Melatonin Reduces Hypoglycemia-Induced Neuronal Death in Rats.

Melatonin, N-aceyl-5-methoxytryptamine, is the main secretory product of the pineal gland and has neuroprotective effects on several brain injuries, including ischemic stroke. In the present study, we hypothesized that exogenous melatonin may decrease hypoglycemia-induced neuronal death through the prevention of superoxide generation. To test our hypothesis, hypoglycemia was induced by injecting human insulin (10 U/kg, i.p.) in rats. Melatonin injection was started immediately after hypoglycemia (10 mg/kg, i.p.). The first melatonin injection was performed at the end of a 30-min isoelectric EEG period. The second and third injections were administered at 1 and 3 h after the first injection. Reactive oxygen species generation, as detected by dihydroethidium staining, was significantly reduced by melatonin treatment. Neuronal injury was reduced by the treatment of melatonin in the hippocampal CA1 and dentate granule cells. Microglia activation was robust in the hippocampus after hypoglycemia, which was almost completely prevented by melatonin treatment. Hypoglycemia-induced cognitive impairment was also significantly prevented by melatonin treatment. The present study suggests that melatonin has therapeutic potential to prevent hypoglycemia-induced brain injury.

A prospective, randomized, double-blind, multicenter trial to evaluate the therapeutic efficacy and safety of palonosetron in the treatment of postoperative nausea and vomiting over a 72-h period.

PURPOSE: We performed a multicenter, randomized, double-blind trial to assess the efficacy and safety of a single, fixed, intravenous dose of palonosetron (0.075 mg) in the treatment of established postoperative nausea and vomiting (PONV). METHODS: Three hundred and eighty-four patients who had at least one risk factors of PONV and underwent surgery under general anesthesia were screened. Those who developed PONV were randomized to receive either 0.075 mg intravenous palonosetron or a placebo. The incidence of nausea and vomiting, severity of nausea, requirements for rescue anti-emetics, and adverse effects at 2, 24, and 72 h after drug administration were evaluated. Complete response (CR) and complete control (CC) rate were compared for 24 and 72 h. RESULTS: Among the 384 patients, 152 (39.6 %) developed PONV and were randomized to either the palonosetron (n = 75) or placebo (n = 77) group. The number of patients with CR at 24 and 72 h was higher in the palonosetron group than the placebo group [0-24 h: n = 49 (68.1 %) vs. n = 30 (40.5 %), p < 0.001; 0-72 h: n = 47 (65.3 %) vs. n = 28 (37.8 %), p < 0.001]. The incidence of PONV at 2, 24, and 72 h periods was lower in the palonosetron group than the placebo group (29.2, 45.8, and 50.0 % in the palonosetron group vs. 50.0, 62.2, and 66.2 % in the placebo group, p = 0.010, 0.048, 0.047, respectively). The incidence of adverse events was not different between the groups. CONCLUSION: A single 0.075 mg IV dose of palonosetron effectively increased the CR rates at 24 and 72 h in these moderate-risk patients with established PONV.

Effect of perioperative intravenous ibuprofen versus acetaminophen on postoperative opioid consumption and pain after general anesthesia: a systematic review and meta-analysis with trial sequential analysis of randomized controlled trials.

BACKGROUND: Ibuprofen and acetaminophen are widely used as adjuvant analgesics for postoperative pain. This meta-analysis compared the effects of intravenous (IV) ibuprofen and acetaminophen on postoperative opioid consumption and pain intensity after general anesthesia. METHODS: PubMed/MEDLINE, EMBASE, and Cochrane Library databases were searched to identify relevant studies published up to May 2023. Randomized controlled trials comparing the effects of perioperative IV ibuprofen and acetaminophen on postoperative opioid consumption and pain after general anesthesia were included in the meta-analysis and trial sequential analysis (TSA). RESULTS: Eight studies with 494 participants were included. Compared to IV acetaminophen, IV ibuprofen significantly reduced 24 h opioid consumption, presented as morphine equivalents (mean difference [MD]: -6.01 mg, 95% CI [-8.60, -3.42], P < 0.00001, I2 = 55%), and pain scores (on a scale of 0-10) at 4-6 h (MD: -0.83, 95% CI [-1.29, -0.37], P = 0.0004, I2 = 65%) and 12 h (MD: -0.38, 95% CI [-0.68, -0.08], P = 0.01, I2 = 11%) postoperatively. These results were statistically significant in TSA. Pain scores at 24 h postoperatively and side effects were not significantly different between the two groups in the meta-analysis, and TSA revealed that the sample size was too small to adequately evaluate the effects, requiring further studies for conclusive results. CONCLUSIONS: Perioperative IV ibuprofen reduced 24 h opioid consumption and pain severity up to 12 h postoperatively compared to acetaminophen. Additional research is required to assess pain intensity beyond 12 h and side effects.

Treatment of postural headache occurred 26 days after spinal pain procedure - A case report.

BACKGROUND: Cerebrospinal fluid (CSF) leakage may cause intracranial hypotension and postural headache. Secondary intracranial hypotension may result from an iatrogenic dural puncture or traumatic injury associated with pain procedures. CASE: A 45-year-old male developed a headache 26 days after spinal pain procedure. Headache was characterized as postural, worsening with standing or sitting and improving while lying down. The pain did not resolve despite the administration of oral and intravenous analgesics. A spinal magnetic resonance imaging revealed epidural venous congestion and a suspicious CSF leak around the left L4/5 level. The patient received an epidural blood patch (EBP), the headache improved dramatically, and the patient was discharged. CONCLUSIONS: Delayed postural headaches may not be directly related to pain management. Nevertheless, intracranial hypotension related to pain management should be suspected even in this case. If confirmed, quickly applying an EBP is an effective treatment option.

Secondary migration of a pre-existing central venous catheter due to a Swan-Ganz catheter insertion - A case report.

BACKGROUND: The entanglement of multiple central venous catheters is a rare and seriouscomplication. The Swan-Ganz catheter is a responsible for various cases. CASE: A 66-year-old male patient was under general anesthesia for a coronary artery bypassgraft surgery. As he had a pre-existing Perm catheter in the right subclavian vein, a SwanGanz catheter was inserted into the left internal jugular vein. Chest radiograph after catheterplacement revealed that the Perm catheter had migrated to the left brachiocephalic vein.The surgeon attempted to reposition it manually, but postoperative radiograph showed thatit had rolled into a loop. On postoperative day 1, radiological intervention was performed tountangle the loop, which was successful. CONCLUSIONS: After placing a Swan-Ganz catheter in patients with a pre-existing central venous catheter, the presence of entanglement should be assessed. In such cases, radiology-guided correction is recommended, as a blind attempt to disentangle can aggravate thecondition.

Prevention of hypoglycemia-induced neuronal death by minocycline.

Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients.

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats.

BACKGROUND: Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment. METHODS: The experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia. RESULTS: The present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non-diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin. CONCLUSION: The present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury.

Psychogenic coma after general anesthesia with remimazolam and remifentanil -a case report.

BACKGROUND: Delayed emergence from general anesthesia is associated with life-threatening conditions with pharmacological, neurological, metabolic, and rarely, psychiatric causes. This case report was presented to report psychogenic coma after recovery from anesthesia with remimazolam and remifentanil. CASE: An elderly woman was unresponsive after recovery from anesthesia with remimazolam and remifentanil. Physical examination, laboratory testing, and radiographic imaging did not reveal any obvious organic causes. Pharmacological or metabolic abnormalities were not found. Absence of those causes strongly suggests that prolonged unconsciousness is related to psychiatric origin. The patient spontaneously regained consciousness after 48 h without any neurological complications. CONCLUSIONS: Anesthesiologists should be aware of the possibility of psychogenic coma for patients with unexplained delay in emergence from anesthesia after the exclusion of other causes.

EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia.

EAAC1 is a neuronal glutamate and cysteine transporter. EAAC1 uptake of cysteine provides substrate for neuronal glutathione synthesis, which plays a key role in both antioxidant defenses and intracellular zinc binding. Here we evaluated the role of EAAC1 in neuronal resistance to ischemia. EAAC1(-/-) mice subjected to transient cerebral ischemia exhibited twice as much hippocampal neuronal death as wild-type mice and a corresponding increase in microglial activation. EAAC1(-/-) mice also had elevated vesicular and cytosolic zinc concentrations in hippocampal CA1 neurons and an increased zinc translocation to postsynaptic neurons after ischemia. Treatment of the EAAC1(-/-) mice with N-acetyl cysteine restored neuronal glutathione concentrations and normalized basal zinc levels in the EAAC1(-/-) mice. Treatment of the EAAC1(-/-) mice with either N-acetyl cysteine or with zinc chelators reduced ischemia-induced zinc translocation, superoxide production, and neuron death. These findings suggest that cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function under ischemic conditions.

Novel alternative for submental intubation - A case report.

BACKGROUND: Submental intubation is commonly used during general anesthesia for maxillofacial surgeries as it provides a safe unrestricted surgical access compared to tracheostomy. During submental intubation, soft tissues and blood clots can become lodged in the endotracheal tube. To overcome this problem, we used a laparoscopic trocar. CASE: A 52-year-old male with maxillofacial injury was scheduled to undergo an open reduction and internal fixation. We performed submental intubation using laparoscopic trocar, which created sufficient space for the insertion of the endotracheal tube. Unlike conventional methods, our method did not require any blunt dissection and caused significantly less soft tissue damage and required significantly less time. CONCLUSIONS: Submental intubation with laparoscopic trocar is a one-step method and is quick and easy-to-perform technique with less complications.

A detection of unexpected blood antibody at the time of transfusion was needed, during the operation -A case report-.

To avoid the occurrence of fatal complications of blood transfusion, several tests are implemented before transfusion. The tests include ABO typing, Rh typing, cross-matching test and blood antibody screening test, and in usual they are completed before transfusion. However in the case of repetitive operations done via brief distance, reexamination for blood antibody tends to be omitted. After 2 previous operations, 30 years old male patient showed positive blood antibody screening during the third operation. Although antibody screening test performed before the first operation, no unexpected blood antibody was detected. During the third operation, after the decision to start transfusion was made, it took two hours to find appropriate blood. There was no significant deterioration of patient's condition but the loss of time could lead to critical consequences. We present this case to make anesthesiologists and surgeons aware of possibility of unexpected blood antibody detection after transfusion.

General anesthesia versus monitored anesthetic care with dexmedetomidine for closed reduction of nasal bone fracture.

BACKGROUND: Reduction of nasal bone fracture can be performed under general or local anesthesia. The aim of this study was to compare general anesthesia (GA) and monitored anesthetic care (MAC) with dexmedetomidine based on intraoperative vital signs, comfort of patients, surgeons and nurses and the adverse effects after closed reduction of nasal bone fractures. METHODS: Sixty patients with American Society of Anesthesiologists physical status I or II were divided into a GA group (n = 30) or MAC group (n = 30). Standard monitorings were applied. In the GA group, general anesthesia was carried out with propofol-sevoflurane-N2O. In the MAC group, dexmedetomidine and local anesthetics were administered for sedation and analgesia. Intraoperative vital signs, postoperative pain scores by visual analog scale and postoperative nausea and vomiting (PONV) were compared between the groups. RESULTS: Intraoperatively, systolic blood pressures were significantly higher, and heart rates were lower in the MAC group compared to the GA group. There were no differences between the groups in the patient, nurse and surgeon's satisfaction, postoperative pain scores and incidence of PONV. CONCLUSIONS: MAC with dexmedetomidine resulted in comparable satisfaction in the patients, nurses and surgeons compared to general anesthesia. The incidence of postoperative adverse effects and severity of postoperative pain were also similar between the two groups. Therefore, both anesthetic techniques can be used during the reduction of nasal bone fractures based on a patient%s preference and medical condition.

Prevention of traumatic brain injury-induced neuron death by intranasal delivery of nicotinamide adenine dinucleotide.

Traumatic brain injury (TBI) is one of the most devastating injuries experienced by military personnel, as well as the general population, and can result in acute and chronic complications such as cognitive impairments. Since there are currently no effective tools for the treatment of TBI, it is of great importance to determine the mechanisms of neuronal death that characterize this insult. Several studies have indicated that TBI-induced neuronal death arises in part due to excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which results in nicotinamide adenine dinucleotide (NAD⁺) depletion and subsequent energy failure. In this study, we investigated whether intranasal administration of NAD⁺ could reduce neuronal death after TBI. Rats were subjected to a weight-drop TBI model that induces cortical and hippocampal neuronal death. The intranasal administration of NAD⁺ (20 mg/kg) immediately after TBI protected neurons in CA1, CA3, and dentate gyrus of the hippocampus, but not in the cortex. In addition, delayed microglial activation normally seen after TBI was reduced by NAD⁺ treatment at 7 days after insult. Neuronal superoxide production and PARP-1 accumulation after TBI were not inhibited by NAD⁺ treatment, indicating that reactive oxygen species (ROS) production and PARP-1 activation are events that occur upstream of NAD⁺ depletion. This study suggests that intranasal delivery of NAD⁺ represents a novel, inexpensive, and non-toxic intervention for preventing TBI-induced neuronal death.

Effect of ulinastatin on the rocuronium-induced neuromuscular blockade.

BACKGROUND: Ulinastatin is a glycoprotein derived from human urine and a serine protease inhibitor found in human urine and blood. Ulinastatin increases both liver blood flow and urine output. Rocuronium is eliminated mainly through the liver and partly through the kidney, hepatic elimination of rocuronium might be enhanced by ulinastatin. We examined the effect of ulinastatin on the neuromuscular block caused by rocuronium. METHODS: Forty four adult patients were randomly divided into two groups of 22 patients each, i.e. the study group and the control group. In the study group, a bolus dose of ulinastatin 5,000 U/kg was administered 2 min before the injection of rocuronium 0.6 mg/kg. In the control group, normal saline was administered instead of ulinastatin. For the monitoring of both onset and recovery from neuromuscular blockade, train-of-four (TOF) and post-tetanic count were used with TOF-Watch Sx. All patients underwent general anesthesia with total intravenous anesthesia (TIVA) of remifentanil and propofol, using the effect site target infusion system. RESULTS: In the study group, the onset of neuromuscular block was significantly slower than in the control group (P < 0.05). The recovery time from the rocuronium injection to the return of PTC was also significantly shorter in the study group than in the control group (P < 0.05). Similarly, times to the return of T1, T2, T3, and T4 (i.e. the first, second, third, and fourth response of TOF) were significantly shorter in the study group than in the control group (P < 0.05). CONCLUSIONS: Ulinastatin significantly delays the onset of neuromuscular block and accelerates the recovery from the block caused by rocuronium.

Frequency of unexpected antibody and consideration during transfusion.

BACKGROUND: In this retrospective study, we measured the frequency of unexpected antibodies in the blood. Specific considerations for preoperative preparations were kept in mind for the patients undergoing surgery positive for these antibodies. METHODS: After reviewing the results of antibody screening tests lasted for 2 years, the frequency of unexpected antibodies was determined. Surgical patients who were positive for unexpected antibodies were selected and divided into two groups based on their potential need for an intra-operative transfusion (groups with high versus low possibility of transfusion). Blood for the high possibility group was prepared before surgery. For the low possibility group for which preoperative blood preparation was not performed, cases of this group were reviewed whether a blood preparation was delayed or not in case of transfusion. RESULTS: Among a total 22,463 cases, 340 (1.52%) had positive results for antibody screening tests. Among the 243 patients who were positive for unexpected antibodies, Lewis, Rh, Xga, and mixed antibodies were found in 85, 25, five, and eight cases, respectively. Out of 243 patients, 117 patients, specificities of the unexpected antibodies were not determined and 125 (51.4%) had a history of pregnancy and delivery, and 49 (20.2%) had a history of transfusion. In the low probability group, transfusions were administered for nine patients; transfusion was delayed for two patients due to difficulties with obtaining matched blood. CONCLUSIONS: Patients with unexpected blood antibodies may be at increased risk for delayed transfusion. For rapid transfusion, it might be helpful to keep a record about blood antibodies and introduce a notification system such as medical alert cards. Preoperative blood preparation is needed for timely intraoperative transfusion.

The comparative study to evaluate the effect of palonosetron monotherapy versus palonosetron with dexamethasone combination therapy for prevention of postoperative nausea and vomiting.

BACKGROUND: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are effective and safe on postoperative nausea and vomiting (PONV). Palonosetron, the newest 5-HT3 antagonist, has potent antiemetic property. We hypothesized that a combination of palonosetron and dexamethasone could more decrease PONV than palonosetron alone. METHODS: Among the patients scheduled to undergo laparoscopic gynecologic surgery, mastoidectomy with tympanoplasty or thyroidectomy under general anesthesia, eighty four female patients with at least two PONV risk factors were enrolled in this study. They were received randomly 0.075 mg palonosetron and 4 mg dexamethasone (group C) or 0.075 mg palonosetron alone (group P). The severity of PONV using Rhodes index and the percentage of complete response during postoperative 24 hours were compared between groups. RESULTS: The frequency of mild/moderate/great/severe PONV based on Rhodes index were 9.8%/0%/0%/0% and 9.3%/2.3%/2.3%/0% in group P and group C, respectively. Complete response for PONV was observed in 90.2% and 86% of patients in group P and group C, respectively. The overall incidence of PONV in group P and C was 9.8% and 14%, respectively. There was no significant difference between the two groups. CONCLUSIONS: There were no differences between palonosetron monotherapy and combination therapy of palonosetron and dexamethasone in patients with high emetogenic risk.

Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration.

Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.

The effect of remifentanil versus N(2)O on postoperative pain and emergence agitation after pediatric tonsillectomy/adenoidectomy.

BACKGROUND: Remifentanil can be an alternative to N(2)O in general anesthesia. Intraoperative remifentanil may lead to acute opioid tolerance. This study aims to assess the effect of remifentanil substituted for 70% N(2)O on postoperative pain in children undergoing tonsillectomy/adenoidectomy. In addition, we evaluated the effect of remifentanil infusion on incidence of emergence agitation in these patients. METHODS: Eighty children, aged 2-12 years, undergoing tonsillectomy/adenoidectomy were randomly allocated to the N(2)O group (Group N; n = 40, sevoflurane and 70% N(2)O) or remifentanil group (Group R; n = 40, sevoflurane with remifentanil infusion at the rate of 0.17 µg/kg/min). In the recovery room, severity of pain and agitation were assessed by an investigator blinded to the assigned group. Time to eye opening and incidence of severe pain and agitation were compared between groups. Logistic regression was used to identify factors related to occurrence of severe pain and agitation. RESULTS: Number of patients with severe postoperative pain was 6 and 16 in groups N and R, respectively (P = 0.012). Incidence of emergence agitation was not significantly different between groups. Remifentanil infusion was a significant factor related to the occurrence of severe postoperative pain (P = 0.015), and age was inversely related to occurrence of emergence agitation (P = 0.001). CONCLUSIONS: In children undergoing tonsillectomy/adenoidectomy, intraoperative remifentanil infusion may increase incidence of severe postoperative pain compared to N(2)O, but it may not affect incidence of emergence agitation.

Reversible airway obstruction caused by changing the size and length of an endotracheal tube in a premature neonate with suspected tracheomalacia -A case report-.

Tracheomalacia is a malformation of the tracheal membranosa. It is maintained during spontaneous breathing but can be altered by bronchoscopy or positive airway pressure. Tracheomalacia is associated with a high mortality and may cause prolonged intubation and ventilation. Here, the case of a 13-day-old infant with jejunoileal stenosis that had surgery is reported. During induction of general anesthesia, endotracheal intubation was attempted several times with different sized endotracheal tubes. Airway obstruction occurred after the endotracheal intubation. After the airway was maintained, the operation was completed. Tracheomalacia was diagnosed after otolaryngology evaluation postoperatively.

Prevention of hypoglycemia-induced neuronal death by hypothermia.

Hypothermia reduces neuronal damage after cerebral ischemia and traumatic brain injury, while hyperthermia exacerbates damage from these insults. Previously we have shown that temperature-dependent modulation of excitotoxic neuronal death is mediated in part by temperature-dependent changes in the synaptic release/translocation of Zn(2+). In this study, we hypothesize that brain temperature also affects hypoglycemia-induced neuronal death by modulation of vesicular Zn(2+) release from presynaptic terminals. To test our hypothesis, we used a rat model of insulin-induced hypoglycemia. Here we found that hypoglycemia-induced neuronal injury was significantly affected by brain temperature, that is, hypothermia inhibited while hyperthermia aggravated neuronal death. To investigate the mechanism of temperature-dependent neuronal death after hypoglycemia, we measured zinc release/translocation, reactive oxygen species (ROS) production, and microglia activation. Here we found that hypoglycemia-induced Zn(2+) release/translocation, ROS production, and microglia activation were inhibited by hypothermia but aggravated by hyperthermia. Even when the insult was accompanied by hyperthermic conditions, zinc chelation inhibited ROS production and microglia activation. Zinc chelation during hyperthermia reduced neuronal death, superoxide production, and microglia activation, which was comparable to the protective effects of hypothermia. We conclude that neuronal death after hypoglycemia is temperature-dependent and is mediated by increased Zn(2+) release, superoxide production, and microglia activation.