA) wall thickness and cross-sectional area were measured. Cerebrospinal fluid (CSF) and blood samples were obtained to assess concentrations of interleukin (IL)-6, C-reactive protein (CRP), endothelin-1, and S100-β using enzyme-linked immunosorbent assays. RESULTS:The SAH and SAH+DEX groups exhibited deteriorated neurological function as well as structural and morphological BA vasospasm. The SAH+DEX group showed an improved neurological function score (ie, a 52% decrease), a 10% reduction in wall thickness, and a BA cross-sectional area enlarged by 157%. Compared with the sham group, CSF levels of IL-6 and CRP in the SAH and SAH+DEX groups, as well as serum IL-6 and CRP levels in the SAH group, were significantly elevated. The SAH+DEX group showed significantly lower CSF IL-6 levels than the SAH group. Serum and CSF levels of endothelin-1 and S100-β were similar across all groups. CONCLUSIONS:DEX administration reduced the severity of cerebral vasospasm and improved neurological function in SAH rats; this may be closely linked to reduced CSF IL-6 levels.
10.1097/ANA.0000000000000504
Dexmedetomidine attenuates subarachnoid hemorrhage-induced acute lung injury through regulating autophagy and TLR/NFκB signaling pathway.
Korean journal of anesthesiology
BACKGROUND:Acute lung injury (ALI) is the most serious complication of subarachnoid hemorrhage (SAH). We investigated role of autophagy and inflammatory signaling pathways in lung damage and therapeutic effects of dexmedetomidine (DEX). METHODS:Fifty male Wistar rats were randomly divided into five groups: sham, SAH, SAH+ DEX5, SAH+DEX25, and SAH+DEX50. SAH was induced using endovascular perforation technique. All rats received mechanical ventilation for 60 minutes. At 2 and 24 h of SAH induction, SAH+DEX groups were treated with 5, 25, and 50 µg/kg of DEX, respectively. Histological ALI score and pulmonary edema were assessed after 48 h. Lung expression of LC3B, ATG3, p62, TLR4, TLR9, and NFκB was assessed using western blotting and quantitative PCR. Blood levels of IL-6, IL-1β, IFN-γ, and TNFα were also assessed. RESULTS:SAH induced ALI and pulmonary edema, which were attenuated in SAH+DEX5 (P < 0.001 for both) and SAH+DEX25 groups (P = 0.001 and P < 0.001 for ALI and edema, respectively). Lung expressions of LC3B and ATG3 were upregulated in SAH group, which was attenuated in SAH+DEX5 and SAH+DEX25 groups. Lung expressions of TLR4, TLR9, and NFκB were increased in SAH group, which was attenuated in SAH+DEX5 group. Blood IL-6 level was increased in SAH group and attenuated in SAH+DEX5 and SAH+DEX25 groups. Blood IFN-γ level was lower in SAH group than in sham group, and it was increased in SAH+DEX25 group. CONCLUSIONS:Low-dose DEX treatment after SAH may protect against ALI by disrupting pathological brain-lung crosstalk and alleviating autophagy flux and TLR-dependent inflammatory pathways.
10.4097/kja.22165
Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies.
Frontiers in immunology
Intracranial aneurysm subarachnoid hemorrhage (SAH) is a cerebrovascular disorder associated with high overall mortality. Currently, the underlying mechanisms of pathological reaction after aneurysm rupture are still unclear, especially in the immune microenvironment, inflammation, and relevant signaling pathways. SAH-induced immune cell population alteration, immune inflammatory signaling pathway activation, and active substance generation are associated with pro-inflammatory cytokines, immunosuppression, and brain injury. Crosstalk between immune disorders and hyperactivation of inflammatory signals aggravated the devastating consequences of brain injury and cerebral vasospasm and increased the risk of infection. In this review, we discussed the role of inflammation and immune cell responses in the occurrence and development of aneurysm SAH, as well as the most relevant immune inflammatory signaling pathways [PI3K/Akt, extracellular signal-regulated kinase (ERK), hypoxia-inducible factor-1α (HIF-1α), STAT, SIRT, mammalian target of rapamycin (mTOR), NLRP3, TLR4/nuclear factor-κB (NF-κB), and Keap1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/ARE cascades] and biomarkers in aneurysm SAH. In addition, we also summarized potential therapeutic drugs targeting the aneurysm SAH immune inflammatory responses, such as nimodipine, dexmedetomidine (DEX), fingolimod, and genomic variation-related aneurysm prophylactic agent sunitinib. The intervention of immune inflammatory responses and immune microenvironment significantly reduces the secondary brain injury, thereby improving the prognosis of patients admitted to SAH. Future studies should focus on exploring potential immune inflammatory mechanisms and developing additional therapeutic strategies for precise aneurysm SAH immune inflammatory regulation and genomic variants associated with aneurysm formation.
10.3389/fimmu.2022.1027756