Biomedical subjects

D Kunis

Publications and source records attributed to D Kunis.

9 recordsLinked to original sources

PubMed2001

Gene therapy effectiveness differs for neuronal survival and behavioral performance.

If neuronal gene therapy is to be clinically useful, it is necessary to demonstrate neuroprotection when the gene is introduced after insult. We now report equivalent neuronal protection if calbindin D(28K) gene transfer via herpes simplex virus amplicon vector occurs immediately, 30 min, or 1 h after an excitotoxic insult, but not after a 4 h delay. Behavioral performance was evaluated for immediate and 1 h delay groups using a hippocampal-dependent task. Despite equivalent magnitude and pattern of sparing of neurons with the immediate and 1 h delay approaches, the delay animals took a significantly longer time after insult to return to normal performance.

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PubMed2001

Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size.

OBJECT: The goals of this study were to determine the effects of delaying induction of mild hypothermia (33 degrees C) after transient focal cerebral ischemia and to ascertain whether the neuroprotective effects of mild hypothermia induced during the ischemic period are sustained over time. METHODS: In the first study, rats underwent 2 hours of middle cerebral artery (MCA) occlusion. Animals in one group were maintained under normothermic conditions (N group, 23 rats) throughout the period of ischemia and reperfusion. Rats in four additional groups were exposed to 2 hours of hypothermia, which commenced at ischemia onset (H0 group, 11 rats) or with delays of 90 (H90 group, 10 rats), 120 (H120 group, 10 rats), or 180 (H180 group, five rats) minutes, and allowed to survive for 3 days. In the second study, animals underwent 1.5 hours of MCA occlusion and were maintained under normothermic (48 rats) or hypothermic (44 rats) conditions during the ischemia period, after which they survived for 3 days, 1 week, or 2 months. All animals were evaluated for neurological findings at 24 hours and 48 hours postischemia and before they were killed. Regions of infarct were determined by examining hematoxylin and eosinstained brain slices obtained at six coronal levels. CONCLUSIONS: Mild hypothermia conferred significant degrees of neuroprotection in terms of survival, behavioral deficits, and histopathological changes, even when its induction was delayed by 120 minutes after onset of MCA occlusion (p < 0.05) compared with normothermic conditions. Furthermore, the neuroprotective effect of mild hypothermia (2-hour duration) that was induced during the ischemia period was sustained over 2 months. These studies lend further support to the use of mild hypothermia in the treatment of stroke.

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PubMed1998

Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia.

Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell's intercellular adhesion molecule (ICAM-1) through the leukocyte integrin, CD11/CD18. We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11/CD18 integrin in a rabbit model of transient focal ischemia. Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral, and internal carotid arteries using aneurysm clips for 2 h, followed by 6 h of reperfusion. Treatment with a maximally saturating dose (4 mg/kg) of a humanized CD11/CD18 monoclonal antibody (Hu23F2G, ICOS Corp., Bothell, WA) (n = 8) or placebo (n = 7) was administered 20 min after occlusion and given as a single intravenous bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin- and eosin-stained sections was significantly reduced in Hu23F2G-treated animals by 57% (Hu23F2G: 15 +/- 6.9%; placebo: 35 +/- 5%; mean +/- SEM, P < 0.05, t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains. Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration. (No. of neutrophils/IND area: Hu23F2G 36.1 +/- 36.7 cm-2, placebo 460.6 +/- 101.8 cm-2, P = 0.001. ) Antagonism of neutrophil migration at the level of the CD11/CD18 integrin reduces ischemic injury in experimental stroke.

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PubMed1994

Cerebral damage caused by interrupted, repeated arterial occlusion versus uninterrupted occlusion in a focal ischemic model.

Temporary intracranial arterial occlusion is often utilized during the surgical treatment of intracranial aneurysms. Although numerous experimental studies have suggested that repetitive, brief periods of global ischemia cause more severe cerebral injury than a similar single period of global ischemia, this issue has not been extensively studied in relation to focal ischemia. It remains controversial whether it is safer to use brief periods of interrupted, temporary occlusion separated by reperfusion periods, or a more prolonged, single temporary occlusion. This question is addressed in studies on a rabbit model of transient, focal cerebral ischemia. Sixteen anesthetized rabbits underwent transorbital occlusion of the left internal carotid, middle cerebral, and anterior cerebral arteries, with one of two paradigms:uninterrupted occlusion (1 hour of temporary occlusion followed by 5 hours of reperfusion in eight rabbits), or interrupted occlusion (three separate 20-minute periods of occlusion, with 10 minutes of reperfusion between occlusions, followed by 4 hours, 40 minutes of reperfusion in eight rabbits). Histopathological evaluation for ischemic neuronal damage and magnetic resonance imaging studies for ischemic edema were conducted 6 hours after the initial arterial occlusion. The animals in the interrupted, repeated occlusion group showed a 59% decrease in the area of cortical ischemic neuronal damage (mean +/- standard error of the mean 10.0% +/- 1.7%) compared with the uninterrupted occlusion group (24.4% +/- 5%, p = 0.016). There was no difference between the groups in the extent of striatal ischemic damage or area of ischemic edema. These results suggest that interrupted, repeated focal ischemia causes less cortical ischemic injury than uninterrupted transient ischemia of a similar total duration. Although caution should be exercised in extrapolating from these results to the clinical situation, they may have important implications for temporary arterial occlusion during intracranial surgery.

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PubMed1993

Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile.

Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h followed by 4.5 h of reperfusion. One hour after the onset of ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.

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PubMed1991

Protection after transient focal cerebral ischemia by the N-methyl-D-aspartate antagonist dextrorphan is dependent upon plasma and brain levels.

Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = -0.50, p less than 0.02 for ischemic neuronal damage; r = -0.66, p less than 0.001 for ischemic MRI high signal). All the rabbits with plasma levels greater than 2,000 ng/ml had less than 12% cortical ischemic neuronal damage and less than 34% MRI high signal. All rabbits with plasma levels greater than 3,000 ng/ml showed less than 7% ischemic neuronal damage and less than 11% MRI high signal. Plasma levels of approximately 2,500 ng/ml correlated with brain dextrorphan levels of approximately 6,000 ng/g. Unanesthetized rabbits with plasma levels of approximately 2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent glutamate or NMDA-induced injury in neuronal culture.

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PubMed1989

Pretreatment with the NMDA antagonist dextrorphan reduces cerebral injury following transient focal ischemia in rabbits.

We studied the efficacy of systemic pre-treatment with dextrorphan (DX), a clinically tested N-methyl-D-aspartate (NMDA) antagonist, in a rabbit model of transient focal cerebral ischemia. Rabbits were treated with either a 24 mg/kg i.v. loading dose followed by 12 mg/kg/h i.v. infusion of 0.48% DX in normal saline (NS), or with an equivalent volume of NS alone. One and 1/2 h after starting the drug or NS, the rabbits underwent a 1 h occlusion of the left internal carotid and anterior cerebral arteries, followed by 4 h of reperfusion. The DX-treated rabbits had significantly less neocortical ischemic neuronal damage (7.4%) than the normal saline group (31.6%) and demonstrated a significant decrease in ischemic cortical edema. DX may prove useful in the treatment of clinical cerebrovascular disease.

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PubMed1989

Protective effect of N-methyl-D-aspartate antagonists after focal cerebral ischemia in rabbits.

We studied the efficacy of postischemic, systemic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan and dextrorphan in a rabbit model of transient focal cerebral ischemia. Twenty-two rabbits underwent 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4.5 hours of reperfusion before sacrifice. One hour after the onset of ischemia, immediately after removing the arterial clips, the rabbits were blindly assigned to treatment with dextromethorphan (20 mg/kg i.v. loading dose followed by 10 mg/kg/hr maintenance infusion, n = 7), dextrorphan (15 mg/kg i.v. loading dose followed by 15 mg/kg/hr maintenance infusion, n = 7), or an equivalent volume of normal saline alone (n = 8). The maintenance infusion of drugs or saline was continued for the duration of the experiment. The formalin-fixed brains were analyzed with magnetic resonance imaging using coronal T2-weighted images, and ischemic neuronal damage was assessed on standard coronal hematoxylin-and- eosin-stained sections. The area of neocortical ischemic neuronal damage was significantly reduced in the groups treated with dextromethorphan (4.2%, p less than 0.01) and dextrorphan (6.1%, p less than 0.01) compared with the controls (36.2%). Magnetic resonance imaging demonstrated significantly smaller areas of cortical edema in the groups treated with dextromethorphan (14.6%, p less than 0.01) and dextrorphan (8.0%, p less than 0.01) compared with the controls (32.9%). These clinically tested antitussives with NMDA-antagonist properties may have therapeutic value in the treatment of human cerebrovascular disease.

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PubMed1988

Delayed treatment with dextromethorphan and dextrorphan reduces cerebral damage after transient focal ischemia.

The N-methyl-D-aspartate (NMDA) antagonists dextromethorphan (DM) and dextrorphan (DX) were found to reduce significantly neocortical severe ischemic neuronal damage (SIND) when administered in a delayed fashion after the ischemic insult. Rabbits underwent occlusion of the left internal carotid artery and anterior cerebral artery for 1 h, followed by 4 h of reperfusion. Immediately after the completion of the 1 h arterial occlusion, animals were blindly treated intravenously with 20 mg/kg loading dose followed by 10 mg/kg/h of DM, 15 mg/kg loading dose followed by 15 mg/kg/h of DX, or an equivalent volume of normal saline (NS) alone. The area of neocortical SIND was 3.7% in the DM group, 4.4% in the DX group, and 41.3% in the normal saline controls. These drugs may have considerable therapeutic potential in clinical stroke.

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