Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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J. Cereb. Blood Flow Metab. · Apr 2010
Xenon is an inhibitor of tissue-plasminogen activator: adverse and beneficial effects in a rat model of thromboembolic stroke.
Preclinical evidence in rodents has proven that xenon may be a very promising neuroprotective agent for treating acute ischemic stroke. This has led to the general thinking that clinical trials with xenon could be initiated in acute stroke patients in a next future. ⋯ Here, using molecular modeling and in vitro and in vivo studies, we show (1) xenon is a tPA inhibitor; (2) intraischemic xenon dose dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage; (3) postischemic xenon virtually suppresses ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. Taken together, these data indicate (1) xenon should not be administered before or together with tPA therapy; (2) xenon could be a golden standard for treating acute ischemic stroke if given after tPA-induced reperfusion, with both unique neuroprotective and antiproteolytic (anti-hemorrhaging) properties.
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J. Cereb. Blood Flow Metab. · Mar 2010
The adverse pial arteriolar and axonal consequences of traumatic brain injury complicated by hypoxia and their therapeutic modulation with hypothermia in rat.
This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone, IAI and hypoxia, IAI and hypoxia before induction of moderate hypothermia (33 degrees C), IAI and hypoxia induced during hypothermic intervention, and IAI and hypoxia initiated after hypothermia. ⋯ When this same hypoxic insult followed the use of hypothermia, no benefit ensued. These studies show that early hypoxia and delayed hypoxia exert damaging axonal and vascular consequences. Although this damage is attenuated by hypothermia, this follows only when hypoxia occurs during hypothermia, with no benefit found if the hypoxic insult proceeds or follows hypothermia.
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J. Cereb. Blood Flow Metab. · Mar 2010
Heat acclimation provides sustained improvement in functional recovery and attenuates apoptosis after traumatic brain injury.
Heat acclimation (HA) offers functional neuroprotection in mice after traumatic brain injury (TBI). This study further characterizes endogenous neuroprotection acquired by HA (34+/-1 degrees C, 30 d) after TBI. We establish here the ability of HA to induce sustained functional benefits and to reduce activation of apoptotic pathways. ⋯ HA mice displayed higher mitochondrial levels of antiapoptotic Bcl-xL, accompanied by lower proapoptotic Bad levels and decreased cytochrome c release, suggesting a higher apoptotic threshold. Taken together with our previous reports, indicating increased Akt phosphorylation and antioxidative capacity, alongside with reduced tumor necrosis alpha levels after TBI in HA animals, the current results support the involvement of an antiapoptotic effect in HA-induced neuroprotection. Current results warrant further study as TBI-induced apoptosis may persist over weeks after injury, possibly providing a target for belated therapeutic intervention.
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J. Cereb. Blood Flow Metab. · Mar 2010
Blood constituents trigger brain swelling, tissue death, and reduction of glucose metabolism early after acute subdural hematoma in rats.
Outcome from acute subdural hematoma is often worse than would be expected from the pure increase of intracranial volume by bleeding. The aim was to test whether volume-independent pathomechanisms aggravate damage by comparing the effects of blood infusion with those of an inert fluid, paraffin oil, on intracranial pressure (ICP), cerebral perfusion pressure (CPP), local cerebral blood flow (CBF), edema formation, glucose metabolism ([18F]-deoxyglucose, MicroPET ), and histological outcome. Rats were injured by subdural infusion of 300 muL venous blood or paraffin. ⋯ Ipsilateral brain edema did not differ between groups at 2 h, but was significantly more pronounced in the blood-treated groups at 24 and 48 h after injury (n=8 per group). These changes caused a 56.2% larger lesion after blood when compared with paraffin (48.1+/-23.0 versus 21.1+/-11.8 mm(3); P<0.02). Blood constituent-triggered pathomechanisms aggravate the immediate effects due to ICP, CPP, and CBF during hemorrhage and lead to early reduction of glucose metabolism followed by more severe edema and histological damage.
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J. Cereb. Blood Flow Metab. · Feb 2010
Prevention of hypoglycemia-induced neuronal death by hypothermia.
Hypothermia reduces neuronal damage after cerebral ischemia and traumatic brain injury, while hyperthermia exacerbates damage from these insults. Previously we have shown that temperature-dependent modulation of excitotoxic neuronal death is mediated in part by temperature-dependent changes in the synaptic release/translocation of Zn(2+). In this study, we hypothesize that brain temperature also affects hypoglycemia-induced neuronal death by modulation of vesicular Zn(2+) release from presynaptic terminals. ⋯ Even when the insult was accompanied by hyperthermic conditions, zinc chelation inhibited ROS production and microglia activation. Zinc chelation during hyperthermia reduced neuronal death, superoxide production, and microglia activation, which was comparable to the protective effects of hypothermia. We conclude that neuronal death after hypoglycemia is temperature-dependent and is mediated by increased Zn(2+) release, superoxide production, and microglia activation.