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We previously showed that treatment with a competitive N-methyl-D-aspartate (NMDA) receptor antagonist GPI-3000 (GPI) improved short-term physiological recovery after incomplete global cerebral ischemia complicated by dense acidosis. We tested the hypothesis that GPI administered after resuscitation from cardiac arrest would improve a more long-ter...
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Over time, memory retrieval is thought to transfer from the hippocampus to a distributed network of neocortical sites. Of these sites, the retrosplenial cortex (RSC) is robustly activated during retrieval of remotely acquired, emotionally valenced memories. It is unclear, however, whether RSC is specifically involved in memory storage or retrieval,...
Under physiological conditions N-methyl-D-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg(2+). Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead...
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... In our opinion, high early survival (90%) in the «classical» model of Katz L and co-authors [29] might also be related to NMDA blockade by N 2 O. Meanwhile, two experimental studies testing effects of two NMDA antagonist, MK-801 and GPI-3000 demonstrated no improvement of survival rate and brain outcome after CA in a dog model [31,32]. These studies did not suggest any mechanisms for the negative results, but they apparently have contributed to a lack of interest for testing NMDA blockade in CA for years. ...
Background:
In different models of hypoxia, blockade of opioid or N-methyl-D-aspartate (NMDA) receptors shows cardio- and neuroprotective effects with a consequent increase in animal survival. The aim of the study was to investigate effects of pre-treatment with Morphine or Ketamine on hemodynamic, acid-base status, early survival, and biochemical markers of brain damage in a rat model of asphyxial cardiac arrest (ACA).
Methods:
Under anaesthesia with Thiopental Sodium 60 mg/kg, i.p., Wistar rats (n = 42) were tracheostomized and catheters were inserted in a femoral vein and artery. After randomization, the rats were pre-treated with: Morphine 5 mg/kg i.v. (n = 14); Ketamine 40 mg/kg i.v. (n = 14); or equal volume of i.v. NaCl 0.9% as a Control (n = 14). ACA was induced by corking of the tracheal tube for 8 min, and defined as a mean arterial pressure (MAP) < 20 mmHg. Resuscitation was started at 5 min after cardiac arrest (CA). Invasive MAP was recorded during experiments. Arterial pH and blood gases were sampled at baseline (BL) and 10 min after CA. At the end of experiments, all surviving rats were euthanised, brain and blood samples for measurement of Neuron Specific Enolase (NSE), s100 calcium binding protein B (s100B) and Caspase-3 (CS-3) were retrieved.
Results:
At BL no differences between groups were found in hemodynamic or acid-base status. After 3 min of asphyxia, all animals had cardiac arrest (CA). Return of spontaneous circulation (MAP > 60 mmHg) was achieved in all animals within 3 min after CA. At the end of the experiment, the Ketamine pre-treated group had increased survival (13 of 14; 93%) compared to the Control (7 of 14; 50%) and Morphine (10 of 14; 72%) groups (p = 0.035). Biochemical analysis of plasma concentration of NSE and s100B as well as an analysis of CS-3 levels in the brain tissue did not reveal any differences between the study groups.
Conclusion:
In rats after ACA, pre-treatment with Morphine or Ketamine did not have any significant influence on hemodynamic and biochemical markers of brain damage. However, significantly better pH level and increased early survival were found in the Ketamine pre-treated group.
... However, in the setting of global brain ischemia, pre or post CA infusion with the NMDA receptor antagonist MK-801 exacerbated post-resuscitation neurological deficits in the dog model [15] . Similarly post-CA intravenous treatment with the NMDA receptor antagonist GPI 3000 was associated with poor survival and neurologic function along with increased neuronal death in the neocortex and hippocampus in dogs subjected to CA and CPR [16] . An interaction between ischemia and competitive NMDA receptor antagonism may be the cause of deleterious outcomes [15]. ...
Neurocognitive deficits are a major source of morbidity in survivors of cardiac arrest. Treatment options that could be implemented either during cardiopulmonary resuscitation or after return of spontaneous circulation to improve these neurological deficits are limited. We conducted a literature review of treatment protocols designed to evaluate neurologic outcome and survival following cardiac arrest with associated global cerebral ischemia. The search was limited to investigational therapies that were utilized to treat global cerebral ischemia associated with cardiac arrest. In this review we discuss potential mechanisms of neurologic protection following cardiac arrest including actions of several medical gases such as xenon, argon, and nitric oxide. The 3 included mechanisms are: 1. Modulation of neuronal cell death; 2. Alteration of oxygen free radicals; and 3. Improving cerebral hemodynamics. Only a few approaches have been evaluated in limited fashion in cardiac arrest patients and results show inconclusive neuroprotective effects. Future research focusing on combined neuroprotective strategies that target multiple pathways are compelling in the setting of global brain ischemia resulting from cardiac arrest.
... These results suggest that blockade of NMDA receptors do not protect cardiac arrestinduced hypoxic brain injury. The lack of neuroprotective effect from NMDA receptor antagonism in a pig model of cardiac arrest and resuscitation has been reported in the literature [28]. It has been known that lowering of the extracellular pH decreases the sensitivity of the glutamate receptors [29] which in turn decreases neuronal excitability and injury. ...
It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.
... In each microscopic field at a magnification of 6400, the percentage of damaged neurons was determined under a light microscope (Shanghai zousun optical instrument Co., Ltd, Shanghai, China) by an experienced doctor from the department of pathology in a blind fashion. The criteria for neuronal cytopathology included an eosinophilic cytoplasm, cytoplasmic vacuolation, perikaryal shrinkage , and nuclear pyknosis [24]. Three sections at least 15 mm apart were examined for each pig and the mean value was taken. ...
Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33°C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation.
... These include Nmethyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, aiming to block the effects of the excitatory neurotransmitter glutamate. 27,28 Other agents currently under investigation include estrogen, 29 caspase inhibitors, 30 lamotrigine (which may also block the effects of glutamate toxicity), 31 immunosuppressants cyclosporin A and FK506, 32 transgenic expression of superoxide dismutase, 33 and even intraventricular delivery of brain-derived neurotrophic factor. 34 All of these agents remain investigational at this point, and no recommendations can be made regarding their use in human subjects at this time. ...
Cardiac arrest survivors commonly suffer ischemic brain injury, and understanding the mechanisms of injury is essential to providing insight for effective therapies for brain protection. Injury can occur at the time of the cardiac arrest and is dependent not only on the duration but also the degree of impaired circulation. Injury can be ongoing even after the return of spontaneous circulation, giving the clinician an additional window of opportunity to treat and protect the injured brain. This section will review the molecular basis of injury with cardiac arrest and will elucidate the different mechanisms of injury between cardiac arrest, pure respiratory arrest, and arrest secondary to toxins (e.g., carbon monoxide). The rationale for multiple postarrest therapies, such as hypothermia and induced hypertension, will also be reviewed.
This volume provides extensive insight into glutamate transporters and receptors, including their role in the brain with other neurochemical parameters in excitotoxicity, and possible treatments. © 2008 Springer Science+Business Media, LLC. All rights reserved.
The high incidence and significant neurological morbidity in patients with cardiovascular disease emphasize our urgent need
to understand the pathophysiology of cerebral ischemic injury and to develop mechanistically-oriented means of neuroprotection.
Cerebral ischemia is simplistically defined as inadequate delivery of oxygen and substrate to brain tissue relative to its
needs. The brain is considerably vulnerable to short periods of ischemia, although some neuronal populations can survive 30
minutes of loss of oxygenation. As blood flow to the brain decreases, numerous well-described compensatory mechanisms are
entrained, including initially cerebral vasodilation and increased oxygen extraction. Once the increase in extraction can
no longer maintain oxidative metabolism, increases in brain lactate level, decreases in brain pH and in high energy phosphates
are striking [1, 2]. As brain blood flow falls below 20 ml/min/100g tissue, marked abnormalities in electroencephalogram (EEG) and somatosensory
evoked potentials occur, and surges in extracellular neurotransmitter levels such as glutamate can be detected. However, only
modest decreases in adenosine triphosphate (ATP) occur at this level of cerebral ischemia, because the decrease in spontaneous
electrical activity acts to conserve energy. Typically, energy failure and reduction of cortical ATP are evident only when
cerebral blood flow (CBF) is reduced to below 10–12 ml/min/100g. Energy failure precipitates cell membrane depolarization,
accompanied by loss of transmembrane ion gradients, i.e., potassium efflux and sodium and calcium intracellular influx.
Mild therapeutic hypothermia has shown to improve long-time survival as well as favorable functional outcome after cardiac arrest. Animal models suggest that ischemic durations beyond 8 min results in progressively worse neurologic deficits. Based on these considerations, it would be obvious that cardiac arrest survivors would benefit most from mild therapeutic hypothermia if they have reached a complete circulatory standstill of more than 8 min.
In this retrospective cohort study we included cardiac arrest survivors of 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest, which remain comatose after restoration of spontaneous circulation. Data were collected from 1992 to 2010. We investigated the interaction of 'no-flow' time on the association between post arrest mild therapeutic hypothermia and good neurological outcome. 'No-flow' time was categorized into time quartiles (0, 1-2, 3-8, >8 min).
One thousand-two-hundred patients were analyzed. Hypothermia was induced in 598 patients. In spite of showing a statistically significant improvement in favorable neurologic outcome in all patients treated with mild therapeutic hypothermia (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.14-1.93) this effect varies with 'no-flow' time. The effect is significant in patients with 'no-flow' times of more than 2 min (OR: 2.72; CI: 1.35-5.48) with the maximum benefit in those with 'no-flow' times beyond 8 min (OR: 6.15; CI: 2.23-16.99).
The beneficial effect of mild therapeutic hypothermia increases with cumulative time of complete circulatory standstill in patients with witnessed out-of-hospital cardiac arrest.
Mild to moderate hypothermia (32-35 degrees C) is the first treatment with proven efficacy for postischemic neurological injury. In recent years important insights have been gained into the mechanisms underlying hypothermia's protective effects; in addition, physiological and pathophysiological changes associated with cooling have become better understood.
To discuss hypothermia's mechanisms of action, to review (patho)physiological changes associated with cooling, and to discuss potential side effects.
Review article.
None.
A myriad of destructive processes unfold in injured tissue following ischemia-reperfusion. These include excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage, cerebral thermopooling, and numerous others. The severity of this destructive cascade determines whether injured cells will survive or die. Hypothermia can inhibit or mitigate all of these mechanisms, while stimulating protective systems such as early gene activation. Hypothermia is also effective in mitigating intracranial hypertension and reducing brain edema. Side effects include immunosuppression with increased infection risk, cold diuresis and hypovolemia, electrolyte disorders, insulin resistance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (<or=30 degrees C), moderate hypothermia does not induce arrhythmias; indeed, the evidence suggests that arrhythmias can be prevented and/or more easily treated under hypothermic conditions.
Therapeutic hypothermia is a highly promising treatment, but the potential side effects need to be properly managed particularly if prolonged treatment periods are required. Understanding the underlying mechanisms, awareness of physiological changes associated with cooling, and prevention of potential side effects are all key factors for its effective clinical usage.
