Lamotrigine Attenuates Cortical Glutamate Release during Global Cerebral Ischemia in Pigs on Cardiopulmonary Bypass

Background: The dose-response effects of pretreatment with lamotrigine (a phenyltriazine derivative that inhibits neuronal glutamate release) in a porcine cerebral ischemia model during cardiopulmonary bypass were studied.

Methods: Sagittal sinus catheters and cortical microdialysis catheters were inserted into anesthetized pigs. Animals undergoing normothermic cardiopulmonary bypass were pretreated with lamotrigine 0, 10, 25, or 50 mg/kg (n = 10 per group). Fifteen minutes of global cerebral ischemia was produced, followed by 40 min of reperfusion and discontinuation of cardiopulmonary bypass. Cerebral oxygen metabolism was calculated using cerebral blood flow (radioactive microspheres) and arterial-venous oxygen content gradients. Concentrations of microdialysate glutamate and aspartate were quantified; electroencephalographic signals were recorded. After cardiopulmonary bypass, blood and cerebrospinal fluid were sampled for S-100B protein, and a biopsy was performed on the cerebral cortex for metabolic profile.

Results: Lamotrigine caused dose-dependent reductions in systemic vascular resistance so that additional fluid was required to maintain venous return. Concentrations of glutamate and aspartate did not change during reperfusion after 50 mg/kg lamotrigine in contrast to fivefold and twofold increases, respectively, with lower doses. There were no intergroup differences in cerebral metabolism, electroencephalographic scores, cortical metabolites, brain lactate, or S-100B protein concentrations in the cerebrospinal fluid and blood.     

Effects of Pentobarbital and Isoflurane on Conditioned Learning after Transient Global Cerebral Ischemia in Rabbits

Background: The acquisition of a conditioned eyeblink response has been used extensively to study the neurologic substrates of learning and memory. We examined the effects of the anesthetics isoflurane and pentobarbital, or hypothermia (30[degrees]C), on the ability of rabbits to acquire an eyeblink conditioned response after 6.5 min of cerebral ischemia.

Methods: New Zealand white rabbits (n = 48) were randomly assigned to sham, normothermic, hypothermic, isoflurane, or pentobarbital groups. In the normothermic, hypothermic, isoflurane, and pentobarbital groups, 6.5 min of global cerebral ischemia was produced. In animals randomized to the isoflurane and pentobarbital groups, a pattern of burst suppression was achieved on the electroencephalogram before the start of the ischemic episode. Animals in the hypothermia group were cooled to 30[degrees]C before ischemia. Seven days after ischemia, eyeblink training was started using an audible tone presented for 100 ms as the conditioned stimulus. The unconditioned stimulus was an air puff directed at the cornea. The delay between the end of conditioned stimulus and the start of the unconditioned stimulus (the trace interval) was 300 ms in duration. A conditioned response was defined as an eyeblink that was initiated during the trace interval. Eighty trials per day and 15 days of training were delivered.

Results: Neurologic deficits were greatest in the normothermia group, and these animals also had fewer conditioned responses than those in the sham, hypothermia, or pentobarbital groups. Animals in the isoflurane group had an intermediate number of conditioned responses that was not significantly different from the normothermia group.     

Effects of Temperature on Cerebral Tissue Oxygen Tension, Carbon Dioxide Tension, and pH during Transient Global Ischemia in Rabbits

Background: A decrease in brain temperature (Tbrain) causes a decrease in the cerebral metabolic rate for oxygen (CMRO2) and provides potent neuroprotection against ischemic damage. In the present study, the effects of mild to moderate hypothermia on cerebral tissue oxygen tension (PO2 brain), carbon dioxide tension (PCO2 brain), and pH (pHbrain) were monitored during short episodes of global cerebral ischemia.

Methods: After approval by the Animal Care and Use Committee, 10 New Zealand white rabbits were anesthetized (1% halothane in air) and mechanical ventilation was adjusted to maintain the arterial carbon dioxide tension at 35 mmHg (alpha-stat). A sensor to measure PO2 brain, PCO2 brain, pHbrain, and Tbrain was inserted into the brain through a burr hole in the skull. Tbrain was adjusted to 38 [degree sign] Celsius, 34.4 [degree sign] Celsius, and 29.4 [degree sign] Celsius in a random sequence in each animal. PO2 brain, PCO sub 2 brain, and pHbrain (all variables are reported at the actual Tbrain) were recorded every 10 s during a 5-min baseline, 3 min of cerebral ischemia induced by inflation of a neck tourniquet, and 10 min of reperfusion at each level of Tbrain. Analysis of variance and Dunnett's test were used for statistical analysis. Data are presented as means +/- SD.

Results: During ischemia, PO2 brain decreased from 56 +/- 3 to 33 +/- 2 mmHg at 38 [degree sign] Celsius, from 58 +/- 3 to 32 +/- 3 mmHg at 34.4 [degree sign] Celsius, and from 51 +/- 2 to 32 +/- 2 mmHg at 29.4 [degree sign] C (p = NS). PCO2 brain increased by 6.7 +/- 2 mmHg at 38 [degree sign] Celsius, by 5.1 +/- 1.4 mmHg at 34.4 [degree sign] Celsius, and by 2.3 +/- 0.8 mmHg at 29.4 [degree sign] Celsius. pH sub brain inversely followed the trend of PCO2 brain.     

Effects of Dantrolene on Extracellular Glutamate Concentration and Neuronal Death in the Rat Hippocampal CA1 Region Subjected to Transient Ischemia

Background: Excessive extracellular glutamate produced by cerebral ischemia has been proposed to initiate the cascade toward neuronal cell death. Changes in extracellular glutamate concentration are closely linked to changes in intracellular calcium ion concentration. Dantrolene inhibits calcium release from intracellular calcium stores. In this study, the authors investigated the effects of dantrolene on extracellular glutamate accumulation and neuronal degeneration in a rat model of transient global forebrain ischemia.

Methods: Male Wistar rats weighing 230-290 g were anesthetized with halothane in nitrous oxide-oxygen and were subjected to 10 min of transient forebrain ischemia using a four-vessel occlusion technique. Fifteen minutes before ischemic injury, dantrolene sodium (5 mm), dimethyl sulfoxide as a vehicle for dantrolene, or artificial cerebrospinal fluid as a control was intracerebroventricularly administered (n = 8 in each group). In the hippocampal CA1 subfield, the extracellular glutamate concentration in vivo was measured during the periischemic period with a microdialysis biosensor, and the number of intact neurons was evaluated on day 7 after reperfusion.

Results: Both dantrolene and dimethyl sulfoxide significantly reduced the ischemia-induced increase in glutamate concentration to a similar extent, i.e., by 53 and 51%, respectively, compared with artificial cerebrospinal fluid (P < 0.01). The number of intact hippocampal CA1 neurons (mean +/- SD; cells/mm) in dantrolene-treated rats (78 +/- 21) was significantly higher than that in artificial cerebrospinal fluid- (35 +/- 14;P < 0.001) and dimethyl sulfoxide-treated (56 +/- 11;P < 0.05) animals. Dimethyl sulfoxide also significantly increased the number of preserved neurons in comparison with artificial cerebrospinal fluid (P < 0.05).     

Fosphenytoin Reduces Hippocampal Neuronal Damage in Rat Following Transient Global Ischemia

Summary Fosphenytoin, a water-soluble disodium phosphate ester of phenytoin, is a phenytoin prodrug with similar anticonvulsant properties. In this study, we evaluated its neuroprotective properties in a cardiac arrest-induced global ischemia model. After 12 minute ischemia, Long-Evans hooded rats were resuscitated, given fosphenytoin (30 mg/kg, i.m.) or saline 5 minutes after the ischemic episode, and killed on day 7. Brains were removed, fixed, and vibratome sectioned to assess the numbers of normal appearing CAI pyramidal neurons and for immunohistological staining of glial fibrillary acidic protein (GFAP). After global ischemia, the number of hippocampal CA1 pyramidal neurons decreased significantly (from 14.33±1.73 to 2.19±0.16 per 100 μm²). Most hippocampal CA1 pyramidal neurons showed signs of injury and GFAP immunoreactivity of the region increased. With fosphenytoin treatment 5 min after ischemia, hippocampal CA1 pyramidal neurons remained at near control level (13.90±0.92), however, GFAP staining was not significantly changed. Our data, although indicating different neuronal and glial responses following fosphenytoin treatment, nevertheless, suggest that fosphenytoin is an effective neuroprotectant against ischemia-induced damage.     

头部重点低温对完全性缺血后兔脑细胞胞浆酶变化的影响

本研究观察了头部重点低温（ＳＨＣ）对兔脑完全性缺血后再灌流时胞浆酶变化的影响。结论：再灌流后尽早实施ＳＨＣ，仍能有效防止脑胞浆酶的泄漏，这将有利于脑细胞的复苏。     

Neuroprotective Effects of Dexmedetomidine in the Gerbil Hippocampus after Transient Global Ischemia

Background: Cerebral ischemia induces a massive release of norepinephrine associated with neuronal death in the brain. It has been demonstrated that alpha2 -adrenoceptor agonists decrease the release and turnover of noradrenaline, and this might prove advantageous in counteracting the neurodegeneration in ischemic brain. Therefore, in the present study, the authors tested whether dexmedetomidine, a selective alpha2 -receptor agonist, has neuroprotective effects in a gerbil transient global ischemia model.

Methods: Ischemia was induced by bilateral carotid occlusion for 5 min in diethylether-anesthetized normothermic gerbils. Dexmedetomidine was administered subcutaneously in four different treatment paradigms (6-8 animals/group): 3 or 30 micro gram/kg 30 min before and thereafter at 3, 12, 24, and 48 h after the occlusion, or 3 or 30 micro gram/kg at 3, 12, 24, and 48 h after the occlusion. Control animals were subjected to forebrain ischemia but received only saline injections. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in the CA1 and CA3 regions of the hippocampus and in the hilus of the dentate gyrus was evaluated in silver-stained 60-micro meter coronal sections.

Results: Compared with saline-treated ischemic animals, dexmedetomidine at a dose of 3 micro gram/kg given before and continued after the induction of ischemia reduced the number of damaged neurons in the CA3 area (2 +/- 3 vs. 17 +/- 20 degenerated neurons/mm2; P <0.05). Also in the dentate hilus, the number of damaged neurons was reduced by dexmedetomidine (3 micro gram/kg) given before and continued after ischemia (5 +/- 7 vs. 56 +/- 42 degenerated neurons/mm2; P <0.01).     

Effects of Delayed Administration of Low-dose Lidocaine on Transient Focal Cerebral Ischemia in Rats

Background: The authors' previous study demonstrated that a clinical antiarrhythmic dose of lidocaine, when given before ischemia, is neuroprotective in a rat model of transient focal cerebral ischemia. In this study, the authors investigated whether the administration of this dose of lidocaine, when delayed until 45 min after the onset of ischemia, also reduces ischemic brain injury.

Methods: Lidocaine was administered as an intravenous bolus (1.5 mg/kg) followed by an intravenous infusion (2 mg [middle dot] kg-1 [middle dot] h-1) for 165 min, beginning 45 min after the onset of a 90-min period of transient focal cerebral ischemia. Control animals were given the same volume of saline. Focal cerebral ischemia was induced by occluding the right middle cerebral artery using an intraluminal suture. Neurologic outcome and body weight loss were quantified 7 days later. The brain was fixed 7 days after ischemia and brain sections were stained with hematoxylin and eosin for assessment of infarct size and the number of intact neurons. In separate experiments, local cerebral blood flow and the electroencephalogram were measured during ischemia and 180 min into the reperfusion period. Infarct size was assessed after 24 h.

Results: Infarct size, at either 24 h or 7 days after ischemia, was not significantly reduced in the lidocaine group. However, the number of intact neurons was significantly increased in both the ischemic penumbra and core of the lidocaine group 7 days after ischemia, compared with the vehicle group. Rats treated with lidocaine demonstrated better neurologic outcome and less weight loss (P < 0.05). Lidocaine treatment had no significant influence on local cerebral blood flow and electroencephalogram during ischemia and reperfusion.     

Neuroprotective Effect of Low-dose Lidocaine in a Rat Model of Transient Focal Cerebral Ischemia

Background: A low concentration of lidocaine (10 [mu]m) has been shown to reduce anoxic damage in vitro. The current study examined the effect of low-dose lidocaine on infarct size in rats when administered before transient focal cerebral ischemia.

Methods: Male Wistar rats (weight, 280-340 g) were anesthetized with isoflurane, intubated, and mechanically ventilated. After surgical preparation, animals were assigned to lidocaine 2-day (n = 10), vehicle 2-day (n = 12), lidocaine 7-day (n = 13), and vehicle 7-day (n = 14) groups. A 1.5-mg/kg bolus dose of lidocaine was injected intravenously 30 min before ischemia in the lidocaine 2-day and 7-day groups. Thereafter, an infusion was initiated at a rate of 2 mg [middle dot] kg-1 [middle dot] h-1 until 60 min of reperfusion after ischemia. Rats were subjected to 90 min of focal cerebral ischemia using the intraluminal suture method. Infarct size was determined by image analysis of 2,3,5-triphenyltetrazolium chloride-stained sections at 48 h or hematoxylin and eosin-stained sections 7 days after reperfusion. Neurologic outcome and body weight loss were also evaluated.

Results: The infarct size was significantly smaller in the lidocaine 2-day group (185.0 +/- 43.7 mm3) than in the vehicle 2-day group (261.3 +/- 45.8 mm3, P < 0.01). The reduction in the size of the infarct in the lidocaine 7-day group (130.4 +/- 62.9 mm3) was also significant compared with the vehicle 7-day group (216.6 +/- 73.6 mm3, P < 0.01). After 7 days of reperfusion, the rats in the lidocaine group demonstrated better neurologic outcomes and less weight loss.     

Effects of Hypothermia, Pentobarbital, and Isoflurane on Postdepolarization Amino Acid Release during Complete Global Cerebral Ischemia

Background: Hypothermia and anesthetics may protect the brain during ischemia by blocking the release of excitatory amino acids. The effects of hypothermia (28 degrees C), pentobarbital, and isoflurane on postischemic excitatory amino acid concentrations were compared.

Methods: Rats were anesthetized with 0.8% halothane/50% N2 O, vascular catheters were placed, and a glass microelectrode and microdialysis cannula were inserted into the cerebral cortex. Experimental groups were: (1) control, pericranial, t = 38 degrees C; (2) hypothermia, t = 28 degrees C; (3) pentobarbital, t = 38 degrees Celsius; and (4) isoflurane, t = 38 degrees C. Halothane/N2 O was continued in groups 1 and 2, whereas a deep burst-suppression or isoelectric electroencephalogram was achieved with the test drugs in groups 3 and 4. Cerebral metabolic rates were similar in groups 2, 3, and 4. After a baseline dialysis sample was collected, animals were killed with potassium chloride. The time to terminal depolarization was recorded, after which three consecutive 10-min dialysate samples were collected. Glutamate, aspartate, gamma-aminobutyric acid, and glycine concentrations were measured using high-performance liquid chromatography.

Results: Times to terminal depolarization were shorter in both pentobarbital and isoflurane groups than with hypothermia (103+/- 15 and 127+/-10 vs. 195+/-20 s, respectively, mean +/-SD). However, times to terminal depolarization in all three groups were longer than in control subjects (control = 70+/-9 s). Postdepolarization concentrations of all compounds were lower in hypothermic animals (vs. normothermic control animals), but no reductions in glutamate, aspartate, or glycine concentrations were noted in pentobarbital or isoflurane groups. gamma-aminobutyric acid concentrations were reduced by both anesthetics, but not to the same degree as with hypothermia.     

神经电生理监测脑血管内栓塞治疗时脑缺血

目的：探讨定量脑电图在脑血管内栓塞治疗时监测脑缺血的作用。方法：１０例颅内血管畸形和动脉瘤进行血管内栓塞治疗的过程行ＥＥＧ功率致密谱阵和体感诱发电位连续监测。结果：ＥＥＧ和ＳＥＰ的变化与中枢神经系统改变的临床观察基本一致，能敏感地检测出脑缺血改变。结论：ｑＥＥＧ是监测栓塞治疗时脑缺血的有效手段。     

Evaluation of a Cerebral Oximeter as a Monitor of Cerebral Ischemia during Carotid Endarterectomy

Background: Stroke is an important contributor to perioperative morbidity and mortality associated with carotid endarterectomy (CEA). This investigation was designed to compare the performance of the INVOS-3100 cerebral oximeter to neurologic function, as a means of detecting cerebral ischemia induced by carotid cross-clamping, in patients undergoing carotid endarterectomy with cervical plexus block.

Methods: Ninety-nine patients undergoing 100 CEAs with regional anesthesia (deep or superficial cervical plexus block) were studied. Bilateral regional cerebrovascular oxygen saturation (rSO2) was monitored using the INVOS-3100 cerebral oximeter. Patients were retrospectively assigned to one of two groups: those in whom a change in mental status or contralateral motor deficit was noted after internal carotid clamping (neurologic symptoms; n = 10) and those who did not show any neurologic change (no neurologic symptoms; n = 90). Data from 94 operations (neurologic symptoms = 10 and no neurologic symptoms = 84) were adequate for statistical analyses for group comparisons. A relative decrease in ipsilateral rSO2 after carotid occlusion (calculated as a percentage of preocclusion value) during all operations (n = 100) was also calculated to determine the critical level of rSO2 decrease associated with a change in neurologic function.

Results: The mean (+/- SD) decrease in rSO2 after carotid occlusion in the neurologic symptoms group (from 63.2 +/- 8.4% to 51.0 +/- 11.6%) was significantly greater (P = 0.0002) than in the no neurologic symptoms group (from 65.8 +/- 8.5% to 61.0 +/- 9.3%). Logistic regression analysis used to determine if a change in rSO2, calculated as a percentage of preclamp value, could be used to predict change in neurologic function was highly significant (likelihood ratio chi-square = 13.7;P = 0.0002). A 20% decrease in rSO2 reading from the preclamp baseline, as a predictor of neurologic compromise, resulted in a sensitivity of 80% and specificity of 82.2%. The false-positive rate using this cutoff point was 66.7%, and the false-negative rate was 2.6%, providing a positive predictive value of 33.3% and a negative predictive value of 97.4%.     

Adenosine: A Sensitive Indicator of Cerebral Ischemia during Carotid Endarterectomy

Background: For the human brain, there are no data available concerning the significance of adenosine and its metabolites as biochemical indicators of cerebral ischemia. Since adenosine may counteract key pathogenetic mechanisms during cerebral ischemia, its sensitivity and specificity as a marker of cerebral ischemia was investigated in relation to hypoxanthine and lactate.

Methods: Arterial and jugular venous concentration changes of adenosine, hypoxanthine, and lactate were studied in 41 patients undergoing carotid endarterectomy. Cerebral tissue oxygenation was monitored continuously by somatosensory-evoked potentials. A carotid artery shunt (n = 6) was placed only after complete loss of somatosensory-evoked potentials.

Results: Before carotid artery clamping jugular venous concentrations of adenosine, hypoxanthine, and lactate in subsequently shunted patients were 229 +/- 88 nM, 1105 +/- 116 nM, and 0.85 +/- 0.52 mM, respectively (mean +/- SD). In patients who required shunting, carotid artery clamping induced a significant increase in jugular venous adenosine (389 +/- 114 nM) and jugular venous hypoxanthine (1444 +/- 168 nM). In contrast, the increase in jugular venous lactate (0.91 +/- 0.48 mM) did not reach statistical significance. Focal cerebral ischemia was indicated by jugular venous adenosine with a sensitivity and specificity of 0.83 and 0.71, respectively.     

Pentoxifylline in Regional Cerebral Ischemia in Cats

The effect of pentoxifylline on regional cerebral ischemia was evaluated in 22 cats. In one group of 10 cats the middle cerebral artery (MCA) was occluded by a transorbital approach, and the cats were maintained on an intensive care protocol for 48 h. Pentoxifylline 10 mg · kg^-1 initiated intravenously 30 niin post-occlusion and followed by 6.3 mg · kg^-1 · h^-1 for 48 h failed to improve the neurologic outcome or infarct size when compared to controls. In another group of 12 cats with the same ischemic lesion, regional cerebral blood flow in the anterior (ischemic) area and an ipsilateral parieto-occipital region was measured by ¹³³Xe wash-out after intra-arterial injection. MCA occlusion reduced the anterior flow by 50% from a mean control value of 62.7 ml · 100 g^-1 · min^-1 to 31.9 ml · 100 g^-1 · min^-1. The parieto-occipital flow was reduced by 20–30%, probably due to diaschisis. Pentoxifylline produced only a brief, although approximately 50%, increase in flow detected over both brain regions and failed to improve the cerebral energy stores as measured 150 min following MCA occlusion. From the neurologic, blood flow and metabolic data, it is concluded that pentoxifylline failed to affect cerebral ischemia favorably in cats.     

Neuroprotective Effects of Riluzole and Ketamine during Transient Spinal Cord Ischemia in the Rabbit

Background: Massive release of central excitatory neurotransmitters is an important initial step in ischemic neuronal injury, and modification of this process may provide neuroprotection. We studied the protective effects of the voltage-dependent sodium channel antagonist riluzole and the N-methyl-d-aspartate receptor antagonist ketamine on hind limb motor function and histopathologic outcome in an experimental model of spinal cord ischemia.

Methods: Temporary spinal cord ischemia was induced by 29 min of infrarenal balloon occlusion of the aorta in 60 anesthetized New Zealand white rabbits. Animals were randomly assigned to one of four treatment groups (n = 15 each): group C, saline (control); group R, riluzole, 8 mg/kg intravenously; group K, ketamine, 55 mg/kg intravenously; group RK, riluzole and ketamine. After reperfusion, riluzole treatment was continued with intraperitoneal infusions. Normothermia (38[degrees]C) was maintained during ischemia, and rectal temperature was assessed before and after intraperitoneal infusions. Neurologic function, according to Tarlov's criteria, was evaluated every 24 h, and infarction volume and the number of eosinophilic neurons and viable motoneurons in the lumbosacral spinal cord was evaluated after 72 h.

Results: Neurologic outcome was better in groups R and RK than in groups C and K. All animals in group C (100%) and all animals but one in group K (93%) were paraplegic 72 h after the ischemic insult versus 53% in group R and 67% in group RK (P < 0.01 each). More viable motoneurons were present in groups R and RK than in controls (P < 0.05).     

氯胺酮对兔脑微循环的影响

应用微循环闭路电视显微系统对１２只兔行颅骨开窗法对软脑膜微循环进行录像。通过直接动态观察发现氯胺酮可显著扩张脑微血管。同时使血流加快，网状毛细血管明显充盈，增多，微血管数目增加，由此引起脑脊液动力学和颅压增高。因此提出，对脑损伤，颅内出血，颅内高压或脑脊液压力异常者应慎用氯胺酮。     

Isoflurane Reduces Ischemia-induced Glutamate Release in Rats Subjected to Forebrain Ischemia

Background: The release of excitatory neurotransmitters during ischemia is thought to contribute to ischemic neuronal injury. Volatile anesthetics have been shown to reduce excitatory neurotransmission in vitro, and it is conceivable that they reduce ischemia-induced neurotransmitter release. The current investigation was conducted to evaluate the effect of isoflurane and N2 O-fentanyl anesthesia on ischemia-induced glutamate release in the rat and to compare it with that of mild hypothermia, an intervention known to reduce glutamate release significantly.

Methods: Microdialysis probes were implanted into the parietal cortex and dorsal hippocampus of four groups of anesthetized rats (n = 5 per group). The hypothermic group was anesthetized with 1.2% halothane. The two isoflurane groups were anesthetized with 0.5 minimum alveolar concentration or electroencephalographic burst-suppression doses of isoflurane ([nearly equal] 2 minimum alveolar concentration). The control group was anesthetized with 70% N2 O-30% Oxygen2 and fentanyl. The pericranial temperature was maintained at 34 degrees Celsius in the hypothermic group and at 38 degrees Celsius in the remaining groups. Ischemia was induced by bilateral carotid artery occlusion with simultaneous hypotension to 35 mmHg for 10 min, followed by a reperfusion period of 70 min. Dialysate was collected before, during, and after ischemia. The concentrations of glutamate and glycine in the dialysate were measured by high-performance liquid chromatography.

Results: Preischemic glutamate and glycine concentrations in the dialysate were similar among the groups. Ischemia resulted in a significant increase in glutamate and glycine concentrations in the N sub 2 O-fentanyl groups in the parietal cortex and in the hippocampus. This increase in neurotransmitter concentrations did not occur in the hypothermic group in either structure. Isoflurane reduced glutamate concentrations in both structures and glycine concentrations in the hippocampus. In the parietal cortex, glycine concentrations did not increase in either isoflurane group.