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Purpose of Review: Many efforts have been made in the last decades to improve outcome in patients who are successfully resuscitated from sudden cardiac arrest. Despite some advances, postanoxic encephalopathy remains the most common cause of death among those patients and several investigations have focused on early neuroprotection in this setting., Recent Findings: Therapeutic hypothermia is the only strategy able to provide effective neuroprotection in clinical practice. Experimental studies showed that therapeutic hypothermia was even more effective when it was started immediately after the ischemic event. In human studies, the use of prehospital hypothermia was able to reduce the time to target temperature but did not result in higher survival rate or neurological recovery in patients with out-of-hospital cardiac arrest, when compared with standard in-hospital therapeutic hypothermia. Thus, intra-arrest hypothermia (i.e., initiated during cardiopulmonary resuscitation) may be a valid alternative to improve the effectiveness of therapeutic hypothermia in this setting; however, more clinical data are needed to demonstrate any potential benefit of such intervention on neurological outcome. Together with cooling, early hemodynamic optimization should be considered to improve cerebral perfusion in cardiac arrest patients and minimize any secondary brain injury. Nevertheless, only scarce data are available on the impact of early hemodynamic optimization on the development of organ dysfunction and neurological recovery in such patients. Some new protective strategies, including inhaled gases (i.e., xenon, argon, nitric oxide) and intravenous drugs (i.e., erythropoietin) are emerging in experimental studies as promising tools to improve neuroprotection, especially when combined with therapeutic hypothermia., Summary: Early cooling may contribute to enhance neuroprotection after cardiac arrest. Hemodynamic optimization is mandatory to avoid cerebral hypoperfusion in this setting. The combination of such interventions with other promising neuroprotective strategies should be evaluated in future large clinical studies.

Background: The angiotensin (Ang) converting enzyme 2 (ACE2)/Ang-(1-7)/Mas receptor pathway is an important component of the renin-angiotensin system and has been suggested to exert beneficial effects in ischemic stroke., Aims: This study explored whether the ACE2/Ang-(1-7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age., Methods: We used three-month and eight-month transgenic mice with neural over-expression of ACE2 (SA) and their age-matched nontransgenic (NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation (OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1-7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species (ROS) production and cell death were measured., Results: (1) Middle cerebral artery occlusion -induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight-month animals; (2) OGD-induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight-month mice; (3) Ang-(1-7) and A779 had opposite effects on OGD-induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production., Conclusions: Angiotensin converting enzyme 2/Ang-(1-7)/Mas axis protects brain from ischemic injury via the Nox/ROS signaling pathway, with a greater effect in older animals., (© 2014 John Wiley & Sons Ltd.)

The use of extracorporeal membrane oxygenation (ECMO) is becoming a popular tool in the treatment of cardiogenic shock. We present two case reports where classical veno-arterial peripherally cannulated ECMO therapy proved insufficient with profuse cerebral hypoxemia. After augmenting the setting into veno-veno-arterial ECMO, we achieved a remarkable improvement of all oxygenation parameters. The simultaneous use of veno-venous and veno-arterial ECMO might display as a novel strategy to counteract the coronary and cerebral hypoxemia in veno-arterial ECMO therapy in patients with therapy-refractory cardiogenic shock or in combined cardiopulmonary failure. In this manuscript, the veno-veno-arterial ECMO setup is described in full detail and different venous cannulas are discussed.

One of the less well-documented, potentially modifiable stroke risk factor is the obstructive sleep apnea. Obstructive sleep apnea increases cardiovascular morbidity and mortality, including stroke risk. The article summarizes the pathophysiological factors in sleep apnea syndrome which can increase stroke risk.

Background: Bilaterally absent N20 components of the sensory evoked potentials (SEP) from the median nerve are regarded as accurately predicting poor outcome after cardiac arrest., Case Presentation: We are reporting on a patient, who regained consciousness despite this ominous finding. Early after cardiac arrest, MRI showed signal alterations in diffusion weighted imaging (DWI) bilaterally in the primary visual and sensorimotor cortex and in the basal ganglia. SEP were repeatedly absent. The patient survived shut out form sensory and visual experience and locked in for voluntary movements, but kept her verbal competence in several languages., Conclusion: SEP inform about integrity only of a narrow cortical strip. It is unguarded, but common practice, to conclude from absent SEP, that a patient has suffered diffuse cortical damage after cardiac arrest. Cerebral MRI with DWI helps to avoid this prognostic error and furthers understanding of the sometimes very peculiar state of mind after cardiac arrest.

Purpose of Review: Fever is common in the ICU among patients with severe brain injury. Fever has been consistently shown to exacerbate brain injuries in animal models and has been consistently associated with poor outcome in human studies. However, whether fever control improves outcome and the ideal means of fever control remain unknown. This review will address recent literature on the impact of fever on severe brain injury and on interventions to maintain normothermia., Recent Findings: Current guidelines generally recommend maintenance of normothermia after brain injury but have scant recommendations on methods to do this. Observational trials have continued to demonstrate the association between fever and poor outcome after severe brain injury. Recent trials have shown the efficacy of more aggressive approaches to fever reduction, whereas a large randomized trial showed the relative ineffectiveness of acetaminophen alone for fever control. Several studies have also described the impact of fever and of fever control on brain physiology., Summary: The value of therapeutic normothermia in the neurocritical care unit (NCCU) is increasingly accepted, yet prospective trials that demonstrate a functional benefit to patients are lacking.

Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4-5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment.

The incidence of preterm birth is on the rise. The outcome of premature birth can vary widely, spanning completely normal development to severe neurologic deficits, with most children showing mild to moderate cognitive delay and increased incidence of neuropsychiatric conditions such as anxiety, attention deficit hyperactivity, and autism spectrum disorders. Several animal models have been employed to study the consequences of prematurity, one of the most promising being chronic perinatal hypoxia in mouse, which recapitulates the cognitive impairments, partial recovery over time and enhanced recovery with environmental enrichment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Stroke and cerebral hypoxia are among the main complications during cardiopulmonary bypass (CPB). The two main reasons for these complications are the cannula jet, due to altered flow conditions and the sandblast effect, and impaired cerebral autoregulation which often occurs in the elderly. The effect of autoregulation has so far mainly been modeled using lumped parameter modeling, while Computational Fluid Dynamics (CFD) has been applied to analyze flow conditions during CPB. In this study, we combine both modeling techniques to analyze the effect of lumped parameter modeling on blood flow during CPB. Additionally, cerebral autoregulation is implemented using the Baroreflex, which adapts the cerebrovascular resistance and compliance based on the cerebral perfusion pressure. The results show that while a combination of CFD and lumped parameter modeling without autoregulation delivers feasible results for physiological flow conditions, it overestimates the loss of cerebral blood flow during CPB. This is counteracted by the Baroreflex, which restores the cerebral blood flow to native levels. However, the cerebral blood flow during CPB is typically reduced by 10-20% in the clinic. This indicates that either the Baroreflex is not fully functional during CPB, or that the target value for the Baroreflex is not a full native cerebral blood flow, but the plateau phase of cerebral autoregulation, which starts at approximately 80% of native flow., (© 2013 Elsevier Ltd. All rights reserved.)

Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus., (© 2013.)

Preconditioning increases the neurons' resistance to subsequent hypoxia. An in vitro study was conducted to explore kinetic aspects of hypoxic preconditioning. Hippocampal slices were exposed to one single or repeated episodes of oxygen and glucose deprivation (OGD). The interval between OGD episodes varied between 30 min and 180 min. OGD led to a significant reduction in the population spike amplitude. Subsequent episodes of OGD did not result in a further reduction in the population spike amplitude if the interval between the episodes was ca. 60 min, which demonstrated that there were preconditioning effects. In the experiment using an interval of 30 min, population spike amplitude decreased after each OGD episode. The set-up described is useful for detecting damaging effects of OGD as well as preconditioning effects. A time window of ca. 60 min is required to induce protective mechanisms., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Despite many efforts, the pathophysiology and mechanism of blast-induced traumatic brain injury (bTBI) have not yet been elucidated, partially due to the difficulty of real-time diagnosis and extremely complex factors determining the outcome. In this study, we topically applied a laser-induced shock wave (LISW) to the rat brain through the skull, for which real-time measurements of optical diffuse reflectance and electroencephalogram (EEG) were performed. Even under conditions showing no clear changes in systemic physiological parameters, the brain showed a drastic light scattering change accompanied by EEG suppression, which indicated the occurrence of spreading depression, long-lasting hypoxemia and signal change indicating mitochondrial energy impairment. Under the standard LISW conditions examined, hemorrhage and contusion were not apparent in the cortex. To investigate events associated with spreading depression, measurement of direct current (DC) potential, light scattering imaging and stereomicroscopic observation of blood vessels were also conducted for the brain. After LISW application, we observed a distinct negative shift in the DC potential, which temporally coincided with the transit of a light scattering wave, showing the occurrence of spreading depolarization and concomitant change in light scattering. Blood vessels in the brain surface initially showed vasodilatation for 3-4 min, which was followed by long-lasting vasoconstriction, corresponding to hypoxemia. Computer simulation based on the inverse Monte Carlo method showed that hemoglobin oxygen saturation declined to as low as ∼35% in the long-term hypoxemic phase. Overall, we found that topical application of a shock wave to the brain caused spreading depolarization/depression and prolonged severe hypoxemia-oligemia, which might lead to pathological conditions in the brain. Although further study is needed, our findings suggest that spreading depolarization/depression is one of the key events determining the outcome in bTBI. Furthermore, a rat exposed to an LISW(s) can be a reliable laboratory animal model for blast injury research.

Background: Recent reports suggest that intensive, progressive training on working memory tasks can lead to generalized cognitive gains., Case Study: A patient, following hypoxic brain damage, showed significant difficulties in working memory and time-perception. This study examined the impact and specificity of any benefits resulting from automated working memory training (AWMT) in comparison with the effects of an equivalent programme that emphasized automated novel problem-solving (APST) which served as an active control. Following initial assessment, the patient trained for 4 weeks (20 days), 20-30 minutes a day on the APST tasks before repeating key outcome measures. He then trained for an identical period on AWMT., Results: There were no cognitive gains apparent following APST. Furthermore, there were no disproportionate gains on digit span following AWMT. AWMT was, however, associated with improvement in time-perception that had previously been resistant to rehabilitation. In line with previous reports, AWMT was also followed by gains on a measure of planning., Conclusion: The results provide encouraging evidence that AWMT may have generalized benefits in the context of impaired WM capacity following brain injury.

Objective: This study describes a case of lesions of the upper motor neuronal pathway with locked-in features after lightning strike and cardiac arrest., Design: A case-review analysis., Methods: In a 29-year-old male who was hit by a lightning strike during farming activities, cardiopulmonary resuscitation was provided first by co-workers and continued with success by the medical rescue service. After conducting advanced life support under monitoring and therapeutic hypothermia, quadriplegia with facial diplegia was recognized. A review was undertaken detailing the clinical course., Results: MR imaging presented signs consistent with hypoxia-induced damage and diffusion-weighted MR images revealed pronounced damages along the upper motor neuronal pathway. A reactive electroencephalogram pattern, sustained eye movement and the patient communicating via eye-blinking were interpreted as locked-in features. Two weeks after admission the patient was transferred to a neurological rehabilitation centre for further professional care., Conclusion: Direct damage of the upper motor neuron pathway due to the current of the lightning should be considered, albeit the relative contribution of hypoxia-induced damage cannot be separated.

Aim of this study was to assess brain oxygen supply in patients with chronic pulmonary embolism (CPE) for elucidation of factors of risk of neurological complications in early postoperative period. We examined 34 patients with diagnosis of CPE. Mean duration of the disease was 3 (1.4-4.2) years. Data on baseline cerebral oxygenation, monitoring of brain oxygen during various stages of surgery, and level of cerebral oxygen supply in immediate postoperative period are presented. More than 40% lowering from initial values of parameters of cerebral oxygenation during circulatory arrest substantially increases risk of development of neurological complications in early postoperative period.

Current study explores the feasibility of using a non-surgical method of oxygen deprivation to create Hypoxic brain damage in neonatal rats for medical studies. 7-day-old Sprague Dowley (SD) rats were kept in a container with low oxygen level (8%) for 1.5h. A second group had bilateral cephalic artery ligation before the 1.5h-low oxygen treatment, a method similar to the popular Rice method, to expose the brain to both hypoxic and ischemic situations. Short term neural functions and brain water weights were evaluated 1 day after the hypoxic treatment. Brain pathology and histology were also examined at 1 day and 3 days after the hypoxic treatment. Both groups showed impaired neural functions and increased brain water weight compared to the controls. Histology studies also revealed injuries in the subcortex, hippocampus and lateral ventricle in the brains from both groups. There is no significant difference in the degree of brain damages observed in the two groups. Our work demonstrated that oxygen deprivation alone is sufficient to cause brain damages similar to those seen in Hypoxic-ischemic brain disease (HIBD). Because this method avoids the invasive surgical procedure and therefore reduces the stress and mortality of laboratory animals during the experiment, we recommend it to be the favorable method for creating rat models for HIBD studies.

Background: Perinatal hypoxia can lead to a wide range of neurological deficits depending on the differential vulnerability of the involved brain regions to oxygen deprivation. It remains unclear whether the differential vulnerability to oxygen deprivation leads to altered neurogenesis in the neonatal brain after perinatal hypoxia. The primary objective was to investigate whether perinatal hypoxia induces deleterious changes in neurogenesis within three representative brain regions (dentate gyrus of the hippocampus, midbrain, and temporal cortex), with regards to common pathological areas clinically. The secondary objective was to investigate whether granulocyte-colony stimulating factor (G-CSF) therapy exerts beneficial effects in neurogenesis in neonatal rat brains subjected to experimental perinatal hypoxia., Materials and Methods: Rat pups were subjected to experimental perinatal hypoxia on the tenth day of life (P10). They were then given G-CSF (30 μg/kg, single injection/day, intraperitoneal injection, P11-16). The neurogenesis efficacy was analyzed on P17 and the radial-arm maze task, a memory task for higher cognitive functions such as problem-solving abilities, was evaluated on P37-58., Results: Perinatal hypoxia caused a significant decrease in neurogenesis within the three representative brain regions, and this deleterious outcome was alleviated by G-CSF (p < 0.05). In addition, the G-CSF therapy markedly improved the decreased performance of long-term cognitive functions induced by perinatal hypoxia (p < 0.05)., Conclusion: This study suggests that G-CSF may be a potentially beneficial therapy, at least in part, through universal recovery of neurogenesis effects in the neonatal brain after perinatal hypoxia insult., (Copyright © 2013. Published by Elsevier B.V.)

Repeated sprint ability (RSA) is a critical success factor for intermittent sport performance. Repeated sprint training has been shown to improve RSA, we hypothesised that hypoxia would augment these training adaptations. Thirty male well-trained academy rugby union and rugby league players (18.4 ± 1.5 years, 1.83 ± 0.07 m, 88.1 ± 8.9 kg) participated in this single-blind repeated sprint training study. Participants completed 12 sessions of repeated sprint training (10 × 6 s, 30 s recovery) over 4 weeks in either hypoxia (13% FiO₂) or normoxia (21% FiO₂). Pretraining and post-training, participants completed sports specific endurance and sprint field tests and a 10 × 6 s RSA test on a non-motorised treadmill while measuring speed, heart rate, capillary blood lactate, muscle and cerebral deoxygenation and respiratory measures. Yo-Yo Intermittent Recovery Level 1 test performance improved after RS training in both groups, but gains were significantly greater in the hypoxic (33 ± 12%) than the normoxic group (14 ± 10%, p<0.05). During the 10 × 6 s RS test there was a tendency for greater increases in oxygen consumption in the hypoxic group (hypoxic 6.9 ± 9%, normoxic (-0.3 ± 8.8%, p=0.06) and reductions in cerebral deoxygenation (% changes for both groups, p=0.09) after hypoxic than normoxic training. Twelve RS training sessions in hypoxia resulted in twofold greater improvements in capacity to perform repeated aerobic high intensity workout than an equivalent normoxic training. Performance gains are evident in the short term (4 weeks), a period similar to a preseason training block.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological abnormalities. Endogenous hydrogen sulfide (H2S) may have multiple functions in brain. The aim of this study is to investigate whether sodium hydrosulfide (NaHS), a H2S donor, provides protection against neonatal hypoxia-induced neurobehavioral deficits. Neonatal mice were subjected to hypoxia (5% oxygen for 120min) at postnatal day 1 and received NaHS (5.6mg/kg) once daily for 3d. Neurobehavioral toxicity was examined at 3-30d after hypoxia. Treatment with NaHS significantly attenuated the delayed development of sensory and motor reflexes induced by hypoxia up to two weeks after the insult. Moreover, NaHS improved the learning and memory performance of hypoxic animals as indicated in Morris water maze test at 30d after hypoxia. In mice exposed to hypoxia, treatment with NaHS enhanced expression of brain derived neurotrophic factor (BDNF) in the hippocampus. Furthermore, the protective effects of NaHS were associated with its ability to repress the hypoxia-induced nitric oxide synthase (NOS) activity and nitric oxide production in the hippocampus of mice brain. Taken together, these results suggest that the long-lasting beneficial effects of NaHS on hypoxia-induced neurobehavioral deficits are mediated, at least in part, by inducing BDNF expression and suppressing NOS activity in the brain of mice., (© 2013 Elsevier B.V. All rights reserved.)

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurobehavioral abnormalities. The purpose of this study was to determine whether administration of melatonin, starting at 1h before hypoxia and then every 24 h for 3 days, influences short and long-term neurobehavioral development and hippocampal impairments in postnatal day 1 mice subjected to hypoxia (5% oxygen and 95% nitrogen for 120 min). Melatonin significantly attenuated hypoxia-induced neurobehavioral deficits, including sensorimotor performance, locomotor functions, and hyperactivity up to two weeks after hypoxia insult. The above-mentioned functional benefits of melatonin were associated with attenuation of cell death in the hippocampus. Importantly, melatonin improved learning and memory performance in the Morris water test, as associated with significantly increased proliferating cells (BrdU-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the hippocampus of hypoxic animals at 30 days after hypoxia. In addition, melatonin significantly decreased microglial activation and overproduction of pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β and nitric oxide) from 3 to 30 days after hypoxia, possibly by inhibiting NF-κB activation in the hippocampus. The present results show that melatonin has short- and long-term protective effects against hypoxia-induced neurobehavioral deficits in the neonatal mouse. These beneficial effects are associated with increasing neurogenesis and attenuation of cell death and inflammatory responses in the hippocampus., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Present study was designed to report the effect of 2% creatine monohydrate supplementation for 8, 12 and 15 weeks on hematology and serum biochemical profile of male albino mouse following hypoxic ischemic insult on postnatal day 10., Methods: 66 Blood samples (2% creatine monohydrate supplemented (N = 34) and unsupplemented (N = 32)) were analyzed for various hematological (blood glucose, packed cell volume, total WBC count, total RBC count) and serum biochemical parameters (cholesterol, AST, ALT, HDL, LDL, total protein, triglycerides)., Results: ALT had higher concentrations in mice feeding on normal diet for 8 (P > 0.01) and 12 weeks (P > 0.01) following asphyxia and in 12 weeks treatment without asphyxia (P = 0.006) when compared with the creatine supplemented mice. LDL (P = 0.011) and cholesterol (P > 0.01) had higher concentrations in mice on normal diet for 12 weeks following hypoxia ischemia. Cholesterol (P > 0.01) in 12 and glucose (P = 0.006) in 15 week treatment group had significantly lower concentrations in creatine supplemented male albino mice when compared with untreated group following hxpoic-ischemic insult., Conclusion: We concluded that creatine supplementation following hypoxic ischemic insult helps in maintain the normal blood chemistry.

The present work was aimed to evaluate the contribution of interoception to the autonomic and behavioral responses to hypoxia. To address this issue, we studied whether the inactivation of the primary interoceptive posterior insular cortex (pIC) may disrupt the autonomic and behavioral effects of hypoxia in conscious rats. Rats were implanted with telemetric transmitters and microinjection cannulae placed bilaterally in the pIC. After one week, rats were injected with bupivacaine (26.5μM 1μL/side) and saline (1μL/side) into the pIC, and exposed to hypoxia (∼6% O2) for 150s, and autonomic and behavioral responses were recorded. Hypoxia produces hypertension, tachycardia followed by bradycardia, and hypothermia. When O2 dropped to ∼8%, rats showed escape behavior. Baseline cardiovascular variables and the pattern of hypoxia-induced autonomic and behavioral responses were not disrupted by pIC inactivation. However, pIC inactivation produced a modest but significant temperature decrease, higher bradycardic and hypertensive responses to hypoxia, and a minimal delay in escape onset. In addition, we measured the hypoxia-induced Fos activation in the nucleus tractus solitarius (NTS), the periaqueductal gray matter (PAG) and the pIC, which are key components of the interoceptive pathway. Hypoxia increased the number of Fos-positive neurons in the NTS and PAG, but not in the pIC. Present results suggest that pIC is not involved in the hypoxia-induced behavioral response, which seems to be processed in the NTS and PAG, but has a role in the efferent control of autonomic changes coping with hypoxia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We examined the relations between texture segregation and contour integration in patients with deficits in spatial attention leading to left or right hemisphere extinction. Patients and control participants were presented with texture and contour stimuli consisting of oriented elements. We induced regularity in the stimuli by manipulating the element orientations resulting in an implicit texture border or explicit contour. Participants had to discriminate curved from straight shapes without making eye movements, while the stimulus presentation time was varied using a QUEST procedure. The results showed that only patients with right hemisphere extinction had a spatial bias, needing a longer presentation time to determine the shape of the border or contour on the contralesional side, especially for borders defined by texture. These results indicate that texture segregation is modulated by attention-related brain areas in the right posterior parietal cortex.

Introduction: Red Bull Stratos was a commercial program that brought a test parachutist protected by a full pressure suit to 127,852 ft (38,964 m), via a stratospheric balloon with a pressurized capsule, from which he free fell and subsequently parachuted to the ground. In light of the uniqueness of the operation and the medical threats faced, medical protocols specific to distinctive injury patterns were developed. One unique threat was that of a flat spin during free fall with resultant exposure to -Gz (toe-to-head) acceleration. In preparation for stratospheric free fall, the medical team conducted a review of the literature on the spectrum of human and animal injury patterns attributable to -Gz exposures. Based on the findings, an emergency medical field response protocol was developed for the rapid assessment, diagnosis, and treatment of individuals suspected of -Gz injury., Methods: A systematic review was conducted on available literature on human and animal studies involving significant -Gz exposure, with subsequent development of an applicable field treatment protocol., Results: The literature review identified pathophysiologic processes and mitigation strategies that were used to develop a prevention and treatment protocol, outlining appropriate interventions using current best medical practices. A medical field treatment protocol was successfully established for the high-altitude balloon program., Discussion: Available literature provided insight into best medical practices for the prevention and treatment of significant -Gz exposures during high-altitude parachute activity. Using the protocol developed for the field medical response, injuries from sustained -Gz exposure can be effectively managed in similar high-altitude and space operations.

Spreading depression (SD) is a profound depolarization of neurons and glia that propagates in a wave-like manner across susceptible brain regions, and can develop during periods of compromised cellular energy such as ischemia, when it influences the severity of acute neuronal damage. Although SD has been well characterized in the cerebral cortex and hippocampus, little is known of this event in the Substantia Nigra (SN), a brainstem nucleus engaged in motor control and reward-related behavior. Transverse brain slices (250 μm; P21-23 rats) containing the SN were subject to oxygen and glucose deprivation (OGD) tests, modeling brain ischemia. SD developed in lateral aspects of the SN within 3.3±0.2 min of OGD onset, and spread through the Substantia Nigra pars reticulata (SNr), as indicated by fast-occurring and propagating increased tissue light transmittance and negative shift of extracellular DC potential. These events were associated with profound mitochondrial membrane depolarization (ΔΨm) throughout the SN, as demonstrated by increased Rhodamine 123 fluorescence. Extracellular recordings from individual SNr neurons indicated rapid depolarization followed by depolarizing block, while dopaminergic neurons in the Substantia Nigra pars compacta (SNc) showed inhibition of firing associated with hyperpolarization. SD evoked in the SNr was similar to OGD-induced SD in the CA1 region in hippocampal slices. In the hippocampus, SD also developed during anoxia or aglycemia alone (associated with less profound ΔΨm than OGD), while these conditions rarely led to SD in the SNr. Our results demonstrate that OGD consistently evokes SD in the SN, and that this phenomenon only involves the SNr. It remains to be established whether nigral SD contributes to neuronal damage associated with a sudden-onset form of Parkinson's disease known as 'vascular parkinsonism'., (Copyright © 2013 Elsevier B.V. All rights reserved.)

H2S may serve as an important neuroprotectant. The present experiments were performed to determine whether H2S could attenuate the injuries sustained by the medullary respiratory centers of neonatal rats that were subjected to cigarette smoke exposure (CS) in utero. Pregnant SD rats were divided into 4 exposure groups: control, CS, CS+NaHS (donor of H2S) and NaHS. Hypoxia decreased the burst frequencies of the hypoglossal rootlets of the medullary slices in CS neonatal rats, and NaHS offset the hypoxia-induced respiratory suppression. Nissl staining indicated that NaHS alleviated the injuries that were sustained by neurons after CS in utero. NaHS also decreased the number of TUNEL-positive neurons and the expression of activated caspase-3 protein in the medulla oblongata of CS neonatal rats. Furthermore, NaHS promoted Bcl-2 protein expression and reduced Bax protein and mRNA expression in the medulla oblongata of CS neonatal rats. Therefore, the present study indicates that the anti-apoptotic effect of H2S protects rat medullary respiratory centers from injuries that would otherwise be sustained from in utero CS exposure., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To study the effect of selective moderate head cooling therapy on maximum length sequences brainstem auditory evoked potential (MLS-BAEP) in newborn piglets with hypoxic-ischemic brain damage., Methods: Sixteen newborn piglets aged 5-7 day old were randomly divided into three groups: normothermic control (n=4), HI (n=6) and mild hypothermia-treated (n=6). HI was induced through temporary occlusion of both carotid arteries, followed by mechanical ventilation with low concentration of oxygen (FiO2=0.06) for 30 minutes. Mild hypothermia was induced by equipment via circulating water. MLS-BAER was recorded before HI and at 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 7 days, 10 days, 13 days and 15 days after HI., Results: Compared with the normothermic control group, all latencies and intervals tended to increase significantly at 72 hours in the HI group and reached peak values on day 7. From day 10, all latencies and intervals tended to decrease, but apart from wave I latency, still differed significantly from those of the normothermic control group. MLS-BAER variables did not reach normal values until day 15. Ⅲ latency, Ⅰ-Ⅲ interval and Ⅰ-Ⅴ interval were significantly reduced in the hypothermia-treated group between 60 and 7 days after HI compared with the HI group (P<0.05). V latency and Ⅲ-Ⅴ interval in the hypothermia-treated group were also reduced compared with the HI group between 72 hours and 7 days after HI (P<0.05)., Conclusions: Both peripheral and central auditory systems are disturbed by HI, which shows as a significant increase in MLS-BAER variables (all latencies and intervals) in newborn piglets. Involvement in central brainstem auditory system reaches a peak on day 7 after injury. MLS-BAER variables still cannot reach to normal values until day 15. Selective moderate head cooling therapy can significantly reduce brainstem damage induced by HI.

Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hippocampal tissue suggests that GluK4 may act through the JNK pathway to regulate the molecular cascades that lead to excitotoxicity. Together, our findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders., (Copyright © 2013 IBRO. All rights reserved.)

Background: Reports on pediatric electroencephalogram of Nepalese patients are rare., Objective: We aimed to study the relationship between provisional clinical and electrophysiological diagnoses of pediatric patients with documentation of demographic profiles, and type and frequency of the disorders/diseases., Methods: Electroencephalographic reports of 634 children from 2006 to 2009 were analyzed at neurophysiology laboratory, department of Basic and Clinical Physiology, B. P. Koirala Institute of Health Sciences, Dharan, Nepal, retrospectively. Chi-Square test was applied after detail descriptive statistics., Results: Male and female were 72.2 % (n=458/634) and 27.76 % (n=176/634) respectively. Most frequent EEG abnormality was seizure disorder (n=370, 59.39%), then febrile seizure (n= 94, 15.08%) and birth asphyxia with hypoxic-induced encephalopathy (n=68, 10.91%). Electroencephalogram showed significant epileptiform discharges in seizure disorder (p=0.001, OR= 2.26, 95 % CI= 1.61 to 3.18) and in cerebral palsy (p=0.049, OR=6.88, 95 % CI=0.89 to 145.95), specifically in 6 to 12 (p=0.001, OR=2.94, 95 % CI=1.43 to 6.06) and one to five (p=0.019) years, respectively. Electroencephalogram detected significantly less epileptiform discharges (p=0.001, OR=0.25, 95 % CI= 0.15 to 0.42) in febrile seizure specifically in 1 to 5 years (p=0.003, OR=0.16, 95 % CI= 0.04 to 0.63)., Conclusion: Predominant Electroencephalographic abnormality was seizure disorder, followed by febrile seizure and birth asphyxia with hypoxic-induced encephalopathy respectively. Electroencephalographic abnormality was highly associated with seizure disorder and cerebral palsy but was not associated with febrile seizure.

Objective: Clinical trials of therapeutic hypothermia (TH) after cardiac arrest excluded patients with persistent hemodynamic instability after return of spontaneous circulation (ROSC), and thus equipoise may exist regarding use of TH in these patients. Our objective was to determine if TH is associated with worsening hemodynamic instability among patients who are vasopressor-dependent after ROSC., Methods: We performed a prospective observational study in vasopressor-dependent post-cardiac arrest patients. Inclusion criteria were age >17, non-trauma cardiac arrest, comatose after ROSC, and persistent vasopressor dependence. The decision to initiate TH (33-34 ° C) was made by the treating physician. We measured cumulative vasopressor index (CVI) and mean arterial pressure (MAP) every 15 min during the first 6h after ROSC. The outcome measures were change in CVI (primary outcome) and MAP (secondary outcome) over time. We graphed median CVI and MAP over time for the treated and not treated cohorts, and used propensity adjusted repeated measures mixed models to test for an association between TH induction and change in CVI or MAP over time., Results: Seventy-five post-cardiac arrest patients were included (35 treated; 40 not treated). We observed no major differences in CVI or MAP over time between the treated and not treated cohorts. In the mixed models we found no statistically significant association between TH induction and changes in CVI or MAP., Conclusion: In patients with vasopressor-dependency after cardiac arrest, the induction of hypothermia was not associated with a decrease in mean arterial pressure or increase in vasopressor requirement., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Hypoxia is one of the major stressors at high altitude. Exposure to hypobaric hypoxia induces several adverse consequences to the structural and functional integrity of brain. In an attempt to understand the proteome modulation, we used 2-DE coupled with MALDI-TOF/TOF for cortex and hippocampus exposed to short-term temporal (0, 3, 6, 12 and 24h) hypobaric hypoxia. This enabled us in the identification of 88 and 73 hypoxia responsive proteins in cortex and hippocampus respectively. We further compared the proteomes of both the regions and identified 37 common proteins along with 49 and 32 specific proteins for cortex and hippocampus respectively. We observed significant up-regulation of glycolytic enzymes like Gapdh, Pgam1, Eno1 and malate-aspartate shuttle enzymes Mdh1 and Got1in cortex as compared to hippocampus deciphering efficient use of energy producing substrates. This was coupled with concomitant increase in expression of antioxidant enzymes like Sod1, Sod2 and Pebp1 in cortex to neutralize the hypoxia-induced reactive oxygen species (ROS) generation. Our comparative proteomics studies demonstrate that efficient use of energy generating pathways in conjugation with abundance of antioxidant enzymes makes cortex less vulnerable to hypoxia than hippocampus., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Blood brain barrier (BBB) dysfunction is a common facet of cerebral ischemia, and the alteration of drug transporter, P-glycoprotein (P-gp), has been documented., Aims: This study explores influence of damaged BBB and elevated P-gp on cerebral verapamil penetration after ischemia both in vivo and in vitro., Methods: Middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (I/R) of rats, and Na(2)S(2)O(4) induced hypoxia/reoxygenation (H/R) damage of rat brain mirovessel endothelial cells (RBMECs) respectively, served as BBB breakdown model in vivo and in vitro. Evans-Blue (EB) extravagation and (125)I-albumin were used to quantify BBB dysfunction; UPLC-MS/MS analytical method was performed to determine accurately the concentration of verapamil in brain tissue and cell. Flow cytometry, immunohistochemistry and western blotting were applied to evaluate transport function and protein expression of P-gp., Results: Overexpressed ICAM-1 and MMP-9 mediated BBB dysfunction after ischemia, which induced EB leakage and (125)I-albumin uptake increase. Enhanced accumulation of verapamil in brain tissue, but intracellular concentration reduced evidently after H/R injury. Transcellular transportation of verapamil elevated when P-gp function or expression was inhibited after H/R injury., Conclusion: These data indicated that BBB penetration of verapamil under ischemia condition was not only depending on BBB breakdown, but also regulated by P-gp., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The protective effect of the mild hypoxia to the epilepsy has been widely tested. Although it is found that the hypoxia protects the brain by up-regulation of hypoxia-inducible factor-1α, few focused on systematic comparisons between different mild hypoxia manipulations and their effects. The male Sprague-Dawley rats were observed following exposure to hypoxia before and after epilepsy for 3 days with 90 min per day. The effects of different mild hypoxia manipulations on kainic acid-induced epilepsy were compared from the perspective of morphology, molecular biology and behavioral test. Results showed that different mild hypoxia manipulations could inhibit the cell apoptosis of kainic acid-induced rat hippocampus and improve their physiological functions. The effect of preconditioning group was better than that of postconditioning group and that of preconditioning and postconditioning with mild hypoxia group was the best among all the groups. The result showed that the preconditioning and postconditioning of mild hypoxia was recommended pre- and post-epilepsy and exposure to mild hypoxia should be prolonged. These findings might provide new ideas and methods for the clinical treatment of epilepsy.

To better understand cellular interactions of the cerebral angiogenesis induced by hypoxia, a spatiotemporal dynamics of cortical microvascular restructuring during an exposure to continuous hypoxia was characterized with in vivo two-photon microscopy in mouse cortex. The mice were prepared with a closed cranial window over the sensory-motor cortex and housed in 8-9 % oxygen room for 2-4 weeks. Before beginning the hypoxic exposure, two-photon imaging of cortical microvasculature was performed, and the follow-up imaging was conducted weekly in the identical locations. We observed that 1-2 weeks after the onset of hypoxic exposure, a sprouting of new vessels appeared from the existing capillaries. An average emergence rate of the new vessel was 15 vessels per unit volume (mm(3)). The highest emergence rate was found in the cortical depths of 100-200 μm, indicating no spatial uniformity among the cortical layers. Further, a leakage of fluorescent dye (sulforhodamine 101) injected into the bloodstream was not detected, suggesting that the blood-brain barrier (BBB) was maintained. Future studies are needed to elucidate the roles of perivascular cells (e.g., pericyte, microglia, and astroglia) in a process of this hypoxia-induced angiogenesis, such as sprouting, growth, and merger with the existing capillary networks, while maintaining the BBB.

Aim of the study was assessment of severity of cardiorespiratory abnormalities and cerebral oxygen supply in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We examined 56 patients with diagnosis of chronic pulmonary thromboembolism and duration of the disease 3 (1.5-4.1) years. According to data of pulmonary angiography pulmonary artery pressure was 78 (58-92) mm Hg, pulmonary vascular resistance - 618 (450-935) dyne/sec/cm-5, Miller index - 25 (22-27). Further investigation revealed changes of anatomo-functional parameters of the heart and parameters of pulmonary ventilation. These changes were associated with insufficient oxygen supply to the brain and lowering of tolerance to hypoxia. Results of this study should be taken into consideration when brain protective measures are provided during surgical treatment of CTEPH.

Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.

We report the case of a patient with sensorimotor conversion that improved transiently during post-anoxic medial temporal ischemia inducing anterograde and retrograde amnesia. Symptoms reappeared in parallel with mnesic recovery. This case raises a hypothesis concerning the role of hippocampi and amygdalae, which are involved in emotionally-associated memory. The amnesia may have modified the patient's "self," giving her a "distant" point of view. Another hypothesis is that cerebral anoxic stress may have "reset" the cerebral network that controls behavior. These findings give clues about the mechanisms of somatoform disorder and highlight the possibility of specific therapeutic strategies to induce cognitive reappraisal of emotionally-associated experiences.

Objectives: To establish whether aminophylline, administered at usual doses for rodents in pharmacological studies, induces brain injury in systemic hypoxaemia in guinea-pigs., Methods:  A hypoxaemia (partial oxygen tension of arterial blood (PaO₂) = 40-60 mmHg) model was developed by low tidal volume mechanical ventilation in guinea-pigs., Key Findings: Under hypoxic conditions, aminophylline significantly increased the concentration of brain-specific creatine kinase in the serum in a dose- and time-dependent manner. A reduced number of hippocampal neuronal cells in the CA1 region, an increase in the concentration of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF), an increase in lipid hydroperoxides and a decrease in the ratio of glutathione to glutathione disulfide in the brain tissues were also observed. These effects were not observed when aminophylline at the same doses was administered under normoxic conditions (PaO₂ = 80-100 mmHg). There was no difference in either serum or CSF concentrations of theophylline between normoxic and hypoxic conditions. Another methylxanthine, caffeine, did not increase the concentration of NSE in CSF., Conclusions: Aminophylline potentially induces brain damage under hypoxic conditions. We suggest that aminophylline treatment has adverse effects in patients with hypoxaemia subsequent to respiratory disorders such as asthma., (© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)

After global cerebral hypoxia, many patients are severely disabled even after intensive neurorehabilitation. Secondary mechanisms of brain injury as a result of biochemical and physiological events occur within a period of hours to months, and provide a window of opportunity for therapeutic intervention. Erythropoietin (EPO) has been shown to be neuroprotective in the brain subjected to a variety of injuries. Fifty-nine 3-month-old male Wistar rats were randomly distributed to experimental groups with respect to the housing (enriched environment - EE, standard housing - SH), to hypoxia exposure, and to EPO treatment. An acute mountain sickness model was used as a hypobaric hypoxia simulating an altitude of 8000 m. One half of the animals received erythropoietin injections, while the others were injected saline. Spatial memory was tested in a Morris water maze (MWM). The escape latency and the path length were measured. Better spatial learning in MWM was only seen in the group that received erythropoietin together with enriched environment. EPO administration itself had no influence on spatial memory. The results were very similar for both latencies and path lengths. These results support the idea that after brain injuries, the recovery can be potentiated by EPO administration combined with neurorehabilitation.

The parietal cortex is considered to be part of a network of brain areas that modulates competitive interactions between targets and irrelevant distracters in early visual cortex, however there is currently little causal evidence to support this in human observers. It is also unclear as to whether parietal influences on visual perception in humans are limited to the contralesional hemispace or whether a unilateral lesion affects visual sensitivity bilaterally. Here we examined visual sensitivity in two patients with spatial neglect and extinction arising primarily from left-parietal damage. We used a sensitive psychophysical task based on those previously used to demonstrate loss of stimulus selection after lesions to extrastriate cortex. Observers discriminated the orientation of a lateralized suprathreshold target grating that appeared alone or in the context of nearby salient disc distracters. For parietal patients, target sensitivity within both the contralesional and ipsilesional fields was compromised by the presence of distracters. Conversely, healthy matched controls were unaffected by distracters. These results indicate that parietal cortex damage can influence visual perception within both the ipsi- as well as the contralesional field., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Metabolic information is essential in the investigation of the pathophysiology of stroke-like episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Here, we used magnetic resonance imaging to evaluate the dynamic metabolic changes before and after a stroke-like episode in two patients with MELAS caused by the mitochondrial DNA mutation A3243G. We performed functional magnetic resonance imaging, including arterial spin labeling and oxygen extraction fraction imaging, and generated cerebral blood flow and oxygen extraction fraction maps. We recruited eight healthy volunteers to define the normal range of the oxygen extraction fraction. We detected a heterogeneous reduction in the oxygen extraction fraction in the brain in the interictal period as well as at the onset of a stroke-like attack. However, the oxygen extraction fraction in the stroke-like lesions normalized in the acute stage. The stroke-like lesions showed consistent hyperperfusion in the acute phase but hypoperfusion in the chronic phase. We have demonstrated the utility of using new magnetic resonance imaging techniques in the evaluation of the pathophysiology of stroke-like lesions. The increased utilization of oxygen in an acute lesion is a novel finding in our study, which might play a role in the oxidative stress., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Long-term synaptic plasticity has been recently described in brainstem areas associated to visceral afferent sensory integration. Chronic intermittent hypoxia (CIH), an animal model for studying obstructive sleep apnea in humans, depresses the afferent neurotransmission in nucleus tractus solitarii (NTS) neurons, which affect respiratory and autonomic regulation. Here we identified the synaptic mechanisms of CIH-induced depression of the afferent neurotransmission in NTS neurons in juvenile rats. We verified that CIH reduced the amplitude of both NMDA and non-NMDA glutamatergic excitatory currents (eEPSCs) evoked by tractus solitarii stimulation (TS-eEPSC) of second-order neurons in the NTS. No changes were observed in release probability, evidenced by absence of any CIH-elicited effects on short-term depression and failures in EPSCs evoked in low calcium. CIH also produced no changes in TS-eEPSC quantal size, since the amplitudes of both low calcium-evoked EPSCs and asynchronous TS-eEPSCs (evoked in the presence of Sr(2+)) were unchanged. Using single TS afferent fiber stimulation in slices from control and CIH rats we clearly show that CIH reduced the quantal content of the TS-eEPSCs without affecting the quantal size or release probability, suggesting a reduction in the number of active synapses as the mechanism of CIH induced TS-eEPSC depression. In accordance with this concept, the input-output relationship of stimulus intensity and TS-eEPSC amplitude shows an early saturation in CIH animals. These findings open new perspectives for a better understanding of the mechanisms underlying the synaptic plasticity in the brainstem sensory neurons under challenges such as those produced by CIH in experimental and pathological conditions.

Anoxia or ischemia causes hyperexcitability and cell death in mammalian neurons. Conversely, in painted turtle brain anoxia increases γ-amino butyric acid (GABA)ergic suppression of spontaneous electrical activity, and cell death is prevented. To examine ischemia tolerance in turtle neurons, we treated cortical sheets with an in vitro mimic of the penumbral region of stroke-afflicted mammalian brain (ischemic solution, IS). We found that during IS perfusion, neuronal membrane potential (V(m)) and the GABA(A) receptor reversal potential depolarized to a similar steady state (-92 ± 2 to -28 ± 3 mV, and -75 ± 1 to -35 ± 3 mV, respectively), and whole-cell conductance (G(w)) increased >3-fold (from 4 ± 0.2 to 15 ± 1 nS). These neurons were electrically quiet and changes reversed after reperfusion. GABA receptor antagonism prevented the IS-mediated increase in G(w) and neurons exhibited enhanced electrical excitability and rapid and irreversible rundown of V(m) during reperfusion. These results suggest that inhibitory GABAergic mechanisms also suppress electrical activity in ischemic cortex. Indeed, after 4 hours of IS treatment neurons did not exhibit any apparent damage; while at 24 hours, only early indicators of apoptosis were present. We conclude that anoxia-tolerant turtle neurons are tolerant of exposure to a mammalian ischemic penumbral mimic solution.

As brain-resident immune cells, microglia (MG) survey the brain parenchyma to maintain homeostasis during development and following injury. Research in perinatal stroke, a leading cause of lifelong disability, has implicated MG as targets for therapeutic intervention during stroke. Although MG responses are complex, work in developing rodents suggests that MG limit brain damage after stroke. However, little is known about how energy-limiting conditions affect MG survival and mobility (motility and migration) in developing brain tissues. Here, we used confocal time-lapse imaging to monitor MG viability and mobility during hypoxia or oxygen-glucose deprivation (OGD) in hippocampal tissue slices derived from neonatal GFP-reporter mice (CX3CR1(GFP/+) ). We found that MG remain viable for at least 6 h of hypoxia but begin to die after 2 h of OGD, while both hypoxia and OGD reduce MG motility. Unexpectedly, some MG retain or recover motility during OGD and can engulf dead cells. Additionally, MG from younger neonates (P2-P3) are more resistant to OGD than those from older ones (P6-P7), indicating increasing vulnerability with developmental age. Finally, transient (2 h) OGD also increases MG death, and although motility is rapidly restored after transient OGD, it remains below control levels for many hours. Together, these results show that MG in neonatal mouse brain tissues are vulnerable to both transient and sustained OGD, and many MG die within hours after onset of OGD. Preventing MG death may, therefore, provide a strategy for promoting tissue restoration after stroke., (Copyright © 2012 Wiley Periodicals, Inc.)

Excitatory synaptic transmission in area CA1 of the mammalian hippocampus is rapidly depressed during hypoxia. The depression is largely attributable to an increase in extracellular adenosine and activation of inhibitory adenosine A(1) receptors on presynaptic glutamatergic terminals. However, sequential exposure to hypoxia results in a slower subsequent hypoxic depression of excitatory synaptic transmission, a phenomenon we have previously ascribed to a reduction in the release of extracellular adenosine. In the present study we show that this delayed depression of excitatory postsynaptic currents (EPSCs) to repeated hypoxia can be reversed by a period of postsynaptic depolarisation delivered to an individual CA1 neuron, under whole-cell voltage clamp, between two periods of hypoxia. The depolarisation-induced acceleration of the hypoxic depression of the EPSC is dependent upon postsynaptic Ca(2+) influx, the activation of PKC and is blocked by intracellular application of GDP-β-S and N-ethylmaleimide (NEM), inhibitors of membrane fusion events. In addition, the acceleration of the hypoxic depression of the EPSC was prevented by the GI mGluR antagonist AIDA, but not by the CB1 cannabinoid receptor antagonist AM251. Our results suggest a process initiated in the postsynaptic cell that can influence glutamate release during subsequent metabolic stress. This may reflect a novel neuroprotective strategy potentially involving retrograde release of adenosine and/or glutamate., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)