异氟烷对化疗性大鼠异食癖恶心呕吐模型神经功能及呕吐相关神经递质的影响

摘要 目的：研究异氟烷预处理对化疗性大鼠异食癖恶心呕吐模型神经功能及呕吐相关神经递质的影响。方法：选用SD大鼠作为研究对象,腹腔注射顺铂以建立化疗性大鼠异食癖恶心呕吐模型（Model组）,腹腔注射等量生理研究作为对照组（Control）,在腹腔注射顺铂前1 h和12 h吸入异氟烷预处理作为异氟烷治疗组（Isoflurane）。记录腹腔注射顺铂0~12 h和12~24 h内各组大鼠摄入高岭土量;在腹腔注射顺铂0 h、12 h和24 h后,通过神经功能缺损评分法对各组大鼠神经功能进行评分;并在腹腔注射顺铂24 h后处死大鼠,收集大鼠回肠和延髓组织以检测5-羟色胺(5-Hydroxytryptamine,5-HT)、5-羟基-吲哚乙酸（5-hydroxy-indole acetic acid,5-HIAA）、色氨酸羟化酶（Tryptophan hydroxylase,TPH）以及单胺氧化酶（Monoamine oxidase,MAOA）含量。结果：与Control组相比,Model组和Isoflurane组大鼠在腹腔注射顺铂0~12 h,12~24 h以及0~24 h内摄入的高岭土量均显著升高（P<0.05）,并且Isoflurane组大鼠均显著Model组。三组大鼠在腹腔注射顺铂0 h、12 h和24 h后,神经功能评分均无显著差异（P>0.05）。与Control组大鼠相比,Model组和Isoflurane组大鼠在腹腔注射顺铂24 h后回肠/延髓组织内5-HT和TPH含量均显著升高,并且Isoflurane组大鼠显著低于Model组大鼠（P<0.05）;与Control组相比,Model组大鼠回肠和延髓组织中5-HIAA/5-HIT比值和MAOA含量均显著降低（P<0.05）;与Model组大鼠相比,Isoflurane组大鼠回肠5-HIAA含量、回肠/延髓5-HIAA/5-HT比值和MAOA含量均显著升高（P<0.05）。结论：异氟烷预处理可用于预防腹腔注射顺铂诱导的恶性呕吐,其机制可能与下降THP含量和提高MAOA含量,抑制5-HT合成以及促进5-HT代谢有关。     

High-Intensity Focused Ultrasound (HIFU) for Dissolution of Clots in a Rabbit Model of Embolic Stroke

It is estimated that only 2-6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (～70%) animals tested. Histological analysis confirmed thatthe sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.     

Species-dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity

Activated protein C (APC) is a protease with anticoagulant and cytoprotective activities. APC is neuroprotective in rodent models of stroke. But, an APC variant with reduced anticoagulant activity, 3K3A-APC, compared to wild-type APC shows greater neuroprotection with no risk for bleeding in stroke models. To determine whether 3K3A-APC exhibits species-dependent neuroprotection similar to that as seen with wild-type APC, we studied murine and human recombinant 3K3A-APC mutants which show approximately 80% reduced anticoagulant activity. Murine 3K3A-APC (0.2 mg/kg i.v.) administered at 4 h after embolic stroke improved substantially functional outcome and reduced by 80% the infract volume 7 days after stroke. Human 3K3A-APC was neuroprotective after embolic stroke in mice, but at significantly higher concentrations (i.e. 2 mg/kg i.v.). Species-dependent neuroprotection, i.e. murine > human 3K3A-APC, was confirmed in a mouse model of permanent middle cerebral artery occlusion. Human 3K3A-APC had by fivefold greater cytoprotective activity than murine 3K3A-APC in oxygen-glucose deprivation model in human brain endothelial cells, whereas murine 3K3A-APC was by 2.5-fold more potent than human 3K3A-APC in a mouse model of NMDA-induced neuronal apoptosis. Thus, 3K3A-APC exhibits species-dependent neuroprotection which should be taken into account when designing human trials for ischemic stroke with APC mutants.     

Decreased Brain KATP Channel Contributes to Exacerbating Ischemic Brain Injury and the Failure of Neuroprotection by Sevoflurane Post-Conditioning in Diabetic Rats

Diabetes leads to exacerbating brain injury after ischemic stroke, but the underlying mechanisms and whether therapeutic intervention with anesthetic post-conditioning can induce neuroprotection in this population are not known. We tested the hypothesis that alteration of brain mitochondrial (mito) K_ATP channels might cause exacerbating brain injury after ischemic stroke and attenuate anesthetic post-conditioning induced neuroprotection in diabetes. We also examined whether hyperglycemic correction with insulin would restore anesthetic post-conditioning in diabetes. Non-diabetic rats and diabetic rats treated with or without insulin were subjected to focal cerebral ischemia for 2 h followed by 24 h of reperfusion. Post-conditioning was performed by exposure to sevoflurane for 15 min, immediately at the onset of reperfusion. The role of the mitoK_ATP channel was assessed by administration of a selective blocker 5-hydroxydecanoate (5-HD) before sevoflurane post-conditioning or by diazoxide (DZX), a mitoK_ATP channel opener, given in place of sevoflurane. Compared with non-diabetic rats, diabetic rats had larger infarct volume and worse neurological outcome at 24 h after ischemia. Sevoflurane or DZX reduced the infarct volume and improved neurological outcome in non-diabetic rats but not in diabetic rats, and the protective effects of sevoflurane in non-diabetic rats were inhibited by pretreatment with 5-HD. Molecular studies revealed that expression of Kir6.2, an important mitoK_ATP channel component, was decreased in the brain of diabetic rats as compared to non-diabetic rats. In contrast, hyperglycemic correction with insulin in diabetic rats normalized expression of brain Kir6.2, reduced ischemic brain damage and restored neuroprotective effects of sevoflurane post-conditioning. Our findings suggest that decreased brain mitoK_ATP channel contributes to exacerbating ischemic brain injury and the failure of neuroprotection by anesthetic post-conditioning in diabetes. Insulin glycemic control in diabetes may restore the neuroprotective effects of anesthetic post-conditioning by modulation of brain mitoK_ATP channel.     

microRNA-124 attenuates isoflurane-induced neurological deficits in neonatal rats via binding to EGR1

Isoflurane anesthesia induces neuroapoptosis in the development of the brain. In this study, neonatal rats and hippocampal neurons were subjected to isoflurane exposure, in which the effect of miR-124 on the neurological deficits induced by isoflurane was evaluated. Isoflurane anesthesia models were induced in neonatal SD rats aged 7 days and then treated with miR-124 agomir, miR-124 antagomir, or LV-CMV-early growth response 1 (EGR1) plasmids. Then, the spatial learning and memory ability of rats were evaluated by Morris water maze. Furthermore, primary hippocampal neurons cultured 7 days were also exposed to isoflurane and transfected with miR-124 agomir, miR-124 antagomir, or LV-CMV-EGR1 plasmids. The targeting relationship of miR-124 and EGR1 was verified by the dual-luciferase reporter gene assay. To identify the effect of miR-124 on neuron activities, the viability and apoptosis of hippocampal neurons were assessed. In response to isoflurane exposure, miR-124 expression was reduced and EGR1 expression was increased in the hippocampal tissues and neurons. The isoflurane anesthesia damaged rats' spatial learning and memory ability, and reduced viability, and promoted apoptosis of hippocampal neurons. EGR1 was targeted and negatively regulated by miR-124. The treatment of miR-124 agomir improved rats' spatial learning and memory ability and notably increased hippocampal neuron viability and resistance to apoptosis, corresponding to an increased brain-derived neurotrophic factor (BDNF) expression, inhibited expression of proapoptotic factors (cleaved-Caspase-3 and Bax), and enhanced the expression of antiapoptotic factor (Bcl-2). Upregulated miR-124 inhibited the expression of EGR1, by which mechanism miR-124 reduced the neurological deficits induced by isoflurane in neonatal rats through inhibiting apoptosis of hippocampal neurons.     

Delayed cardioprotection by isoflurane: role of K(ATP) channels

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (K(ATP)) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7-10 days of age (n = 5-16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means +/- SD) by 50% (10 +/- 5%) versus untreated controls (20 +/- 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 +/- 4%) versus untreated controls (54 +/- 6%). The mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) completely (55 +/- 3%) and the sarcolemmal K(ATP) channel blocker HMR 1098 partially (62 +/- 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 +/- 5%). We conclude that both mitochondrial and sarcolemmal K(ATP) channels contribute to isoflurane-induced delayed cardioprotection.     

Candesartan Reduces the Hemorrhage Associated with Delayed Tissue Plasminogen Activator Treatment in Rat Embolic Stroke

We have previously reported that angiotensin receptor blockade reduces reperfusion hemorrhage in a suture occlusion model of stroke, despite increasing matrix metalloproteinase (MMP-9) activity. We hypothesized that candesartan will also decrease hemorrhage associated with delayed (6 h) tissue plasminogen activator (tPA) administration after embolic stroke, widening the therapeutic time window of tPA. Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) and treated with either candesartan (1 mg/kg) alone early at 3 h, delayed tPA (10 mg/kg) alone at 6 h, the combination of candesartan and tPA, or vehicle control. Rats were sacrificed at 24 and 48 h post-eMCAO and brains perfused for evaluation of neurological deficits, cerebral hemorrhage in terms of hemoglobin content, occurrence rate of hemorrhage, infarct size, tissue MMP activity and protein expression. The combination therapy of candesartan and tPA after eMCAO reduced the brain hemorrhage, and improved neurological outcome compared with rats treated with tPA alone. Further, candesartan in combination with tPA increased activity of MMP-9 but decreased MMP-3, nuclear factor kappa-B and tumor necrosis factor-α expression and enhanced activation of endothelial nitric oxide synthase. An activation of MMP-9 alone is insufficient to cause increased hemorrhage in embolic stroke. Combination therapy with acute candesartan plus tPA may be beneficial in ameliorating tPA-induced hemorrhage after embolic stroke.     

The influence of isoflurane on the synaptic activity of 5-hydroxytryptamine

The effects of isoflurane on uptake of 5-hydroxytryptamine(serotonin; 5-HT) by rat brain synaptosomes and binding of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ketanserin to 5-HT_1A and 5-HT₂ receptors were examined. Isoflurane caused a concentration-dependent decrease in synaptosomal 5-HT uptake that was kinetically defined as non-competitive; exposure to isoflurane decreased V_max but had no effect on the apparent K_m. Removal of the drug from the reaction mixture resulted in the return of 5-HT accumulation rates to control levels. Isoflurane inhibited 8-OH-DPAT binding to hippocampal membranes by up to 27±6% at 4.5 mM, but did not significantly affect ketanserin binding to 5-HT₂ receptors. These findings suggest that presynaptic actions are more important than postsynaptic actions in the modulation of serotonergic neutrotransmission by isoflurane.     

Postanesthetic Effects of Isoflurane on Behavioral Phenotypes of Adult Male C57BL/6J Mice

Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane-treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia.     

The Contribution of the Blood Glutamate Scavenging Activity of Pyruvate to its Neuroprotective Properties in a Rat Model of Closed Head Injury

The removal of excess glutamate from brain fluids after acute insults such as closed head injury (CHI) and stroke is expected to prevent excitotoxicity and the ensuing long lasting neurological deficits. Since blood glutamate scavenging accelerates the removal of excess glutamate from brain into blood and causes neuroprotection, we have evaluated here whether the neuroprotective properties of pyruvate could be partly accounted to its blood glutamate scavenging activity. The neurological outcome of rats after CHI improved significantly when treated with intravenous pyruvate (0.9 mmoles/100 g) but not with pyruvate administered together with glutamate. Pyruvate, at 5 μmole/100 g rat was neither protective not able to decrease blood glutamate but displayed the latter two properties when combined with 60 μg/100 g of glutamate-pyruvate transaminase. Since the neurological recovery from CHI was correlated with the decrease of blood glutamate levels, we conclude that pyruvate blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms.     

In vivo 19F-NMR study of isoflurane elimination from brain

The time course of isoflurane elimination from rabbit brain was studied in vivo with 19F-NMR spectroscopy. Two exponential decay functions with different time constants were observed and assigned to two distinct brain compartments. Isoflurane has a 26 min time constant for one compartment (similar to a value of 25 min with halothane) but 174 min in the second one, compared with 320 min for halothane. The shorter half-life for isoflurane may be due to lower solubility of this agent in brain tissue. Comparison of isoflurane 19F chemical shifts in solvents in isolated brain lipids and in whole brain tissue indicates that the anesthetic present in the brain exists in a single environment (on the NMR time scale), which is a weighted average of both hydrophilic and hydrophobic environments.     

Effect of orphanin FQ/nociceptin (OFQ/N) and isoflurane on the prolactin secretory response in OFQ/N knockout mice

The prolactin secretory response to subcutaneous injection of orphanin FQ/nociceptin (OFQ/N) was measured in wild-type and OFQ/N knockout mice. These injections were given with and without isoflurane anesthesia, to determine if isoflurane would affect the prolactin secretory response. OFQ/N injection significantly increased prolactin levels in males and females, regardless of genotype, with a more robust response in females. Isoflurane pretreatment did not affect prolactin levels in controls or in animals injected with OFQ/N. This is the first report that exogenously administered OFQ/N stimulates prolactin secretion in mice and that brief isoflurane exposure does not significantly affect this response.     

Neurovascular protection conferred by 2-BFI treatment during rat cerebral ischemia

Stroke is caused by vascular dysfunction and currently there are no effective therapeutics to stroke induced brain damage. In contrast to an intense emphasis on neuroprotection, relatively few studies have addressed means of vascular protection in cerebral ischemia. Here we discovered that the ligand to immidazolin receptor, 2-BFI, not only provided potent neuroprotection during middle cerebral artery occlusion in rat, which confirmed our previous reports, but also protected the integrity of the cerebral vasculature. Treatment with 2-BFI twice daily after the occlusion of the middle cerebral artery for 14d significantly improved the neurological deficits, reduced brain infarction, and importantly, protected the cerebral vasculature as evidenced by the increased expression of an endothelial marker, von Willebrand factor, and better preservation of the cerebral vasculature, as viewed under a confocal microscope on rat brain perfused with FITC-labeled dextran. These results indicated that 2-BFI contributes to protection of neurovasculature. Understanding the molecular mechanisms could eventually lead to development of more effective therapies for stroke.     

异氟烷对小鼠星型胶质细胞Sirt1和MAO-A基因表达的影响

目的:探讨异氟烷对小鼠星形胶质细胞Sirt1和MAO-A基因表达的影响。方法:给予体外培养的新生小鼠原代星形胶质细胞不同浓度异氟烷处理,实验分为对照组和异氟烷处理组(0.5ISO、1.0ISO、1.5ISO),其中异氟烷组细胞分别给予0.5 MAC、1.0MAC和1.5 MAC三个浓度的异氟烷处理2小时,对照组给予O_2处理2小时,然后提取细胞RNA和蛋白检测Sirt1和MAO-A的mRNA和蛋白表达变化。结果:与对照组相比,异氟烷下调小鼠星形胶质细胞的Sirt1和MAO-A mRNA和蛋白水平,异氟烷浓度越大下调越明显。结论:异氟烷可抑制小鼠星形胶质细胞的Sirt1和MAO-A基因表达。     

家兔自发性蛛网膜下腔出血早期脑损伤模型的初步研究

目的：建立一种可重复的、有典型神经损伤症状的自发性蛛网膜下腔出血（sAH）动物模型,为研究蛛网膜下腔出血后早期脑损伤（EBI）的机制提供可靠的动物模型。方法：选用新西兰大耳白兔60只,随机分为实验组、对照组、空白组。采用枕大池穿刺一次注入自体动脉血法建立SAH模型。在4h、8h、12h、24h、48h、72h时间点,观察比较行为学与脑组织形态学的变化。结果：（1）实验组枕大池和蛛网膜下腔内发现大量的血凝块和血液。（2）实验组光镜下可观察到蛛网膜下腔大量红细胞,神经元细胞水肿,电镜下可见胶质细胞空泡样改变,神经元细胞线粒体肿胀,髓鞘内存在空泡和板层分离现象。（3）实验组造模后均出现明显的神经系统损伤,对照组4h出现典型神经系统损伤表现,12h后恢复正常,空白组未见神经系统损伤表现。结论：枕大池一次注血法是一种简便、可重复的症状性自发性蛛网膜下腔出血早期脑损伤模型,适宜于研究早期脑损伤的致病机制。     

Mesenchymal stem cells-based therapy of brain ischemic stroke in rat

Mesenchymal stem cells (MSCs)-based therapy is a promising modern attempt to improve the recovery after stroke. Experiments were carried out on inbred Wistar-Kyoto rats. MSCs were isolated, expanded in cultute and labeled with vital fluorescent dye PKH-26. Animals were subjected to middle cerebral artery occlusion (MCAO), followed by injection of 5 x 10(6) rat MSCs into the tail vein 3 days after MCAO. Control group animals received PBS injection (negative control). Therapy results were estimated by the following parameters: behavioral and neurological testing, the brain injure area, the state of damaged region "border" zone and the vessels quantity in the "borden" area. It was shown that control group animals (PBS injection) did not restore their initial behavioral and neurological state, while the experimental group animals (MSCs injection) showed the same parameters as intact rats at 2-3 weeks after MCAO. The size of the damaged region in the control group was approximately 1.5 as large as in the experimental group. The damage in the experimental group was limited to neocortex; caudate nucleus, capsula externa and piriform cortex remained uninjured. Small vessels quantity in the "border" regions was twine higher compared to control group and was approximately equal to an intact brain vessel number. Moreover, it was shown for the first time that after MSCs transplantation the vessels quantity in the neocortex and caudate putamen of contralateral hemisphere was twice as much as in control. We demonstrated that the MSCs transplantation definitely exerted a positive influence upon the brain tissue reparation after stroke.     

mito KATP和κ-阿片受体介导肢体缺血后处理对抗大鼠脑缺血／复灌损伤

目的：观察肢体缺血后处理（LIPC）在大鼠局灶性脑缺血／复灌损伤中的神经保护作用及其作用机制。方法：将大鼠随机分为6组：空白对照组,单侧LIPC组,双侧LIPC组（bLIPC）,bLIPC＋mito KATP阻断剂5-lydroxydecanoate（5-HD））预处理组,bLIPC＋κ-阿片受体拮抗剂nor-binaltorphimine（nor-BNI）预处理组,bLIPC＋双侧后肢体外循环组。采用线栓法建立大鼠大脑中动脉栓塞（MCAO）模型,术后进行神经系统症状评分,血浆强啡肽和脑啡肽水平测定,大脑梗死面积测定。结果：单侧L1PC能改善大鼠局灶性脑缺血／复灌损伤后的神经系统功能评分（P〈0．05）,并减少大脑梗死面积（P〈0．01）;而双侧12PC能显著提高大鼠局灶性脑缺血／复灌损伤后的神经系统功能评分,并显著减少大脑梗死面积（P〈0．01）,比单侧LIPC的作用更为明显（P〈0．05）。双侧L／PC后5、15、30min,1和2h这五个时间点,血浆强啡肽水平显著增高（P〈0．01）,12和24h这两个时间点恢复至正常水平;而血浆脑啡肽水平的改变与双侧LIPC前比较无显著差异（P〉0．05）。nor-BNI预处理（25nmol）和5-HD预处理（10mg／kg）均消除了双侧LIPC所致的神经系统功能评分增加和大脑梗死面积减少（P〈0．01）。结论：LIPC在大鼠局灶性脑缺血／复灌损伤中具有显著的神经保护作用,其作用可能与LIPC诱导内源性阿片激动剂释放和激活mito KATP有关。     

Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia

Aim

Aquaporin-4(AQP4) expression in the brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection.

Materials and methods

An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5 mg/kg, i.p. melatonin or placebo at 30 min prior, 60 min post and 120 min post 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.

Key findings

Melatonin at 60 min post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde (MDA) were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C (PKC) influenced AQP4 expression in the cerebral cortex and dorsal striatum.

Significance

Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.