Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits?

We performed three sets of experiments to investigate the safety of intrathecal magnesium and to determine its optimal dose for protection, if any, against ischemic spinal cord injury in rabbits. First, we examined neurotoxicity of 0.3, 1, 2, or 3 mg/kg of magnesium sulfate (n = 6 each). Significant sensory dysfunction was observed in the 3-mg/kg group 7 days after administration. Motor dysfunction was found in two rabbits in both the 2- and 3-mg/kg groups. The area of destruction in laminae V-VII was observed in one, two, and one rabbit in the 1-, 2-, and 3-mg/kg groups, respectively. Second, we investigated the temporal profile (6 h, 48 h, and 96 h [n = 3 each]) of histopathologic changes after 3 mg/kg of magnesium sulfate and confirmed similar changes in the rabbits with motor dysfunction at 48 and 96 h. Third, we evaluated the effects of 0.3 mg/kg or 1 mg/kg of magnesium sulfate or saline (n = 6 each) administered before ischemia on hindlimb motor function and histopathology after spinal cord ischemia (15 min). Magnesium did not improve neurologic or histopathologic outcome 96 h after reperfusion. The results indicate that intrathecal magnesium has a risk of neurotoxicity and shows no evidence of protective effects against ischemic spinal cord injury.     

缺血预处理对兔主动脉阻断后脊髓一氧化氮、后肢神经功能和肌电图的影响

目的　探讨缺血预处理 (IPC)对缺血预处理对兔主动脉阻断后脊髓功能和一氧化氮(NO)的影响。方法　 2 4只日本大白兔随机分为假手术组 (A组 )、缺血再灌注组 (B组 )和IPC保护组 (C组 ) ,每组 8只。分别于首次预处理即刻 (C 40 )、缺血即刻 (I0 )、缺血 45min(I45)、再灌注后 60min(R60 )和术后 7d处死动物前即刻 (R7d)采血检测血清和R7d脊髓组织NO的浓度。术后观察后肢神经功能的评分、后肢针电极肌电图 (EMG)和脊髓组织病理学的改变。结果　缺血再灌注损伤后B组血清NO浓度较缺血前和A、C组对应时点值显著升高 (P <0 .0 1)。C组R7d血清NO浓度明显低于其他时点及A组R7d测定值 (P <0 .0 5或 0 .0 1)。B组脊髓组织NO浓度显著高于A、C组(P <0 .0 1)。B组后肢神经功能和脊髓病理学评分均显著性低于A、C组 (P <0 .0 5或 0 .0 1) ,其后肢EMG亦较C组有显著性病理改变 (P <0 .0 1)。结论　IPC对家兔主动脉阻断后脊髓缺血再灌注损伤有良好的保护作用 ,其保护作用机制与抑制NO的生成有关。     

The protective action of chlorpromazine on the spinal cord of rabbits submitted to ischemia and reperfusion is dose-dependent

BACKGROUND: Chlorpromazine (CPZ), at high doses, has been shown to protect the central nervous system in experimental models of ischemia and reperfusion. The purpose of this study was: 1) to investigate the protection afforded by different doses of CPZ on the spinal cord of rabbits submitted to ischemia and reperfusion. 2) to correlate the motor impairment of the hind limbs and the percentage of damaged neurons in the anterior horns of the lumbar spinal cord in treated and untreated animals. METHODS: Seventy-two New Zealand white rabbits were divided into 6 equal groups (n=12): sham operation, control and 4 study groups. Spinal cord ischemia was obtained by clamping the abdominal aorta caudally to the renal arteries for 30 min, after which it was released and the animals were observed for a period of 48 hrs. The control animals received 3 ml/kg of 0.9% NaCl, i.v., 10 min before aorta clamping. The experimental animals received CPZ, i.v., at doses of 2, 1 and 0.5 mg/kg, 10 min before aorta clamping. In one group 1 mg/kg of CPZ was given 10 min before aorta clamping and the same dose was repeated 2 hrs after the beginning of reperfusion. The spinal cord of the control animals and of those who received one CPZ dose of 2 mg/kg was processed for light microscopy examination. RESULTS: Motor scores of the hind limbs, graded 0 to 4, obtained 48 hrs after the beginning of reperfusion showed that CPZ was effective at doses of 2 and 1 mg/kg. No significant difference was observed with the dose of 0.5 mg/kg. However, the best results were obtained with the dose of 2 mg/kg administered in a fractionated manner. Histological examination revealed that at the dose of 2 mg/kg, CPZ protected a significant number of neuronal cells and that motor recovery hardly occurred when the number of damaged neurons exceeded 50%. CONCLUSIONS: 1) The neuroprotective action of CPZ is dose-dependent in the ischemic spinal cord of rabbits. The lower protective dose is 1 mg/kg, which is too high for human beings. 2) There is an inverse correlation between motor recovery and percentage of damaged neurons, and the critical point seems to be between 30% and 50%.     

Collaborative therapy with nebivalol and L-NAME for spinal cord ischemia/reperfusion injury

Postoperative neurologic deficit is the most devastating complication after thoracoabdominal aortic aneurysm repair. Our aim was to investigate whether nebivolol has protective effects during ischemia or reperfusion and the most effective mechanism of protection via inhibiting nitric oxide (NO) release with an NO synthase inhibitor in an experimental model of spinal cord ischemia/reperfusion injury. Spinal cord ischemia was induced by occlusion of the infrarenal aorta for 30 min. Thirty-one rabbits were divided into five groups according to the administration period of nebivolol and/or N(G)-nitro-L-arginine methyl ester (L-NAME): control group; group NI, nebivolol during ischemic period; group NR, nebivolol during reperfusion period; group NILR, nebivolol during ischemic period and L-NAME during reperfusion period; and group LINR, L-NAME during ischemic period and nebivolol during reperfusion period. Blood samples were taken at both ischemia and reperfusion periods to obtain nitrite/nitrate levels. After neurologic evaluation at 24 hr of reperfusion, malondialdehyde (MDA) levels were measured. Neurologic impairment was significantly lower in group LINR (Tarlov score 3.4 +/- 0.6, p < 0.05). MDA levels were lower in nebivolol-treated animals, but the lowest value was achieved in the NR group, 35.6 +/- 2.7 nmol/g (p < 0.001). Nitrite levels were decreased significantly in all nebivolol-treated animals in the reperfusion period, but the lowest value was measured in the LINR group (455 +/- 137 vs. 1,760 +/- 522 nmol/mL, p < 0.001). Prophylactic use of nebivolol reduced neurologic injury, and combining with L-NAME provided the best clinical improvement by attenuating the inflammatory mileu in this experimental model. Combination of nebivolol and L-NAME appears to be an effective option for spinal cord protection against ischemia/reperfusion injury.     

In Which Period of Injury Is Resveratrol Treatment Effective: Ischemia or Reperfusion?

The periods of ischemia and reperfusion represent different characteristics by lack of oxygen and reoxygenation. The aim of this experimental spinal cord injury model was to investigate whether resveratrol has protective effects during ischemia or reperfusion and the mechanism of the protection by using N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase. Rabbits were divided into seven groups according to the time of administration of resveratrol or L-NAME (RI and RR, resveratrol during ischemia or reperfusion; IL and RL, L-NAME during ischemia or reperfusion; RILR, resveratrol during ischemia and L-NAME during reperfusion; LIRR, L-NAME during ischemia and resveratrol during reperfusion; control group). After neurologic evaluation at the twenty-fourth hour of reperfusion, lumbar spinal cords were removed for electron microscopic evaluation, immunohistochemical staining for apoptosis, and malondialdehyde (MDA) and myeloperoxidase (MPO) measurements. The RILR group had the best functional recovery, with a mean 3.6 Tarlov score (P < 0.05), and showed near normal electron microscopic findings (scores of 7.6 +/- 0.9 for the control group and 3.9 +/- 2.9 for the RILR group, P < 0.05). MPO and MDA levels were decreased in all groups compared with the control group, but only the decrement in the RILR group reached statistical significance. Immunohistochemical analysis showed that the groups including resveratrol and L-NAME together had the best staining for apoptosis. Resveratrol exhibits important protection by means of neurologic outcome, histopathologic analysis, and biochemical analysis, especially when used in during ischemia followed by L-NAME administration during reperfusion. Also, resveratrol protects against apoptosis, especially when combined with L-NAME.     

Peri-ischemic aminoguanidine fails to ameliorate neurologic and histopathologic outcome after transient spinal cord ischemia.

Inhibition of neurotoxic events that lead to delayed cellular damage may prevent motor function loss after transient spinal cord ischemia. An important effect of the neuroprotective substance aminoguanidine (AG) is the inhibition of inducible nitric oxide synthase (iNOS), a perpetrator of focal ischemic damage. The authors studied the protective effects of AG on hind limb motor function and histopathologic outcome in an experimental model for spinal cord ischemia, and related these findings to the protein content of iNOS in the spinal cord. Temporary spinal cord ischemia was induced by 28 minutes of infrarenal balloon occlusion of the aorta in 40 anesthetized New Zealand White rabbits. Animals were assigned randomly to two treatments: saline (n = 20) or AG (n = 20; 100 mg/kg intravenously before occlusion). Postoperatively, treatment was continued with subcutaneous injections twice daily (saline or 100 mg/kg AG). Normothermia (38 degrees C) was maintained during ischemia, and rectal temperature was assessed before and after subcutaneous injections. Animals were observed for 96 hours for neurologic evaluation (Tarlov score), and the lumbosacral spinal cord was examined for ischemic damage after perfusion and fixation. Lastly, iNOS protein content was determined using Western blot analysis 48 hours after ischemia in five animals from each group. Neurologic outcome at 96 hours after reperfusion was the same in both groups. The incidence of paraplegia was 67% in the saline-treated group versus 53% in the AG-treated group. No differences in infarction volume, total number of viable motoneurons, or total number of eosinophilic neurons were present between the groups. At 48 hours after reperfusion, iNOS protein content in the spinal cord was increased in one animal in the AG-treated group and in three animals in the control group. The data indicate that peri-ischemic treatment with high-dose AG in rabbits offers no protection against a period of normothermic spinal cord ischemia. There was no conclusive evidence of spinal cord iNOS inhibition after treatment with AG.     

Erdosteine ameliorates neurological outcome and oxidative stress due to ischemia/reperfusion injury in rabbit spinal cord.

OBJECTIVE: Oxygen-derived free radicals have been suggested as important in degeneration after spinal cord ischemia. The aim of this study was to investigate whether erdosteine has a protective effect against spinal cord ischemia during aortic cross clamping. MATERIALS AND METHODS: New Zealand White rabbits (n=21) were divided into three groups. In the ischemia/reperfusion group (I/R) (n=8), the infrarenal aorta of rabbits was cross clamped for 21 min and then reperfused. In erdosteine group, the administration of erdosteine solution (50 mg/kg) was started two days before aortic cross-clamping and rabbits (n=8) were subjected to ischemia and reperfusion. Animals in control group (n=5) underwent a surgical procedure similar to the other groups but the aorta was not clamped. The animals were sacrificed at 72 h and histopathological, and biochemical analyses were carried out on the lumbar spinal cords. RESULTS: Erdosteine treatment was associated with improved neurological function in the postoperative period. Histopathological examination of spinal cord tissues in erdosteine group revealed changes consistent with mild ischemic injury, but rabbits in I/R group with paraplegia had total destruction of the motor neurons. Biochemical analyses of spinal cord tissues, in the I/R group, revealed a significant increase in the superoxide dismutase, xanthine oxidase, adenosine deaminase and myeloperoxidase activities, and a significant depletion in glutathione peroxidase activity when compared to that of control rabbits. Erdosteine treatment prevented the increase of all these enzymes except adenosine deaminase. Ischemia/reperfusion produced a significant increase in the tissue malondialdehyde levels. Ischemia/reperfusion-induced increments in malondialdehyde content of the spinal cord were significantly prevented by erdosteine treatment. CONCLUSIONS: The present study demonstrated that erdosteine treatment before aortic cross clamping ameliorates neurological outcome, neuronal injury and oxidative stress in the rabbit spinal cord.     

The role of nitric oxide synthase inhibition in the adverse effects of etomidate in the setting of focal cerebral ischemia in rats

We evaluated the effect of N(G)-nitro-L-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and L-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/L-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and L-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/L-NAME, an EEG burst suppression dose of etomidate and L-NAME (30 mg/kg); or e/L-NAME/arg, an EEG burst suppression dose of etomidate, L-NAME (30 mg/kg), and L-arginine (bolus of 300 mg/kg with an infusion at 35 mg x kg(-1) x min(-1)). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm(3), mean +/- sd) was larger in the etomidate group (153 +/- 17) than the halothane anesthetized h/control group (93 +/- 16) (P < 0.05) but did not differ between the e/L-NAME (162 +/- 17) and h/L-NAME groups (155 +/- 26). Injury volume in the e/L-NAME/arg group (88 +/- 15) was not different from the h/control group (93 +/- 16) and was less than that in either the etomidate or the e/L-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with L-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 +/- 17 versus 155 +/- 26). Administration of a large dose of L-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.     

Acute remote ischemic preconditioning II: the role of nitric oxide

The purpose of this study was to determine whether nitric oxide (NO) plays a role in the mechanism of acute "classic" as well as acute remote ischemic preconditioning (IP). Thirty-two male Wistar rats were divided into five experimental groups. The rat cremaster flap in vivo microscopy model was used for assessment of ischemia/reperfusion injury. In the control group (CG, n = 8), a 2-hr flap ischemia was induced after preparation of the cremaster muscle. The animals of group NO (n = 6) received 500 nmol/kg of the NO-donor spermine/nitric oxide complex (Sper/NO) intravenously 30 min prior to ischemia. The group LN + P (L-NAME + preclamping, n = 6) received 10 mg/kg Nomega-nitro-L-arginine methyl ester (L-NAME) intravenously before preclamping of the flap pedicle (10-min cycle length, 30-min reperfusion). L-NAME (10 mg/kg) was administered in group LN + T (L-NAME + tourniquet, n = 6) before ischemia of the right hindlimb was induced, using a tourniquet for 10 min after flap elevation. The limb was then reperfused for 30 min. Thereafter, flap ischemia was induced in each group as in group CG. In vivo microscopy was performed after 1 hr of flap reperfusion in each animal. Group NO demonstrated a significantly higher red blood cell velocity (RBV) in the first-order arterioles and capillaries, a higher capillary flow, and a decreased number of leukocytes adhering to the endothelium (stickers) of the postcapillary venules by comparison to all other groups (P < 0.05). The average capillary RBV and capillary flow were still higher in the CG than in the groups receiving L-NAME (P < 0.05). The data show that NO plays an important role in the mechanism of both acute "classic" as well as acute remote IP, since the administration of a NO-donor previous to ischemia simulates the effect of IP, whereas the nonspecific blocking of NO synthesis by L-NAME abolishes the protective effect of flap preconditioning.     

Anesthetic preconditioning with sevoflurane does not protect the spinal cord after an ischemic-reperfusion injury in the rat

Anesthetic preconditioning (APC) is a protective mechanism, whereby exposure to a volatile anesthetic renders a tissue resistant to a subsequent ischemic insult. We hypothesized that APC of the rat spinal cord with sevoflurane would reduce neurologic deficit after an ischemic-reperfusion injury. Rats were randomly assigned to 1 of 5 groups. The ischemic preconditioning (IPC) group (n = 14) had 3 min of IPC, 30 min of reperfusion, and 12 min of ischemia. The chronic APC (cSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane on each of 2 days before ischemia. The acute APC (aSEVO) group (n = 14) had 1 h of APC with 3.5% sevoflurane followed by a 1-h washout period before the induction of ischemia. The controls (n = 14) underwent no preconditioning before ischemia. IPC attenuated the ischemia-reperfusion injury, whereas aSEVO and cSEVO groups were no better than control animals. Histologic evaluation of the spinal cord showed severe neurologic damage in all groups except for the IPC group and sham-operated rats. APC with sevoflurane did not reduce neurologic injury in a rat model of spinal cord ischemia. Traditional ischemic preconditioning had a strong protective benefit on neurologic outcome.     

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

STUDY DESIGN: Randomized study. OBJECTIVES: To evaluate the effects of thalidomide on spinal cord ischemia/reperfusion injury via reduced TNF-alpha production. SETTING: Animal experimental laboratory, Clinical Research Institute of Seoul National University Hospital, Seoul, Korea. METHODS: Spinal cord ischemia was induced in rabbits by occluding the infrarenal aorta. Rabbits in group N did not undergo ischemic insult, but rabbits in groups C (the untreated group), THA, and THB underwent ischemic insult for 15 min. The THA and THB groups received thalidomide (20 mg/kg) intraperitoneally (i.p.) before ischemia, but only the THB group received thalidomide (i.p., 20 mg/kg) after 24 and 48 h of reperfusion. After evaluating neurologic functions at 1.5 h, 3, and 5 days of reperfusion, rabbits were killed for histopathologic examination and Western blot analysis of TNF-alpha. RESULTS: The THA and THB groups showed significantly less neurologic dysfunction than the C group at 1.5 h, 3, and 5 days of reperfusion. The number of normal spinal motor neurons in ventral gray matter was higher in THA and THB than in C, but no difference was observed between THA and THB. Western blot analysis showed a significantly higher level of TNF-alpha in C than in THA and THB at 1.5 h of reperfusion, but no difference was observed between C, THA, or THB at 3 or 5 days of reperfusion. CONCLUSION: Thalidomide treatment before ischemic insult reduces early phase ischemia/reperfusion injury of the spinal cord in rabbits.     

Nitric oxide synthesis inhibition modifies the cardiotoxicity of tetracaine and lidocaine

Suppression of nitric oxide (NO) production alters the toxicity of cocaine and bupivacaine. We undertook this study to determine whether the systemic toxicity of two other local anesthetics that differ in antiarrhythmic activity, plasma clearance, and biotransformation are similarly affected by nitric oxide synthase (NOS) inhibition. Sprague-Dawley rats anesthetized with 70% N2O and 0.5% halothane mixed with O2 were pretreated with saline (0.2 mL x kg(-1) x min(-1) i.v.) or N(omega)-nitro-L-arginine methyl ester (L-NAME; a competitive inhibitor of NOS) (2 mg x kg(-1) x min(-1) i.v.) for 30 min. The animals were then given tetracaine (3 mg x kg(-1) x min(-1) i.v.) or lidocaine (8 mg x kg(-1) x min(-1) i.v.) until cardiac arrest (asystole). Doses of lidocaine or tetracaine that produced arrhythmias, seizures, isoelectric encephalogram, and asystole were determined. Hemodynamic recordings were performed throughout the experiments, and plasma was collected to measure the concentration of lidocaine or tetracaine. L-NAME decreased tetracaine and lidocaine doses that produced arrhythmias (> or = 2 degrees atrioventricular conduction block) (tetracaine 14 +/- 2 mg/kg; lidocaine 102 +/- 9 mg/kg) versus saline treatment (tetracaine 28 +/- 2 mg/kg; lidocaine 136 +/- 9 mg/kg; P < 0.05). The tetracaine and lidocaine doses required to produce asystole were also smaller in animals with L-NAME pretreatment than those in saline-pretreated animals. L-NAME reduced the arrhythmia dose of tetracaine more than the arrhythmia dose of lidocaine (28 of 14 = 2.0 fold and 136 of 102 = 1.3-fold). The plasma concentration of lidocaine, but not tetracaine, was significantly higher at each sample time in L-NAME-pretreated animals than in saline-pretreated animals. Inhibition of NOS by L-NAME enhances the cardiotoxicity of lidocaine and tetracaine, with a greater effect on tetracaine than on lidocaine. Altered drug clearance by L-NAME was insufficient to explain these findings because L-NAME pretreatment increased the plasma levels of only lidocaine, not tetracaine. Implications: Inhibition of nitric oxide production in rats markedly enhances the cardiovascular toxicity of lidocaine and tetracaine. Altered drug clearance by N(omega)-nitro-L-arginine methyl ester was insufficient to explain these findings because N(omega)-nitro-L-arginine methyl ester pretreatment increased the plasma levels of only lidocaine, not tetracaine.     

一氧化氮合成酶抑制剂对大鼠损伤脊髓血流及功能的影响

通过Nystrom脊髓后路压迫模型（35．0g／10min）造成脊髓中度损伤，应用激光多普勒血流仪观测了大鼠伤前30min，蛛网膜下腔注射生理盐水及亚硝基左旋精氨酸甲酯（L－NAME）0．15mg、1．5mg三组动物伤后局部脊髓血流的动态变化，并评定了伤后4周神经功能恢复情况。结果发现，L－NAME0.15mg短时间内抑制了脊髓血流，而L－NAME1．5mg较长时间抑制了脊髓血流。4周后L－NAME0．15mg组脊髓功能优于盐水组，而L－NAME1．5mg组脊髓功能较盐水组差。结果提示，适量的L－NAME由于短时间限制了一氧化氮（NO）的释放，有利于神经功能恢复；大剂量的L－NAME由于持续抑制了NO释放而致脊髓损伤加重。     

The effects of FK506 on neurologic and histopathologic outcome after transient spinal cord ischemia induced by aortic cross-clamping in rats

Spinal cord injury is a devastating complication of thoracoabdominal aortic surgery. We investigated the effect of the immunosuppressant FK506, a macrolide antibiotic demonstrated to have neuroprotective effects in cerebral ischemia models, in a rat model of transient spinal cord ischemia. Spinal cord ischemia was induced in anesthetized rats by using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy. Experimental groups were as follows: sham-operation; control, receiving only vehicle; FK506 A, receiving FK506 (1 mg/kg IV) before clamping; and FK506 B, receiving FK506 (1 mg/kg IV) at the onset of reperfusion. Neurologic status was assessed at 24 h and then daily up to 96 h with a 0 to 6 scale (0, normal function; 6, severe paraplegia). Rats were randomly killed at 24, 48, or 96 h, and spinal cords were harvested for histopathology. Physiologic variables did not differ significantly among experimental groups. All control rats suffered severe and definitive paraplegia. FK506-treated rats had significantly better neurologic outcome compared with control. Histopathologic analysis disclosed severe injury in the lumbar gray matter of all control rats, whereas most FK506-treated rats had less injury. These data suggest that FK506 can improve neurologic recovery and attenuate spinal cord injury induced by transient thoracic aortic cross-clamping. IMPLICATIONS: A single dose-injection of the immunosuppressant FK506 significantly improved neurologic outcome and attenuated spinal cord injury induced by transient thoracic aortic cross-clamping in the rat.     

Transcranial myogenic motor-evoked potentials after transient spinal cord ischemia predicts neurologic outcome in rabbits

OBJECTIVE: Myogenic transcranial motor-evoked potentials (tc-MEPs) were applied to monitor spinal cord ischemia in the repairs of thoracoabdominal aortic aneurysms. We investigated whether tc-MEPs after spinal cord ischemia/reperfusion could be used to predict neurologic outcome in leporine model. METHODS: Tc-MEPs were measured at 30-second intervals before, during, and after spinal cord ischemia (SCI) induced by balloon occlusion of the infrarenal aorta. Twenty rabbits were divided into five groups. Four groups (n = 4 animals in each group) had transient ischemia induced for 10, 15, 20, or 30 minutes. In fifth group, the terminal aorta at the aortic bifurcation was occluded for 30 minutes. All animals were evaluated neurologically 48 hours later, and their spinal cords were removed for histologic examination. RESULTS: The tc-MEPs in each SCI group rapidly disappeared after SCI. After reperfusion, the recovery of tc-MEPs amplitude was inversely correlated to duration of SCI. Tc-MEPs amplitude at one hour after reperfusion was correlated with both neurologic score and number of neuron cells in the spinal cord 48 hours later. Logistic regression analysis demonstrated that the neurologic deficits differed significantly between animals with tc-MEPs amplitude of less than 75% of the baseline and those with an amplitude of more than 75%. CONCLUSIONS: The amplitude of tc-MEPs after ischemia /reperfusion of the spinal cord showed a high correlation with durations of SCI, with neurologic deficits, and with pathologic findings of the spinal cord. Tc-MEPs, therefore, could be used to predict neurologic outcome. In particular, tc-MEPs whose amplitude recovered by less than 75% indicated a risk of paraplegia.     

The influence of dextrose administration on neurologic outcome after temporary spinal cord ischemia in the rabbit

The influence of dextrose administration on neurologic outcome after temporary spinal cord ischemia was examined in New Zealand white rabbits. Spinal cord ischemia was produced by infrarenal balloon occlusion of the aorta in unanesthetized animals. Animals were observed for 3 days for neurologic evaluation. Fasted animals received intravenous dextrose, 0.5 g.kg-1, or placebo before a period spinal cord ischemia. The dextrose was administered as either a bolus of a 50% solution (D50) 15 min before ischemia or as an infusion of a 5% solution (D5W) over 90 min before ischemia. With either mode of administration, preocclusion plasma glucose level was moderately increased as compared with that in animals that received lactated Ringer's solution in equivalent volume, i.e., for the D50 bolus: 291 +/- 82 (SD) versus 166 +/- 67 mg.dl-1 (P less than 0.005); and for D5W infusion: 177 +/- 38 versus 137 +/- 13 mg.dl-1 (P less than 0.01). With either mode of administration, neurologic outcome was poorer (P less than 0.025) at 72 h in the animals that had received dextrose. For example, of the 10 animals that received D5W by infusion, nine were paraplegic (unable to walk) 72 h after ischemia, whereas only three of 10 control animals were paraplegic. The adverse effect of an increased blood glucose level has been demonstrated previously for cerebral ischemia. The present results are the first demonstration that increased plasma glucose may result in a worsened neurologic outcome after spinal cord ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The time course of acquisition of ischemic tolerance and induction of heat shock protein 70 after a brief period of ischemia in the spinal cord in rabbits

We examined the time course of development of ischemic tolerance in the spinal cord and sought its mechanism exploring the expression of heat shock protein 70 (HSP70). Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta. In Experiment 1, neurologic and histopathologic outcome was evaluated 48 h after prolonged ischemia (20 min) that was given 2 days, 4 days, or 7 days after a short period of ischemia (ischemic pretreatment) sufficient to abolish postsynaptic component of spinal cord evoked potentials. Control animals were given prolonged ischemia 4 days after sham operation. In Experiment 2, HSP70 expression in motor neurons after pretreatment without exposure to prolonged ischemia was examined by immunohistochemical staining. Ischemic pretreatment 4 days (but not 2 days or 7 days) before 20 min ischemia exhibited protective effects against spinal cord injury. In the cytoplasm, HSP70 immunoreactivity was mildly increased after 2, 4, and 7 days of ischemic pretreatment. However, the incidence of nuclear HSP70 immunoreactivity 2 days, 4 days, and 7 days after ischemic pretreatment was 2 of 6 animals, 4 of 6 animals, and 1 of 6 animals, respectively (none in the control group). These results suggest that ischemic tolerance is apparent 4 days after ischemic pretreatment and that HSP70 immunoreactivity in the nucleus may provide some insight into the mechanisms of ischemic tolerance in the spinal cord.     

Inhibiting a spinal cord signaling pathway protects against ischemia injury in rats

Objective

The aim of the study was to examine whether the cannabinoid agonist WIN55212-2 could attenuate ischemic spinal cord injury (SCI) in rats through inhibition of GAPDH/Siah1 signaling.

Effects of thoracic aortic occlusion and cerebrospinal fluid drainage on regional spinal cord blood flow in dogs: correlation with neurologic outcome

We studied the effect of thoracic aortic occlusion and cerebrospinal fluid (CSF) drainage on regional spinal cord blood flow and its correlation with neurologic outcome. Using isotope-tagged microspheres, we determined blood flow to the gray and white matter of five regions of the spinal cord in dogs: group I (control), group II (cross-clamp only), group III (cross-clamp plus CSF drainage). At 60 minutes after thoracic aortic occlusion in group II, median gray matter blood flow (GMBF) in the lower thoracic and lumbar cord decreased from 23.1 and 27.0 ml/100 gm/min at baseline to 4.0 and 2.5 ml/100 gm/min, respectively. The addition of CSF drainage improved GMBF during aortic cross-clamping in the lower thoracic and lumbar cord to 11.3 (p less than 0.05) and 15.1 ml/100 gm/min (p less than 0.03), respectively. After removal of the aortic cross-clamp, median blood flow more than tripled from baseline blood flow in group II, whereas CSF drainage prevented significant reperfusion hyperemia. Both low GMBF during cross-clamping and reperfusion hyperemia were associated with a worse neurologic outcome. In group II, no dog was neurologically normal, and more than 60% of the dogs had spastic paraplegia. In contrast, almost 60% of dogs in group III were normal, and none had spastic paraplegia (p less than 0.001). We conclude that CSF drainage in dogs during thoracic aortic occlusion maintained spinal cord perfusion above critical levels, diminished reperfusion hyperemia, and improved neurologic outcome.     

Adenosine analogue reduces spinal cord reperfusion injury in a time-dependent fashion

BACKGROUND: We hypothesized that inflammation during spinal cord reperfusion worsens ischemic injury. ATL-146e, an adenosine A(2A) agonist with known anti-inflammatory properties, was used to test this hypothesis at varied intervals to determine the time course of reperfusion injury. METHODS: Forty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group (n = 14 animals) received 0.06 microg/kg/min systemic ATL-146e over 3 hours, beginning after 30 minutes of ischemic time. A second group (n = 6 animals) received ATL-146e over 1.5 hours. A third group (n = 3 animals) received ATL-146e over 1 hour, and a fourth group (n = 17 animals) received saline solution. All animals were assessed at 48 hours for hind limb motor function (Tarlov scale, 0-5). RESULTS: Animals that received ATL-146e for 3 hours (Tarlov score, 4.3 +/- 0.22; P <.001) or 1.5 hours (Tarlov score, 2.7 +/- 0.6; P <.05) had improved neurologic outcomes compared with rabbits that received saline solution (Tarlov score, 0.6 +/- 0.29). Animals that received ATL-146e for 1 hour (Tarlov score, 0.7 +/- 0.8) were not significantly different from those animals that received saline solution. CONCLUSIONS: Systemic ATL-146e, given during reperfusion, results in time-dependent improvement in spinal cord function after ischemia. This implies that the mechanism of spinal reperfusion injury includes leukocyte-mediated inflammation at a critical post-ischemic time interval.