Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This experiment evaluated the potential for ketamine HCl, a non-competitive glutamate antagonist, to minimize injury resulting from temporary focal cerebral ischemia. Male spontaneously hypertensive rats were randomly assigned to receive either ketamine (n = 13) or halothane anesthesia (n = 12) during 2 h of reversible middle cerebral artery occlusion (MCAO). Ketamine was administered as a 50 mg/kg i.v. loading dose followed by a continuous 1.25 mg/kg/min i.v. infusion beginning 25 min prior to ischemia and continued until 30 min after reperfusion. An additional group of rats (ketamine-shams, n = 8) underwent craniectomy and ketamine administration (as above) but the middle cerebral artery was not ligated. Physiologic values were similar between groups with the exception of plasma glucose which was elevated in the halothane-MCAO group. After 4 days recovery, rats in all groups were neurologically evaluated. There were no differences between the two groups undergoing MCAO for neurologic grading or open field behavior, although both groups performed worse than did ketamine-shams (P less than 0.05). In contrast, motor performance revealed more severe deficits in the ketamine-MCAO rats vs either the halothane-MCAO or ketamine-sham groups (P less than 0.05). Cerebral infarct volume was then planimetrically measured after triphenyl tetrazolium chloride (TTC) staining of fresh brain sections. Mean +/- S.D. infarct volume was not different between the halothane-MCAO (134 +/- 51 mm3) and ketamine-MCAO (131 +/- 64 mm3) groups. Seven of 8 sham rats were free of TTC demarcated injury and in the remaining rat injury was minimal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of ketamine on outcome from temporary middle cerebral artery occlusion in the spontaneously hypertensive rat. 177 49

Lactic acidosis has been proposed to be one factor promoting cell death following cerebral ischemia. We have previously demonstrated that cultured neurons and glial are killed by relatively brief (10 min) exposure to acidic solutions of pH less than 5 (Goldman et al., 1989). In the present series of experiments, we investigated the relationship between changes in intracellular pH (pHi) and cellular viability. pHi was measured using fluorescent pH probes and was manipulated by changing extracellular pH (pHe). Homeostatic mechanisms regulating pHi in neurons and glia were quickly overwhelmed: neither neurons nor glial cells were able to maintain baseline pHi when incubated at pHe below 6.8. Neuronal and glial death was a function of both the degree and the duration of intracellular acidification, such that the LD50 following timed exposure to HCl increased from pH, 3.5 for 10-min acid incubations to pHi 5.9 for 2-hr exposures and pHi 6.5 for 6-hr exposures. Replacement of HCl with lactic acid raised the LD50 to pHi 4.5 for 10-min acid exposures, but did not change the LD50 for longer exposures: pHi measurements concurrent with extracellular acidification suggested that the greater cytotoxicity of lactic acid relative to that of HCl was caused by the more rapid intracellular acidification associated with lactic acid. The onset of death after exposure to moderately acidic solutions was delayed in some cells, such that death of the entire cell population became evident only 48 hr after acid exposure. During this latency period, cellular viability indices and ATP levels fell in parallel.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acid-induced death in neurons and glia. 186 26

Regional CBF (rCBF) and regional cerebral blood volume (rCBV) were evaluated by N,N,N'-trimethyl-N'-(2)-hydroxy-3-methyl-5-[123I]iodobenzyl-1, 3-propanediamine-2 HCl- and 99mTC-labeled red blood cells, respectively, and single-photon emission computerized tomography (SPECT) in a patient with focal cerebral ischemia. Sequential transmission computerized tomography (TCT) and SPECT functional data were compared with clinical findings to monitor the pathophysiological events occurring in stroke. A lack of correlation between rCBF-rCBV distributions and blood-brain barrier (BBB) breakdown was found in the acute phase. In the face of more prolonged alteration of BBB, as seen by TCT enhancement, a rapid evolution of transient phenomena such as luxury perfusion was shown by SPECT studies. Follow-up of the patient demonstrated a correlation between the neurological recovery and a parallel relative improvement of the cerebral perfusion.
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PMID:Sequential assessment of regional cerebral blood flow, regional cerebral blood volume, and blood-brain barrier in focal cerebral ischemia: a case report. 348 73

Phosphorylation of nuclear protein was investigated in cerebral anoxia up to 30 min with rabbit brain and in cerebral ischemia up to 6 h with gerbil brain in vitro. Isolated nuclei were incubated in the presence of [gamma-32P]ATP and were then fractionated into the NaCl-soluble, HCl-soluble, and phenol-soluble protein fraction. Each protein fraction was further separated by gel electrophoresis, and profiles of 32P incorporation were evaluated in these pathophysiological conditions. 32P incorporation of the acidic phenol-soluble nonhistone chromatin protein became significantly suppressed in cerebral anoxia after 15 min, and there were decreases of 32P incorporation in protein with high molecular weight and increase in protein with low molecular weight on gel electrophoresis. With gerbil brain nuclei, 32P incorporation into the NaCl-soluble and HCl-soluble fraction was increased without significant decrease in the phenol-soluble fraction after an ischemic period of 3 h. However, further separation of the phenol-soluble fraction demonstrated decrease of 32P incorporation in protein with high molecular weight and increase in protein with low molecular weight. At present, the significance of these findings, particularly in relation to chromatin template activity or irreversibility of these pathophysiological conditions, is not clear.
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PMID:Phosphorylation of chromatin proteins in cerebral anoxia and ischemia. 745 12

Effects of cocaine on intracellular free calcium concentration ([Ca2+]i) in cultured canine cerebral vascular smooth muscle cells were studied using digital imaging microscopy and the calcium molecular fluorescent indicator, fura-2. Acute treatment of cerebral vascular smooth muscle cells with cocaine HCl, from a low concentration of 10(-9) M up to 10(-5) M, induced significant increases of [Ca2+]i. Irrespective of the changes in [Ca2+]i, the subcellular distribution of [Ca2+]i appeared heterogeneous in both normal and cocaine-treated cells. These results suggest that cocaine induces cerebral vasospasm by a rapid elevation of [Ca2+]i in vascular smooth muscle cells; these ionic events could play a crucial role in the pathogenesis of cocaine-induced cerebral ischemia and stroke.
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PMID:Acute cocaine results in rapid rises in intracellular free calcium concentration in canine cerebral vascular smooth muscle cells: possible relation to etiology of stroke. 888 Jul 53

Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
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PMID:Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers. 926 Jul 29

Recent studies have demonstrated a neuroprotective effect of the noncompetitive N-methyl-D-aspartate receptor antagonist aptiganel HCl (Cerestat) in focal cerebral ischemia. In the present study, we investigated the protective ability of aptiganel HCl after controlled cortical impact injury (impact depth = 2 mm; impactor velocity = 7 mm/sec) of the left temporoparietal cortex in rats. Intravenous aptiganel HCl (2 mg/kg) or a respective volume of vehicle was injected 15 min after trauma. Animals were sacrificed 24 h after trauma. Contusion volume was measured planimetrically from hematoxylin-eosin-stained coronal slices. Hemispheric swelling and water content were determined gravimetrically. Thirty minutes before sacrifice, a Codman intracranial pressure (ICP) probe was placed in the right hemisphere, and ICP as well as mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored. Aptiganel HCl reduced contusion volume by 13.6% in treated rats (p < 0.05). Hemispheric swelling was also significantly diminished by 31.5% in accordance to a decrease in hemispheric water content (controls, 82.78 +/- 0.12%, vs. aptiganel HCl, 82.30 +/- 0.18%, p < 0.05). Posttraumatic ICP was not significantly lower in the aptiganel HCl treated animals (25.5 +/- 2.4 mm Hg vs. 32.0 +/- 2.7 mm Hg, p = 0.096). MABP was found to be higher in the treatment group 24 h after injury (107.8 +/- 3.6 mm Hg vs. 89.9 +/- 2.4 mm Hg, p < 0.001), resulting in a higher CPP (82.6 +/- 4.2 mm Hg vs. 57.2 +/- 4.6 mm Hg, p < 0.05). Taken together, aptiganel HCl exerts various beneficial effects following experimental traumatic brain injury. It decreases contusion volume and hemispheric swelling as well as water content. Thus, this drug appears promising for further clinical trials in brain trauma.
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PMID:Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat. 952 19

Recent studies have demonstrated the neuroprotective properties of the novel imidazoquinoline benzodiazepine receptor partial agonist, PNU-101017, in the gerbil forebrain ischemia model. The compound effectively reduces delayed post-ischemic (5 min bilateral carotid occlusion) hippocampal CA1 neuronal degeneration even when its administration is withheld until 4 h after reperfusion and the effect is unrelated to hypothermia. The purpose of the present study was to determine the comparative abilities of PNU-101017 versus the full agonist diazepam to attenuate post-ischemic CA1 damage. Male gerbils were treated either 30 min before ischemia induction or immediately after reperfusion with an initial dose of PNU-101017 (30 mg/kg i.p.) or diazepam (10 mg/kg i.p.) with a second dose being given at 2 h after reperfusion. Possible hypothermic effects of either compound were prevented by external heating. In vehicle (0.05 N HCl)-treated gerbils, the loss of hippocampal CA1 neurons at 5 days was 85%. PNU-101017 pretreatment reduced the loss to 50% (p<0.05 vs. vehicle) whereas pretreatment with diazepam attenuated damage to only 17% (p<0.001 vs. vehicle). Delaying treatment with PNU-101017 until just after reperfusion still resulted in a reduction in CA1 degeneration statistically that was indistinguishable from that seen with pretreatment. In contrast, diazepam post-treatment did not significantly decrease CA1 neuronal loss. These results suggest that a benzodiazepine receptor partial agonist may have greater neuroprotective practicality than a full agonist for the treatment of global cerebral ischemia. The mechanistic basis for this difference may relate to the partially pro-excitatory neuronal response to endogenous GABA before and after neuronal insult.
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PMID:Comparative neuroprotective properties of the benzodiazepine receptor full agonist diazepam and the partial agonist PNU-101017 in the gerbil forebrain ischemia model. 966 60

The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.
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PMID:The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats. 1159 55

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170+/-9, saline: 760+/-95, PJ34: 472+/-61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction
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PMID:Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats. 1721 62


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