Brain Reperfusion Research Articles

Cinnamophilin Inhibits Neutrophilic Respiratory Burst and Protects Against Ischemia-Reperfusion Brain Damage

We have shown that administration of Cinnamophilin (CINN) effectively reduced oxidative damage, DNA lipid peroxidation, neutrophil infiltration, and ischemic brain damage by inhibiting oxidative stress and the resulting inflammation in experimental stroke. In this study the potential CINN to ameliorate neutrophilic respiratory burst and reduce neutrophil infiltration was investigated. Neutrophils pretreated or co-treated with CINN, were stimulated by phorbol 12-myristate 13-acetate (PMA) and the levels of superoxide radical (O2-.) and hydrogen peroxide (H2O2) produced were determined by dihydroethidium (DHE) and dihydrorhodamine-123 (DHR) fluorescence assays, respectively, while myeloperoxidase activity (MPO) was measured by the guaiacol method. Our results showed that both pretreatment and co-treatment with CINN significantly inhibited H2O2 production in PMA-stimulated neutrophils. Additionally, cotreatment, but not pretreatment, with CINN effectively inhibited O2-. production in the PMA-stimulated neutrophils. Both treatments did not effectively reduce the MPO activity in neutrophil. Finally, animals treated with CINN at reperfusion brain insults significantly reduced brain infarction and neutrophil infiltration, as well as improved neurobehavioral outcome following cerebral ischemic reperfusion. These results support pluripotent neuroprotection actions offered by CINN against cerebral ischemia-reperfusion.

Postischemic Long-Term Treatment with Qiangli Tianma Duzhong Capsule Improves Brain Functional Recovery via the Improvement of Hemorrheology and the Inhibition of Platelet Aggregation in a Rat Model of Focal Cerebral Ischemia

Qiangli Tianma Duzhong capsule (TMDZ), a Chinese herbal drug, is clinically used to improve functional outcome in patients with ischemic stroke in China. This study was conducted to establish whether postischemic long-term treatment with TMDZ could reduce the loss of injured hemisphere and confer the improvements of neurological outcome in chronic survival of rats with 2 h middle cerebral artery occlusion (MCAO)/reperfusion brain injury and its primary mechanisms. We found that TMDZ (44.5, 89, or 178 mg/kg), administered per os 6 h after the onset of ischemia and for 28 consecutive days, significantly improved the behavior deficits, beginning on day 7, and further improved later. TMDZ treatment also markedly reduced the tissue loss of the injured hemisphere and improved histopathology. In the meantime, TMDZ treatment could improve hemorrheology and inhibit platelet aggregation. These results provide the first evidence that post-ischemic long-term treatment with TMDZ confers the improvements of neurological outcome and the loss of injured hemisphere in an animal ischemic stroke model, and its mechanisms might be associated with the improvements of hemorrheology and the inhibition of platelet aggregation.

Methyl‐isobutyl amiloride reduces brain Lac/NAA, cell death and microglial activation in a perinatal asphyxia model

Na⁺/H⁺ exchanger (NHE) blockade attenuates the detrimental consequences of ischaemia and reperfusion in myocardium and brain in adult and neonatal animal studies. Our aim was to use magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry to investigate the cerebral effects of the NHE inhibitor, methyl isobutyl amiloride (MIA) given after severe perinatal asphyxia in the piglet. Eighteen male piglets (aged < 24 h) underwent transient global cerebral hypoxia-ischaemia and were randomized to (i) saline placebo; or (ii) 3 mg/kg intravenous MIA administered 10 min post-insult and 8 hourly thereafter. Serial phosphorus-31 (³¹P) and proton (¹H) MRS data were acquired before, during and up to 48 h after hypoxia-ischaemia and metabolite-ratio time-series Area under the Curve (AUC) calculated. At 48 h, histological and immunohistochemical assessments quantified regional tissue injury. MIA decreased thalamic lactate/N-acetylaspartate and lactate/creatine AUCs (both p < 0.05) compared with placebo. Correlating with improved cerebral energy metabolism, transferase mediated biotinylated d-UTP nick end-labelling (TUNEL) positive cell density was reduced in the MIA group in cerebral cortex, thalamus and white matter (all p < 0.05) and caspase 3 immunoreactive cells were reduced in pyriform cortex and caudate nucleus (both p < 0.05). Microglial activation was reduced in pyriform and midtemporal cortex (both p < 0.05). Treatment with MIA starting 10 min after hypoxia-ischaemia was neuroprotective in this perinatal asphyxia model.

Protective Effect of Crocin against Cerebral Ischemia in a Dose-dependent Manner in a Rat Model of Ischemic Stroke

Crocin is a water-soluble carotenoid isolated from the Crocus sativus L (saffron) stigma. It has previously been reported that it has protective effects against renal, cardiac, and global cerebral ischemic injury. However its therapeutic effects remain to be clarified regarding ischemic reperfusion injuries, brain edema, and activity of antioxidant enzymes in a transient model of focal cerebral ischemia. Transient focal cerebral ischemia was induced by 60-minute middle cerebral artery occlusion (MCAO), followed by 23-hour reperfusion. Crocin at doses of 15, 30, 60, and 120 mg/kg intraperitoneally were injected at the start of ischemia. Infarct volume and neurologic outcome were evaluated 24 hours after MCAO. For the therapeutic time window measurement, crocin (60 mg/kg) was given 1, 3, and 6hours after ischemia; 24 hours later brain edema and antioxidant enzyme activity were assessed. The results indicated that treatment with crocin at doses of 30, 60, and 120 mg/kg significantly decreased infarct volume by 64%, 74%, and 73%, respectively. Administration of crocin (60 mg/kg) 1 hour before, at the start, or 1hour after ischemia reduced brain edema by 48%, 52%, and 51%, respectively. Moreover, crocin (60 mg/kg) significantly reduced malondialdehyde (MDA) content and increased activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the ischemic cortex (P< .001). Our findings indicate that crocin has protective effects against ischemic reperfusion injury and cerebral edema in a rat model of stroke. These effects of crocin may have been exerted primarily by suppression of the production of free radicals and increased antioxidant enzyme activity.

Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling.

Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10–30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3–1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca2+] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.

Reperfusion brain injury

Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion.

Reduction of ischemic brain injury by administration of palmitoylethanolamide after transient middle cerebral artery occlusion in rats

Stroke is the third leading cause of death and the leading cause of long-term disability in adults. Current therapeutic strategies for stroke, including thrombolytic drugs, such as tissue plasminogen activator offer great promise for the treatment, but complimentary neuroprotective treatments are likely to provide a better outcome. To counteract the ischemic brain injury in mice, a new therapeutic approach has been employed by using palmitoylethanolamide (PEA). PEA is one of the members of N-acyl-ethanolamine family maintain not only redox balance but also inhibit the mechanisms of secondary injury on ischemic brain injury. Treatment of the middle cerebral artery occlusion (MCAo)-induced animals with PEA reduced edema and brain infractions as evidenced by decreased 2,3,5-triphenyltetrazolium chloride (TTC) staining across brain sections. PEA-mediated improvements in tissues histology shown by reduction of lesion size and improvement in apoptosis level (assayed by Bax and Bcl-2) further support the efficacy of PEA therapy. We demonstrated that PEA treatment blocked infiltration of astrocytes and restored MCAo-mediated reduced expression of PAR, nitrotyrosine, iNOS, chymase, tryptase, growth factors (BDNF and GDNF) and GFAP. PEA also inhibited the MCAo-mediated increased expression of pJNK, NF-κB, and degradation of IκB-α. PEA-treated injured animals improved neurobehavioral functions as evaluated by motor deficits. Based on these findings we propose that PEA would be useful in lowering the risk of damage or improving function in ischemia–reperfusion brain injury-related disorders.

The role of protein kinase C in ischemic tolerance induced by hyperoxia in rats with stroke.

Recent studies suggest that normobaric hyperoxia (HO) protects the rat brain from ischemia reperfusion (IR) injury. Protein kinase C (PKC) is a key signaling molecule involved in protection against IR injury but its role in protective effect of HO in brain injury in unknown. In this study we attempted to see if PKC is involved in the effect of HO. Rats were divided into four main experimental groups. The first two were exposed to 95 % oxygen (HO) in a chamber 4 h/day for 6 consecutive days. Each of these groups had a control group exposed to 21 % oxygen. To investigate the role of PKC during HO, chelerythrin chloride (CHEL, 1 mg/kg/day), a PKC inhibitor, or its vehicle was given to animals for 6 days. After 24 h, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h reperfusion neurological deficit scores, infarct volume, brain edema and blood-brain Barrier (BBB) permeability were assessed. HO decreased the infarct volume and brain edema in comparison with controls. PKC inhibition was associated with a significant increase in infarct size in both HO and control animals. PKC inhibition was unable to change brain edema in the experimental groups. Both HO and PKC inhibition reduced the BBB permeability within 24 h post occlusion of middle cerebral artery. Although both HO and PKC inhibition were associated with inhibition of BBB permeability during ischemic brain injury in rats, the neuroprotective effect of HO was independent of PKC in the MCAO model.

Studies of isolated global brain ischaemia: II. Controlled reperfusion provides complete neurologic recovery following 30 min of warm ischaemia - the importance of perfusion pressure

Neurologic injury after sudden death is likely due to a reperfusion injury following prolonged brain ischaemia, and remains problematic, especially if the cardiac arrest is unwitnessed. This study applies a newly developed isolated model of global brain ischaemia (simulating unwitnessed sudden death) for 30 min to determine if controlled reperfusion permits neurologic recovery. Among the 17 pigs undergoing 30 min of normothermic global brain ischaemia, 6 received uncontrolled reperfusion with regular blood (n = 6), and 11 were reperfused for 20 min with a warm controlled blood reperfusate containing hypocalcaemia, hyper-magnesemia, alkalosis, hyperosmolarty and other constituents that were passed through a white blood cell filter and delivered at flow rates of 350 cc/min (n = 3), 550 cc/min (n = 2) or 750 cc/min (n = 6). Neurologic deficit score (NDS) evaluated brain function (score 0 = normal, 500 = brain death) 24 h post-reperfusion and 2,3,5-triphenyltetrazolium chloride (TTC) staining determined brain infarction. Regular blood (uncontrolled) reperfusion caused negligible brain O(2) uptake by IN Vivo Optical Spectroscopy (INVOS) (<10-15% O(2) extraction), oxidant damage demonstrated by raised conjugated diene (CD) levels (1.78 ± 0.13 A233 mn), multiple seizures, 1 early death from brain herniation, high NDS (249 ± 39) in survivors, brain oedema (84.4 ± 0.6%) and extensive cerebral infarctions. Conversely, controlled reperfusion restored surface brain oxygen saturation by INVOS to normal (55-70%), but the extent of neurologic recovery was determined by the brain reperfusion pressure. Low pressure reperfusion (independent of flow) produced the same adverse functional, metabolic and anatomic changes that followed uncontrolled reperfusion in seven pigs (three at 350 cc/min, two at 550 and two at 750 cc/min). Conversely, higher reperfusion pressure in four pigs (all at 750 cc/min) resulted in NDS of 0-70* indicating complete (n = 2) or near complete (n = 2) neurological recovery, negligible CDs production (1.29 ± 0.06 A233mn)*, minimal brain oedema (80.6 ± 0.2%)* and no infarction by TTC stain. Brain injury can be avoided after 30 min of normothermic cerebral ischaemia if controlled reperfusion pressure is >50 mmHg, but the lower pressure (<50 mmHg) controlled reperfusion that is useful in other organs cannot be transferred to the brain. Moreover, INVOS is a poor guide to the adequacy of cerebral perfusion and the capacity of controlled brain reperfusion to restore neurological recovery. *P < 0.001 versus uncontrolled or low pressure controlled reperfusion.

Sevoflurane-induced delayed neuroprotection involves mitoKATP channel opening and PKC ε activation

There is an increasing body of evidence that a brief exposure to anesthesia induces ischemic tolerance in rat brain (anesthetic preconditioning). However, it is unknown whether preconditioning with sevoflurane, a commonly used volatile anesthetic in current clinical practice, produces a delayed window of neuroprotection against ischemia and what the mechanisms are for this protection. To address these issues, adult male Sprague-Dawley rats were subjected to middle cerebral arterial occlusion (MCAO) for 2h. Sevoflurane preconditioning was induced 24h before brain ischemia by exposing the animals to sevoflurane at 1.0 minimum alveolar concentration (2.4%) in oxygen for 60min. Animals preconditioned with sevoflurane had lower neurological deficit scores and smaller brain infarct volumes than animals with brain ischemia at 6 and 24h after MCAO, respectively. Application of a selective antagonist for mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, 5-hydroxydecanoate (5-HD, 40mg/kg i.p.) 30min before sevoflurane exposure attenuated this beneficial effect. Moreover, protein kinase C ε (PKC ε) was translocated to the membrane fraction at 6h, but not 24h, after brain reperfusion in animals preconditioned with sevoflurane and this effect was also abolished by 5-HD. We concluded that sevoflurane preconditioning induces a delayed neuroprotection and that mitochondrial K(ATP) channels and PKC ε may be involved in this neuroprotection.

Effect of Treatment with Cyanidin-3-O-β-D-Glucoside on Rat Ischemic/Reperfusion Brain Damage

This study investigated the effect of cyanidin-3-O-β-glucoside on an experimental model of partial/transient cerebral ischemia in the rats in order to verify the effectiveness of both pre- and posttreatments. Cyanidin-3-O-β-glucoside-pretreated rats were injected with 10 mg/Kg i.p. 1 h before the induction of cerebral ischemia; in posttreated rats, the same dosage was injected during reperfusion (30 min after restoring blood flow). Cerebral ischemia was induced by bilateral clamping of common carotid arteries for 20 min. Ischemic rats were sacrificed immediately after 20 min ischemia; postischemic reperfused animals were sacrificed after 3 or 24 h of restoring blood flow. Results showed that treatment with cyanidin increased the levels of nonproteic thiol groups after 24 h of postischemic reperfusion, significantly reduced the lipid hydroperoxides, and increased the expression of heme oxygenase and γ-glutamyl cysteine synthase; a significant reduction in the expression of neuronal and inducible nitric oxide synthases and the equally significant increase in the endothelial isoform were observed. Significant modifications were also detected in enzymes involved in metabolism of endogenous inhibitors of nitric oxide. Most of the effects were observed with both pre- and posttreatments with cyanidin-3-O-β-glucoside suggesting a role of anthocyanin in both prevention and treatment of postischemic reperfusion brain damage.

Choice of Anesthesia Mode, Neuroprotective Therapy in the Surgical Repair of Extracranial Vessels

Objective: to improve the direct results of carotid endarterectomy, by reducing the number of perioperative complications via the choice of an anesthesia mode and a neuroprotective regimen for possible neurological complications. Subjects and methods. Total intravenous diprivan anesthesia versus regional cervical plexus anesthesia after Pashchuk and inhaled sevorane anesthesia was evaluated in 190 patients with carotid endarterectomy. The parameters of cerebral blood flow and the markers for brain damage were studied. Results. Sevorane anesthesia has been shown to maintain optimal cerebral blood flow, which limits ischemia and reperfusion brain damages and results in fewer postoperative complications. Neurological disorders were an indication for neuroprotective therapy and, according to which, the patients were divided into 2 matched groups. Therapy with mexidol and cytoflavin, which had already become traditional, was used in Group 1. Group 2 patients were given the current neuroprotective agent citicoline (ceraxone) with actovegin. The performed trials showed that the neuroprotective therapy used in Group 2 was more effective (5% significance level) than that in Group 1. Conclusion. Inhalational sevorane anesthesia versus total intravenous diprivan anesthesia and regional cervical plexus anesthesia is characterized by optimal cerebral blood flow values, less neuronal damage, and fewer postoperative neurological complications. Irrespective of the mode of anesthesia, neuroprotective therapy involving ceraxone in combination with actovegin is preferred for the intensive therapy of postoperative neurological disorders. Key words: diprivan, sevorane, neuron-specific enolase, linear cerebral blood flow velocity, carotid endarterectomy, cerebral perfusion pressure, brain-specific protein antibodies, ceraxone.

Neuroprotective effects of olprinone after cerebral ischemia/reperfusion injury in rats

Olprinone hydrochloride, a specific phosphodiesterase III inhibitor, has anti-inflammatory effects in addition to its inotropic and vasodilatory effects. The purpose of this study was to examine the beneficial effects of olprinone on cerebral ischemia reperfusion injury. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of olprinone on inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAo) in rats. Focal cerebral ischemia was induced by transient MCAo in the right hemisphere, via the external carotid artery into the internal carotid to block the origin of the median carotid artery. The rats were subjected to artery occlusion (2 h) followed by reperfusion (22 h). Olprinone was administered 5 min before reperfusion. MCAo-induced cerebral ischemia was associated with an increase in inducible nitric oxide synthase expression, nitrotyrosine formation, as well as IL-1β expression and ICAM-1 expression in ischemic regions. Olprinone treatment showed marked reduction in infarct size compared with control rats. These expressions were markedly inhibited by olprinone treatment. We also demonstrated that olprinone reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia–reperfusion brain injury. Based on these findings we propose that olprinone would be useful in lowering the risk of damage or improving function in ischemia–reperfusion brain injury-related disorders.

PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in cholesterol homeostasis through enhanced degradation of the LDL receptor (LDLR) in liver. As novel inhibitors/silencers of PCSK9 are now being tested in clinical trials to treat hypercholesterolemia, it is crucial to define the physiological consequences of the lack of PCSK9 in various organs. LDLR regulation by PCSK9 has not been extensively described during mouse brain development and injury. Herein, we show that PCSK9 and LDLR are co-expressed in mouse brain during development and at adulthood. Although the protein levels of LDLR and apolipoprotein E (apoE) in the adult brain of Pcsk9(-/-) mice are similar to those of wild-type (WT) mice, LDLR levels increased and were accompanied by a reduction of apoE levels during development. This suggests that the upregulation of LDLR protein levels in Pcsk9(-/-) mice enhances apoE degradation. Upon ischemic stroke, PCSK9 was expressed in the dentate gyrus between 24 h and 72 h following brain reperfusion. Although mouse behavior and lesion volume were similar, LDLR protein levels dropped ∼2-fold less in the Pcsk9(-/-)-lesioned hippocampus, without affecting apoE levels and neurogenesis. Thus, PCSK9 downregulates LDLR levels during brain development and following transient ischemic stroke in adult mice.

Brain ischemia changes the long term response to antidepressant drugs in mice

Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke.

The protective roles of mitochondrial ATP-sensitive potassium channels during hypoxia–ischemia–reperfusion in brain

The role of ATP-sensitive potassium (K ATP) channels in cerebral ischemia–reperfusion has been well documented. K ATP channel openers protect neuron by mimicking ischemic preconditioning. However, the different protection between the mitochondrial and sarcolemma K ATP openers has been seldom studied. In the experiment, we investigated the effects of K ATP channel openers diazoxide and pinacidil on the hypoxia–ischemia–reperfusion in cultured hippocampal neurons and gerbil brain. The cultured hippocampal neurons and gerbil brain were pretreated with diazoxide or pinacidil before oxygen-glucose deprivation (OGD) and cerebral ischemia–reperfusion, respectively. Survival rate, apoptosis rate and lactate dehydrogenase (LDH) releasing after the reperfusion were subsequently detected. Then the subunits mRNA was detected by RT-PCR. The survival rate and LDH content in diazoxide group increased more than that in pinacidil group (86.21 ± 2.73% vs. 78.59 ± 1.94%, P < 0.05; 133.29 ± 15.00 U/L vs. 193.47 ± 3.39 U/L, P < 0.01). The apoptosis rate in diazoxide group decreased significantly more than that in pinacidil group (23.82 ± 0.14% vs. 37.05 ± 0.67%, P < 0.01). Diazoxide pretreatment increased the expression of Kir6.1 mRNA obviously. The results suggested that mitoK ATP channels opener diazoxide played a major protective role on cerebral ischemia–reperfusion. Furthermore, diazoxide might become a new treatment for cerebral ischemia diseases through increasing the expression of Kir6.1 mRNA.

Induced Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Pathophysiology, Current Treatment, and Nursing Considerations

Hypoxic-ischemic encephalopathy (HIE) can lead to devastating neurodevelopmental consequences such as cerebral palsy, seizure disorders, and significant developmental delays. HIE in the newborn is often the result of a hypoxic event, such as uterine rupture, placental abruption, or cord prolapse. Biphasic brain injury occurs in HIE. The first phase involves activation of the sympathetic nervous system as a compensatory mechanism. The second phase, known as reperfusion brain injury, occurs hours later. Induced hypothermia, a neuroprotective strategy for treating HIE, targets the second phase to prevent reperfusion injury. NICU nurses are in a unique position to detect patient instability and to maintain the therapeutic interventions that contribute to the healing process. This article highlights the significant role nurses play in the management of infants diagnosed with HIE who are treated with induced hypothermia.

Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats

NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. The aim of this study is identifying apocynin as a critical modulator of NADPH oxidase and elucidating its role as a neuroprotectant in an experimental model of brain ischemia in rat. Treatment of apocynin 5min before of reperfusion attenuated cerebral ischemia in rats. Administration of apocynin showed marked reduction in infarct size compared with that of control rats. Medial carotid artery occlusion (MCAo)-induced cerebral ischemia was also associated with an increase in, nitrotyrosine formation, as well as IL-1β expression, IκB degradation and ICAM expression in ischemic regions. These expressions were markedly inhibited by the treatment of apocynin. We also demonstrated that apocynin reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia–reperfusion brain injury. This new understanding of apocynin induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases.

Neurocritical Care of a Reperfused Brain

Cerebral hyperperfusion and reperfusion injuries are not infrequently encountered following in reperfusion of ischemic or hypoperfused brain. Mechanism of injury could be related to tissue plasminogen activator toxicity, oxidative stress, and hyperperfusion due to impaired cerebral autoregulation in already maximally dilated cerebral vasculature and compromised cerebral hemodynamic reserve. Reperfusion injury can present as headaches and seizures in mild forms and as subarachnoid hemorrhage, intracranial hemorrhage, cerebral edema, and encephalopathy in its most severe manifestation. Prevention and identifying those at risk of hyperperfusion syndromes are the best strategy. Active treatment includes basic neurocritical care with reduction of blood pressure to a reperfused brain and timely neuroprotection and cerebral edema control measures are the mainstay of its management approach.

951 Tacrolimus and Leu-Ile Inhibit Hypoxic-Ischemic Encephalopathy in Newborn Rats

We used a neonatal rat hypoxia ischemia (HI)/ reperfusion brain damage model and investigated the neuroprotective effects of the immunosuppressant tacrolimus (FK506) and the hydrophobic peptide Leu-Ile, which has an active site similar to that of FK506 but is not an immunosuppressant. Method: HI was induced in 7- or 8-day-old Wister rat pups by transient right carotid artery occlusion, followed by exposure to 8% O. After HI insult, the rats were intraperitoneally administered FK506, Leu-Ile, a combination of the 2 drugs, or vehicle. Twenty-four hours or 7 d after HI, we analyzed the decreasing ratio of cerebral hemispheric weights and then histologically examined the brain tissue by HE, Iba-1, and caspase-3 staining. Body weight gain was also monitored. Result: The decreasing ratio of cerebral hemispheric weights in the FK506, Leu-Ile, and combination groups was lower than that in the vehicle group, but this ratio was significantly different only between the vehicle and FK506 groups. Pathological analysis showed that neurocytic injury had a strong suppressive effect in the FK506 and combination groups and a mild effect in the Leu-Ile group. During the 7-d experiment, the FK506 group showed lower body weight gain than the other groups. Conclusion: Combination treatment with Leu-Ile and FK506 had a stronger neuroprotective effect and lesser side effects; thus, we concluded that combination therapy might have potential for clinical application in neonatal HIE.