Effect of melatonin on ischemia reperfusion injury induced by middle cerebral artery occlusion in rats.

Free radicals have been implicated in neuronal injury during ischemia reperfusion in stroke. Therefore, in the present study, melatonin, a potent antioxidant, was studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. Melatonin (10, 20 and 40 mg/kg i.p.) was administered four times in an animal at the time of middle cerebral artery occlusion, 1 h after middle cerebral artery occlusion, at the time of reperfusion and 1 h after reperfusion. Two hours after reperfusion, rats were euthanized for estimation of oxidative stress markers (malondialdehyde and reduced glutathione). The doses of 20 and 40 mg/kg of melatonin significantly attenuated the raised level of malondialdehyde (287+/-28, 279+/-52 nmol/g wet tissue, respectively) as compared to the levels (420+/-61 nmol/g wet tissue) in vehicle-treated middle cerebral artery-occluded rats. There was an insignificant change in levels of reduced glutathione at these doses (95+/-42, 88.7+/-36 microg/g wet tissue, respectively) as compared to those in the vehicle-treated middle cerebral artery-occluded rats (108.21+/-21 microg/g wet tissue). However, there was an insignificant difference between 20 and 40 mg/kg treated rats. Therefore, the dose of 20 mg/kg i.p. was used to evaluate the neuroprotective effect by using diffusion-weighted imaging (30 min after reperfusion), assessing the neurological deficit (24 h after middle cerebral artery occlusion) and estimating oxidative stress markers (72 h after middle cerebral artery occlusion). In the 20 mg/kg melatonin-treated group, percent ischemic lesion volume on diffusion-weighted imaging was significantly attenuated (9.8+/-3.9) as compared to that in the vehicle-treated group (21.4+/-4.7). The neurological deficit was significantly improved in the melatonin group (1.8+/-0.06) as compared to that in the vehicle-treated (2.9+/-0.38) group. The level of malondialdehyde (321.4+/-31 nmol/g wet tissue) and reduced glutathione (142.6+/-13 microg/g wet tissue) in the melatonin-treated group was also significantly decreased as compared to the level of malondialdehyde (623+/-22 nmol/g wet tissue) and reduced glutathione (226.6+/-19 microg/wet tissue) in the vehicle-treated group. The present study indicates that melatonin has a neuroprotective action in focal ischemia, which may be attributed to its antioxidant property.     

Evaluation of Withania somnifera in a middle cerebral artery occlusion model of stroke in rats

1. Stroke causes brain injury in millions of people worldwide each year. Despite the enormity of the problem, there is currently no approved therapy that can reduce infarct size or neurological disability. One of the approaches that can be used in limiting the neurological damage after stroke is the use of prophylactic treatment in patients with a high-risk of stroke. The present study was undertaken to investigate the effect of the Indian herbal plant Withania somnifera as a prophylactic treatment in the middle cerebral artery (MCA) occlusion model of stroke in rats. 2. Two groups of male Wistar rats were pretreated with a hydroalcoholic extract of W. somnifera (1 g/kg, p.o.) for 15 and 30 days. Thereafter, rats were subjected to focal ischaemia by occlusion of the MCA using an intraluminal thread. After 2 h MCA occlusion, reperfusion was allowed by retracting the thread. Animals were assessed for ischaemic changes using diffusion-weighted imaging 30 min after reperfusion. Twenty-four hours later, rats were subjected to motor performance tests and were subsequently killed for the estimation of the marker of oxidative stress malondialdehyde (MDA). The control group received vehicle and a similar protocol was followed. 3. Significant motor impairment, with elevated levels of MDA, was observed in vehicle-treated MCA-occluded rats. In addition, diffusion-weighted imaging showed increased signal intensity in the right hemisphere compared with the contralateral hemisphere. Treatment with W. somnifera for 15 days did not improve motor performance or decrease the elevated levels of MDA. However, when the pretreatment time of W. somnifera was increased to 30 days, it prevented motor impairment and significantly decreased the raised levels of MDA compared with vehicle-treated rats. In the W. somnifera (30 days)-pretreated group, the percentage hemispheric lesion area in diffusion-weighted imaging was significantly attenuated (17 +/- 2%) compared with the vehicle-treated MCA-occluded group (30 +/- 4%). 4. Because W. somnifera has been documented to have anti-oxidant properties, the protection afforded by W. somnifera could be due to its anti-oxidant effect. The present study provides first evidence of the effectiveness of an Indian herb in focal ischaemia.     

Effect of combination of endothelin receptor antagonist (TAK-044) and aspirin in middle cerebral artery occlusion model of acute ischemic stroke in rats

The present study was carried out to investigate the effect of the combination of an endothelin antagonist TAK-044 and an antiinflammatory agent aspirin in middle cerebral artery (MCA) occlusion model of acute ischemic stroke in rats. Male Wistar rats were pretreated with TAK-044 (5 mg/kg, i.p.) and aspirin (50 mg/kg, i.p.) for 7 days individually and in combination in different groups, and were thereafter subjected to focal ischemia for 2 h by occlusion of MCA using intraluminal thread. Twenty-four hours later, the rats were subjected to motor performance tests and killed subsequently for estimation of markers of oxidative stress malondialdehyde (MDA), reduced glutathione (GSH) and superoxide dismutase (SOD). The control group received the vehicle and the same protocol was followed. In vehicle-treated MCA occluded rats, significant (p < 0.01) motor impairment, with elevated levels of MDA (600.8 +/- 14.4 nmol/g tissue) and decreased levels of GSH (61.1 +/- 3.1 microg/g tissue) and SOD (8.5 +/- 0.5 U/mg protein,) was observed. Pretreatment with TAK-044 and aspirin for 7 days significantly improved motor function and attenuated the raised levels of MDA (475 +/- 14 and 538 +/- 17.3 nmol/g tissue, respectively) and the decrease in GSH (101 +/- 5 and 100 +/- 4.5 microg/g tissue, respectively) and SOD (12.1 +/- 0.5 and 10.5 +/- 0.6 U/mg protein, respectively), as compared to vehicle-treated MCA occluded rats. Combination of both the agents did not show a significant difference as compared to the individual drugs alone. The present study demonstrates that, although protection was observed with both the drugs (TAK-044 and aspirin), there was no enhanced effect when both agents were given in combination.     

Focal cerebral ischemia-induced escape deficit in rats is ameliorated by a reversible inhibitor of monoamine oxidase-a: implications for a novel animal model of post-stroke depression

The present investigation was conducted to examine whether a reversible inhibitor of monoamine oxidase (MAO)-A, T-794, affects the shuttle-box escape deficit induced by transient middle cerebral artery (MCA) occlusion (MCAO). MCA-occluded and sham-operated rats (surgery on day 0) were subjected to daily shuttle-box session from day 7 to 9 (training series) and from day 13 to 15 (test series) and received twice daily administration of T-794 (10 mg/kg p.o., b.i.d.) or vehicle from the evening of day 9. In the final shuttle-box session of test series (day 15), while MCA-occluded-vehicle-treated rats showed significantly more escape failures than sham-operated-vehicle-treated rats, the failures made by MCA-occluded rats were significantly decreased by T-794 to the level of the sham-operated group. Additionally, biochemical examination was conducted after behavioral evaluation to examine possible involvement of the brain monoamine system in the observed behavioral syndrome. In occluded hemisphere of MCA-occluded rats, catecholamine levels were decreased and ratios of deaminated metabolite to corresponding monoamine were increased compared with the respective values of the sham-operated group, and these changes were reversed by T-794. Results are discussed in terms of possible relevance of the MCAO-induced escape deficit to post-stroke depression.     

Beta-hydroxybutyrate,a cerebral function improving agent,protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia

In our previous study, beta-hydroxybutyrate (BHB) was found to prolong survival time and to inhibit cerebral edema by improving energy metabolism in the hypoxia, anoxia and global cerebral ischemia models. In this study, the cerebroprotective effect of BHB was examined in rats with permanent (p)-occlusion and transient (t)-occlusion of middle cerebral artery (MCA). BHB (30 mg x kg(-1) x h(-1) was continuously administered through the femoral vein. In rats with p-MCA occlusion, BHB significantly reduced infarct area at 24 h after the occlusion, but not at 72 h after the occlusion. In rats with 2-h t-MCA occlusion followed by 22-h reperfusion, BHB significantly reduced cerebral infarct area, edema formation, lipid peroxidation and neurological deficits. Moreover, in the t-MCA occlusion model, delayed administration of BHB started at 1 h after the initiation of the MCA occlusion also significantly reduced cerebral infarct area. Taking together the results obtained in our previous study into account, these results indicate that BHB decreased cerebral edema formation and infarct area by improving of the cerebral energy metabolism during ischemia and by inhibition of lipid peroxidation after reperfusion.     

Cerebral acetylcholine levels and long-term spatial cognitive impairment following middle cerebral artery occlusion in rats.

The behavioral and neurochemical changes in the chronic phase of permanent occlusion of the right middle cerebral artery (MCA) in rats were investigated. Nineteen MCA-occluded rats failed to solve the 8-arm radial maze task (cognitively impaired rats), while 11 MCA-occluded rats could complete it (cognitively unimpaired rats). When a delay of 60 min was imposed in the task, however, 5 cognitively unimpaired rats failed to complete the task. The rats that underwent behavioral testing were studied for any changes in ACh levels in various brain regions using HPLC with electrochemical detection. The ACh levels in the infarcted areas decreased considerably in all MCA-occluded rats, but no region of the infarcted areas correlated with the spatial cognitive deficit. The ACh levels tended to decrease in the frontal cortex of the cognitively impaired rats and greatly increased in both ipsilateral and contralateral parietal cortex of the cognitively unimpaired rats. A significant correlation was observed between the ACh levels and spatial cognitive deficit in the contralateral frontal cortex, and ipsilateral and contralateral parietal cortex. These results suggest that the cholinergic function of the frontal and parietal cortices might play a role in acquiring spatial cognition in MCA-occluded rats.     

Protective effect of Nardostachys jatamansi in rat cerebral ischemia

The protective effect of Nardostachys jatamansi (NJ) on neurobehavioral activities, thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), thiol group, catalase and sodium-potassium ATPase activities was studied in middle cerebral artery (MCA) occlusion model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 h using intraluminal 4-0 monofilament and reperfusion was allowed for 22 h. MCA occlusion caused significant depletion in the contents of glutathione and thiol group and a significant elevation in the level of TBARS. The activities of Na(+)K(+) ATPase and catalase were decreased significantly by MCA occlusion. The neurobehavioral activities (spontaneous motor activity and motor coordination) were also decreased significantly in MCA occlusion group. All the alternations induced by ischemia were significantly attenuated by 15 days pretreatment of NJ (250 mg/kg po) and correlated well with histopathology by decreasing the neuronal cell death following MCA occlusion and reperfusion. The study provides first evidence of effectiveness of NJ in focal ischemia most probably by virtue of its antioxidant property.     

Cardioprotective effects of the vasodilator/beta-adrenoceptor blocker, carvedilol, in two models of myocardial infarction in the rat.

The purpose of this study was to evaluate the cardioprotective effects of carvedilol, a beta-adrenergic blocker and vasodilator, in two models of ischemic myocardial damage in the rat. Following coronary artery occlusion for 0.5 h and reperfusion for 24 h (MI/R group), left ventricular (LV) injury was determined by planimetric analysis of triphenyltetrazolium chloride-stained tissue, and polymorphonuclear leukocyte infiltration was assessed by measuring myeloperoxidase (MPO) activity. In the vehicle-treated MI/R group, infarct size was 14.2 +/- 1.3% of the LV (n = 16), and MPO activity was increased to 2.8 +/- 0.7 from 0.14 +/- 0.03 U/g tissue in the vehicle-treated sham-occluded group (p less than 0.01). Carvedilol (1 mg/kg i.v., 15 min prior to coronary artery occlusion and at 3.5 h following reperfusion) reduced myocardial infarct size to 7.5 +/- 1.2% of the LV (n = 14; p less than 0.01) and attenuated the increase in MPO activity to 1.4 +/- 0.4 U/g tissue (p less than 0.05). A lower dose of carvedilol (i.e. 0.3 mg/kg i.v.) did not limit myocardial infarct size or the increase in MPO activity. In a model of permanent coronary artery occlusion, 24-hour survival was reduced from 85% in sham-occluded animals (n = 38) to 44% in the vehicle-treated MI group (n = 84; p less than 0.01). In comparison to the vehicle-treated MI group, carvedilol (0.3 mg/kg i.v., 15 min prior to coronary artery occlusion and 1 mg/kg 4 h after occlusion) improved survival by 55% (n = 64; p less than 0.05, compared to the vehicle-treated MI group), whereas the same dose of propranolol (n = 42) had no significant effect on survival. These results indicate that carvedilol reduces myocardial ischemia/reperfusion injury, and significantly improves survival in a permanent coronary artery occlusion model of myocardial infarction.     

Protective effect of serofendic acid on ischemic injury induced by occlusion of the middle cerebral artery in rats

We previously reported that a sulfur-containing neuroprotective substance named serofendic acid purified and isolated from fetal calf serum prevented glutamate neurotoxicity in rat cortical cultured neurons. In the present study, we investigated the effect of serofendic acid on ischemic injury induced by a transient occlusion of the middle cerebral artery in rats. Serofendic acid was intracerebroventricularly administered 30 min after the onset of the occlusion. Serofendic acid (30 nmol) significantly reduced total infarct volume, similar to edaravone (30 nmol), a free radical scavenger. Treatment with serofendic acid (1-30 nmol) reduced the infarct volume in a dose-dependent manner. Moreover, serofendic acid (30 nmol) improved neurological deficit scores. These results suggest that intracerebroventricular administration of serofendic acid prevents the neurodegeneration induced by a transient focal cerebral ischemia and reperfusion.     

Adenosine kinase inhibition protects brain against transient focal ischemia in rats

Endogenous adenosine released locally during cerebral ischemia is neuroprotective, and agents which decrease adenosine inactivation may potentiate its protective effects. The effects of 5′-deoxy-5-iodotubercidin (5′d-5IT), an inhibitor of the adenosine-catabolizing enzyme, adenosine kinase, were studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. 5′d-5IT or the vehicle (10% DMSO in saline) was administered i.p. 30 min before, and 2 h and 6 h after the induction of middle cerebral artery occlusion. The infarct volume was determined using 2,3,5-triphenyltetrazolium chloride staining 48 h after middle cerebral artery occlusion. The infarct volume was significantly reduced in rats treated with 1.85 mg/kg×3 (57% reduction, P<0.001) or 1.0 mg/kg×3 (34% reduction, P<0.05), but not 0.3 mg/kg×3 5′d-5IT compared to vehicle-treated rats. The reduction of infarct volume was accompanied by a significant improvement in behavioral measures of neurological deficit. These data further support a role of adenosine in neuroprotection and suggest that adenosine kinase inhibition may be a useful approach to the treatment of focal cerebral ischemia.     

新型神经保护剂TQ0701-2对大鼠脑缺血再灌注损伤的保护作用

目的：研究新型神经保护剂TQ0701-2对大鼠脑缺血再灌注损伤的保护作用。方法：将120只雄性SD大鼠随机分为假手术组、模型组、依达拉奉组（3.0mg/kg）以及TQ0701-2高剂量组（6.0mg/kg）、中剂量组（3.0mg/kg）、低剂量组（1.5mg/kg）。假手术组仅进行手术而不造成缺血状态,其余各组均采用Longa线栓法制备大鼠MCAO模型,在缺血2h后进行再灌注。TQ0701-2三个剂量组和依达拉奉组分别在缺血前30min以及再灌注0、2h尾静脉注射TQ0701-2和依达拉奉,假手术组和模型组则给予等量的生理盐水。再灌注24h后观察大鼠神经功能损伤症状、脑组织梗死率以及病理组织学的改变。结果：模型组大鼠神经功能损伤严重,脑组织梗死率也明显增高（P〈0.01vs假手术组）。与依达拉奉的保护作用相同,TQ0701-2高中低三个剂量均能显著降低MCAO大鼠的神经功能评分和脑组织梗死率（P〈0.01vs模型组）,并且三个剂量的改善作用是随着浓度增大而增强的,具有剂量相关性。另外,TQ0701-2对大鼠脑缺血再灌注所致的神经元变性、坏死也有一定的保护作用。结论：研究表明,依达拉奉衍生物TQ0701-2对大鼠的脑缺血再灌注损伤有明显的神经保护作用。     

脂质胞壁酸诱导的延迟预适应对大鼠局灶性脑缺血/再灌注损伤的保护作用

目的 探讨LTA诱导的延迟预适应对大鼠局灶性脑缺血／再灌注损（I／R）损伤的作用。方法 采用改良Longa法制作大鼠右大脑中动脉（MCA）闭塞2h造成局灶性脑缺血模型，恢复血液灌流24h。大鼠在施行脑缺血前24h腹腔注射脂质胞壁酸（LTA，1mg／kg）诱导延迟预适应，检测脑组织再灌注24h后组织中超氧化物歧化酶（SOD）、丙二醛（MDA）和一氧化氮（NO）含量以及大鼠神经症状，并用透射电镜观测大鼠大脑皮层神经细胞的超微结构改变。结果 LTA预适应能明显减少脑I／R后组织中MDA的含量（P〈0、01），提高SOD的水平（P〈0．01），减轻神经细胞的超微结构损伤和保护细胞膜结构完整性，LTA预适应还能明显改善脑I／R后的神经功能，减少神经缺欠评分值（P〈0．01）。LTA预适应亦能明显降低I／R导致脑组织中NO含量的升高（P〈0．01）。结论 LTA诱导的延迟预适应能显著减少大鼠脑组织再灌注损伤，减少脑组织坏死，其作用机制与减少脑I／R后自由基和NO毒性作用有关。     

Effects of sodium beta-aescin on expression of adhesion molecules and migration of neutrophils after middle cerebral artery occlusion in rats.

AIM: To investigate the effects of sodium beta-aescin on neutrophil migration and expression of adhesion molecules (ICAM-1 and E-selectin) after middle cerebral artery occlusion (MCAO) in rats. METHODS: Rats were pretreated with sodium beta-aescin for 7 d and then subjected to cerebral ischemia/reperfusion (I/R) injury induced by an MCAO. After a 2-h ischemia and a 24-h reperfusion, the infarct volume and neurological deficit were determined by the method of TTC staining and the Longa's score. The effect of sodium beta-aescin on the migration of neutrophils was evaluated by measuring the activity of myeloperoxidase (MPO) enzyme. The expressions of adhesion molecules were determined by immunohistochemistry and Western blot. RESULTS: Sodium beta-aescin significantly reduced the cerebral infarct volume and ameliorated the neurological deficit (P<0.05 or P<0.01). The MPO activity and the expressions of ICAM-1 and E-selectin in the vehicle-treated rats were increased significantly (P<0.01) after cerebral I/R. After treatment with sodium beta-aescin, the enzymatic activity of MPO and the expressions of these adhesion molecules were significantly reduced compared with the vehicle-treated group (P<0.05 or P<0.01). CONCLUSION: Sodium beta-aescin can attenuate brain injury, down-regulate the protein expressions of ICAM-1 and E-selectin, and reduce the migration of neutrophils after cerebral I/R.     

Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model

The neuroprotective effects of YM872 ([2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl]acetic acid monohydrate), a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist with high water solubility, were examined in rats with transient middle cerebral artery (MCA) occlusion. The right MCA of male SD rats was occluded for 3 h using the intraluminal suture occlusion method. YM872 significantly reduced the infarct volume 24 hours after occlusion, at dosages of 20 and 40 mg/kg/h (iv infusion) when given for 4 h immediately after occlusion. Furthermore, delayed administration of YM872 (20 mg/kg/h iv infusion for 4 h, starting 2 or 3 h after the occlusion) also reduced the infarct volume and the neurological deficits measured at 24 h. Additionally, the therapeutic efficacy of YM872 persisted for at least seven days after MCA occlusion in animals treated with YM872 for 4 h starting 2 h after MCA occlusion. These data demonstrate that AMPA receptors contribute to the development of neuronal damage after reperfusion as well as during ischemia in the focal ischemia models and that the acute effect of the blockade of AMPA receptors persists over a long time period. YM872 shows promise as an effective treatment for patients suffering from acute stroke.     

Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia

We tested the hypothesis that combined use of trophic factors and caspase inhibitors increases brain resistance to ischaemia in mice. Intracerebroventricular administration of bFGF (>10 ng) 30 min after MCA occlusion decreased infarct size and neurological deficit in a dose-dependent manner following 2 h ischemia and reperfusion (20 h). Combined administration of the subthreshold doses of bFGF (3 ng) and caspase inhibitors (z-VAD.FMK, 27 ng or z-DEVD.FMK, 80 mg) reduced infarct volume by 60%, and reduced neurological deficit. Treatment with a subthreshold dose of bFGF (3 ng) extended the therapeutic window for z-DEVD.FMK (480 ng) from 1 to 3 h after reperfusion. Caspase-3 activity in the ischaemic brain was increased 30 min and 2 h after reperfusion but, was significantly reduced in bFGF-treated animals by 29 and 16%, respectively. Caspase-3 activity was not reduced by a direct bFGF effect because addition of bFGF (10 nM - 2 microM) did not decrease recombinant caspase-3 activity, in vitro. Our data show that combining caspase inhibitors and bFGF lengthens the treatment window for the second treatment, plus lowers the dosage requirements for neuroprotection. These findings are important because low doses of caspase inhibitors or bFGF reduce the possibility of side effects plus extend the short treatment window for ischaemic stroke.     

白三烯受体拮抗剂ONO—1078对大鼠局灶性脑缺血的神经保护作用

AIM: To determine whether ONO-1078 (pranlukast), a potent leukotriene receptor antagonist, has neuroprotective effect on focal cerebral ischemia in the rat. METHODS: Focal cerebral ischemia was induced by 30 min of middle cerebral artery (MCA) occlusion and followed by 24 h reperfusion. ONO-1078 (0.003-1.0 mg/kg) or vehicle (saline 1 mL/kg) was ip injected 30 min before MCA occlusion and 2 h after reperfusion. The neurological score, infarct volume, neuron density (in cortex, hippocampus, and striatum), brain edema, and albumin exudation around the vessels were determined 24 h after reperfusion. RESULTS: ONO-1078 slightly improved the neurological deficiency, and dramatically decreased infarct volume and neuron loss which showed a bell shaped dose response effect with highest effect at doses of 0.01-0.3 mg/kg. Enlargement of the ischemic hemisphere and albumin exudation were inhibited at doses of 0.01-1.0 mg/kg. CONCLUSION: ONO-1078 has the protective effect on focal cerebral ischemia in rats, which is partially attributed to the inhibition of brain edema. This may represent a novel approach to the treatment of acute cerebral ischemia with cysteinyl leukotriene receptor antagonists.     

人参皂苷Rg_1对大鼠脑缺血再灌注损伤及内皮细胞粘附作用的影响(英文)

目的研究抑制白细胞浸润和粘附分子表达是否为人参皂苷Rg1改善大鼠脑缺血再灌注损伤的作用机理之一。方法大鼠给予人参皂苷Rg125,50和100 mg·kg-1ig,7 d。末次给药1 h后采用右侧大脑中动脉阻断制备缺血再灌注模型。缺血2 h,再灌注22 h后,分别用Longa等的计分法和TTC染色法测定大鼠神经功能及脑梗死面积;用伊文思蓝法测定脑缺血2 h再灌注4 h后对血脑屏障的损伤程度。缺血2 h再灌注22 h后测定髓过氧化物酶(MPO)活性,并用蛋白质印迹法测定大脑缺血区粘附分子细胞间粘附分子-1(ICAM-1)和E-选择素的表达。结果缺血再灌注前给予人参皂苷Rg1(50和100 mg·kg-1)可明显改善神经功能症状,减少脑梗死面积,减轻血脑屏障的损伤,降低缺血再灌注所致脑组织内MPO活性及ICAM-1和E-选择素的表达增高。结论人参皂苷Rg1可通过抑制白细胞浸润和粘附分子表达的途径改善大鼠脑缺血再灌注损伤。     

仙人掌多糖对大鼠局灶性脑缺血的神经保护作用

摘要目的观察仙人掌多糖对大脑中动脉栓塞（MCAO）诱导的大鼠缺血 再灌注损伤的神经保护作用。方法雄性SD大鼠随机分为假手术组、缺血组、0.9%氯化钠溶液组、仙人掌多糖治疗组（200 mg·kg－1·d －1,ip）。采用MCAO法制作大鼠缺血 再灌注损伤模型。分别于大鼠缺血2 h再灌注3,6,8 h后进行神经行为学评分;8 h后2,3,5 三苯基氯化四氮唑（TTC）染色测定脑梗死体积;缺血2 h再灌注22 h后脑组织切片苏木精 伊红（HE）染色显微镜下形态学观察。结果与0.9%氯化钠溶液组相比,再灌注8 h后仙人掌多糖治疗组神经行为学评分平均下降（2.35±0.47）分（P＜0.05）,梗死灶体积减少（P＜0.05）;大鼠皮质及海马组织神经细胞丢失、神经胶质增生、核固缩、核深染等形态学均有明显改善（P＜0.05）。结论仙人掌多糖可以缓解大鼠大脑中动脉栓塞症状,具有一定的神经保护作用。     

Use of diffusion-weighted MRI and neurological deficit scores to demonstrate beneficial effects of isradipine in a rat model of focal ischemia.

The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0-3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine's neuroprotective activity.     

Nefiracetam improves the impairment of local cerebral blood flow and glucose utilization after chronic focal cerebral ischemia in rats

In this study we investigated the effects of nefiracetam (DM-9384) on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMR(glc)) in the chronic phase after middle cerebral artery (MCA) occlusion in rats. Nefiracetam (10 mg/kg) was administered orally once a day for 2 weeks from day 15 after MCA occlusion. On day 28 after MCA occlusion, LCBF and LCMR(glc) were measured by an autoradiographic image-processing method. In MCA-occluded rats, LCBF and LCMR(glc) in the ischemic side of seven regions including the frontal cortex were significant decreased compared with those of the nonischemic side. Nefiracetam significantly improved the impairment of LCBF in the frontal cortex, parietal cortex, caudate putamen, ventral thalamus, amygdaloid nucleus and hippocampus. It also improved the decrease of LCMR(glc) in the frontal cortex, ventral thalamus and hippocampus. These results suggested that nefiracetam has ameliorating effects on chronic disorders of LCBF and LCMR(glc) induced by MCA occlusion.