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T Dalkara

Publications and source records attributed to T Dalkara.

At least 37 records · Page 2Linked to original sources
PubMed1999

Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia.

Large infarcts develop in pinealectomized rats subjected to middle cerebral artery occlusion, which was attributed to loss of antioxidant action of melatonin. However, melatonin also has vascular actions, and pinealectomy may induce hypertension. The authors investigated (1) whether hemodynamic factors contribute to infarct development in pinealectomized rats, (2) whether melatonin administration can reverse the unfavorable effect of pinealectomy on infarct formation, and (3) whether melatonin can reduce the infarct volume in nonpinealectomized rats subjected to focal transient ischemia (2 hours middle cerebral artery occlusion, 22 hours reperfusion). Rats were pinealectomized 3 months before ischemia to eliminate any possible action of pinealectomy-induced hypertension on stroke. Blood pressure and regional CBF values during ischemia and reperfusion were not significantly different between pinealectomized and sham-operated rats, suggesting that pinealectomy-induced increase in infarct was not related to hemodynamic factors. The infarct volume resumed to the level of sham-operated rats on melatonin administration. Injection of melatonin (4 mg/kg) before both ischemia and reperfusion reduced infarct volume by 40% and significantly improved neurologic deficit scores in pinealectomized as well as sham-operated rats subjected to middle cerebral artery occlusion. These data suggest that physiologic melatonin release as well as exogenously given melatonin has a neuroprotective action in focal cerebral ischemia.

Animals↗
PubMed1999

Formulation and in vitro/in vivo investigation of carbamazepine controlled-release matrix tablets.

Carbamazepine controlled-release tablet formulations containing hydroxypropyl methylcellulose (HPMC) as matrix material at different concentrations were developed and evaluated in vitro and in vivo. The formulation containing 10% HPMC (HPMC-10) showed a controlled-release profile comparable to that of a commercially available, controlled-release carbamazepine preparation (Tegretol CR 200). The kinetics of controlled-release carbamazepine tablets was examined in eight healthy volunteers. The peak plasma concentration of 1.99 +/- 0.56 micrograms.ml-1 was obtained for HPMC-10 at 15.0 +/- 9.0 h, and 1.33 +/- 0.35 micrograms.ml-1 for Tegretol CR 200 at 15.2 +/- 8.9 h, and AUC0-infinity values of 85.2 +/- 30.8 micrograms.h.ml-1 and 76.9 +/- 20.7 micrograms.h.ml-1, respectively. Developed formulation (HPMC-10) was found to be bioequivalent to Tegretol CR 200 and, controlled release was obtained with smoother concentration-time curve resulting in less fluctuations.

Adult↗
PubMed1998

Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation.

Apoptotic cell death is prominent in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and is found in cerebral ischemia. Using a murine model of delayed cell death, we determined that cleavage of zDEVD-amino-4-trifluoromethyl coumarin (zDEVD-afc) in brain homogenate, a measure of caspase activation, increased initially 9 hours after brief (30 minutes) middle cerebral artery occlusion along with caspase-3p20 immunoreactive cleavage product as determined by immunoblotting. zDEVD-afc cleavage activity was blocked by pretreatment or posttreatment with the caspase-inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl-ketone (zDEVD-fmk), and ischemic damage was reduced when the drug was injected up to 9 hours after reperfusion. The protection was long lasting (21 days). Hence, the period before caspase activation defined the therapeutic opportunity for this neuroprotective agent after mild ischemic brain injury. Prolonged protection after caspase inhibition plus the extended treatment window may be especially relevant to the treatment of neurodegenerative disorders.

Animals↗
PubMed1998

Mechanisms of motor dysfunction after transient MCA occlusion: persistent transmission failure in cortical synapses is a major determinant.

BACKGROUND AND PURPOSE: Failure of prompt motor recovery after spontaneous recirculation or thrombolytic therapy may be due to an unsatisfactory restoration of synaptic activity within cortex and/or blockade of electrical impulses at the severely ischemic subcortical region. METHODS: Afferent, efferent, and synaptic activities were focally examined within the rat sensorimotor cortex by recording the somatosensory-evoked potential (SEP) and motor area response evoked by stimulation of premotor afferents (PmEP) intracortically and the motor-evoked potential (MEP) generated by stimulation of the forelimb area from the brain stem. The effect of ischemia on electrical activity in the cortex and on axonal conduction in the subcortical region was studied differentially by proximal or distal occlusion of the MCA. RESULTS: MEP consisted of direct and indirect waves generated by direct activation of pyramidal axons and indirect excitation of pyramidal neurons via cortical synapses, respectively. MEP, PmEP, and SEP disappeared on proximal occlusion. Following reperfusion after 1 to 3 hours of ischemia, the direct wave of MEP readily recovered but the indirect wave showed no improvement, suggesting a restored axonal conduction but impaired cortical synaptic transmission. The synaptic defect, which also caused a poor recovery in PmEP and SEP and on electrocorticogram, was persistent and detected 24 hours after 1 hour of proximal occlusion. CONCLUSIONS: Our data suggest that motor dysfunction is caused by loss of cortical excitability and blockade of motor action potentials at the subcortical level during ischemia. After brief transient ischemia, axonal conduction readily recovers; however, a persistent transmission failure at cortical synapses leads to motor dysfunction.

Action Potentials↗
PubMed1997

Monitoring cellular edema at single-neuron level by electrical resistance measurements.

Electrical resistance measurements have been used for investigating extracellular volume fraction (EVF) of brain tissue. Conventional techniques using multiple metal electrodes are limited in their spatial resolution, and thus not suitable for detecting local EVF changes at cellular level. We used a multibarrelled glass microelectrode to monitor cellular swelling locally at single-neuron level. The microelectrode was placed in CA1 region of the rat hippocampus, in situ. A constant current pulse was applied between one of the barrels and a reference electrode placed in the neck. The resultant voltage drop, which was directly proportional to the resistance of the immediate environment surrounding the tip of the microelectrode, was recorded through another barrel. A third barrel was used for iontophoretic injection of N-methyl-D-aspartate (NMDA) for inducing local cellular edema. The effect of diffuse edema induced by bilateral carotid artery ligation on EVF was also investigated. NMDA application increased the local tissue resistance by 2.0-, and ischemia, by 3.4-folds. We conclude that the method described can detect changes in EVF of minute volumes of brain tissue, and is suitable for monitoring very local effects of drugs or changes in the metabolism on cell volume.

Animals↗
PubMed1996

Attenuated hippocampal damage after global cerebral ischemia in mice mutant in neuronal nitric oxide synthase.

To address the importance of nitric oxide or its reaction products as mediators of neurotoxicity in brain, tissue injury was assessed after transient global ischemia in mice rendered mutant in the gene for neuronal nitric oxide synthase. Halothane-anesthetized wild type and mutant mice were subjected to temporary occlusion of the basilar plus both carotid arteries for 5 or 10 min followed by three days of reperfusion. Hippocampal injury, assessed both by qualitative grading and by cell counting in the CA1 subregion, was significantly less in the mutant mice group after 5 or 10 min of ischemia. Mutant mice exhibited a lower mortality (P < 0.01), less weight loss, more normal grooming and spontaneous motor activity and better grasping in the 10 min group. There were no obvious differences in cerebrovascular anatomy or hemodynamics between wild type and mutant mice. The data suggest that a deficiency of neuronal nitric oxide synthase confers increased resistance to transient global cerebral ischemia, and support the suggestion that selective neuronal nitric oxide synthase inhibitors might reduce tissue injury associated with global cerebral ischemia.

Animals↗
PubMed1996

Effects of cerebral ischemia on N-methyl-D-aspartate and dihydropyridine-sensitive calcium currents. An electrophysiological study in the rat hippocampus in situ.

BACKGROUND AND PURPOSE: During cerebral ischemia, both promoting and limiting factors are present for activation of the N-methyl-D-aspartate (NMDA) receptor ion channel and the dihydropyridine (DHP)-sensitive Ca2+ channels. We investigated the activity of these channels during ischemia and reperfusion in the rat hippocampus in situ. METHODS: Reversible ischemia was induced by bilateral carotid artery ligation. NMDA and BAY K8644 were applied by iontophoresis or pneumatic ejection, and extracellular field potential and resistance changes were recorded from the CA1 region of the rat hippocampus. Resting membrane potentials of the CA1 neurons were also recorded. RESULTS: DC potential shifts produced by NMDA and BAY K8644 were reduced when ischemia depressed the evoked activity more than 50%. They disappeared on total failure of synaptic transmission and recovered during reperfusion. When the evoked activity was depressed less than 50%, DC shifts were greater than their preischemic values; however, BAY K8644-induced potentiation did not reach statistical significance. CA1 neurons were depolarized during ischemia. CONCLUSIONS: These data suggest that ischemia severe enough to cause transmission failure inactivates NMDA and DHP-sensitive Ca2+ currents. During less intense ischemia and reperfusion, NMDA and DHP-sensitive Ca2+ channels are functional, and their overactivation may lead to neurotoxicity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression.

Nitric oxide (NO) is known to mediate increases in regional cerebral blood flow elicited by CO2 inhalation. In mice with deletion of the gene for neuronal NO synthase (NOS), CO2 inhalation augments cerebral blood flow to the same extent as in wild-type mice. However, unlike wild-type mice, the increased flow in mutants is not blocked by the NOS inhibition, N omega-nitro-L-arginine, and CO2 exposure fails to increase brain levels of cGMP. Topical acetylcholine elicits vasodilation in the mutants which is blocked by N omega-nitro-L-arginine, indicating normal functioning of endothelial NOS. Moreover, immunohistochemical staining for endothelial NOS is normal in the mutants. Thus, following loss of neuronal NOS, the cerebral circulatory response is maintained by a compensatory system not involving NO.

Acetylcholine↗
PubMed1995

Cerebrovascular responses under controlled and monitored physiological conditions in the anesthetized mouse.

Control of physiological parameters such as respiration, blood pressure, and arterial blood gases has been difficult in the mouse due to the lack of technology required to monitor these parameters in small animals. Here we report that anesthetized and artificially ventilated mice can be maintained under physiological control for several hours with apparently normal cerebrovascular reactivity to hypercapnia and mechanical vibrissal stimulation. SV-129 mice were anesthetized with urethane (750 mg/kg i.p.) and alpha-chloralose (50 mg/kg i.p.), intubated, paralyzed, and artificially ventilated. Respiratory control was maintained within physiological range by reducing the inspiratory phase of the respiratory cycle to < 0.1 s and by adjusting end-tidal CO2 to give a PCO2 of 35 +/- 3 mm Hg. In these mice, mean arterial pressure (95 +/- 9 mm Hg), heart rate (545 +/- 78 beats/min), and arterial pH (7.27 +/- 0.10) could be maintained for several hours. Body temperature was kept at 36.5-37.5 degrees C. We observed stable regional CBF (rCBF) measurements (as determined by laser-Doppler flowmetry) when systemic arterial blood pressure was varied between 40 and 130 mm Hg. Hypercapnia led to a 38 +/- 15% (5% CO2) and 77 +/- 34% (10% CO2) increase in rCBF. Mechanical stimulation of contralateral vibrissae for 1 min increased rCBF by 14 +/- 4%. Changes in rCBF compare favorably with those observed previously in another rodent species, the Sprague-Dawley rat. After placement of a closed cranial window, cerebrovascular reactivity to hypercapnia and whisker stimulation was intact and well maintained during 2-h superfusion with artificial CSF.

Anesthesia↗
PubMed1994

Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase.

The proposal that nitric oxide (NO) or its reactant products mediate toxicity in brain remains controversial in part because of the use of nonselective agents that block NO formation in neuronal, glial, and vascular compartments. In mutant mice deficient in neuronal NO synthase (NOS) activity, infarct volumes decreased significantly 24 and 72 hours after middle cerebral artery occlusion, and the neurological deficits were less than those in normal mice. This result could not be accounted for by differences in blood flow or vascular anatomy. However, infarct size in the mutant became larger after endothelial NOS inhibition by nitro-L-arginine administration. Hence, neuronal NO production appears to exacerbate acute ischemic injury, whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal isoform.

Amino Acid Oxidoreductases↗
PubMed1994

Dual role of nitric oxide in focal cerebral ischemia.

The importance of nitric oxide (NO) in the pathophysiology of cerebral ischemia was examined following middle cerebral artery occlusion in rats. A significant increase in infarct size developed following inhibition of NO synthase (NOS) activity by L-arginine analogues whereas intravenous L-arginine dose-dependently decreased infarct volume in the same models. Protection after L-arginine administration was associated with enhanced blood flow within the perinfarct zone as demonstrated by simultaneous recording of rCBF and electrocorticogram activity within subjacent brain. Selective NOS inhibition by 7-nitroindazole (7-NI) significantly reduced infarct volume at doses of 25 and 50 mg kg and in amounts that did not decrease the response of pial vessels to topical acetylcholine. Together these data suggest that enhanced NO production within the cerebrovasculature protects brain tissue during focal ischemia via hemodynamic mechanisms whereas neuronal overproduction may facilitate or mediate neurotoxicity. Recent data using transgenic animals lacking NOS activity support the latter conclusion.

Acetylcholine↗
PubMed1994

Formulation and in vitro-in vivo evaluation of buccoadhesive morphine sulfate tablets.

Buccoadhesive controlled-release systems for the delivery of morphine sulfate were prepared by compression of hydroxypropyl methylcellulose (HPMC) with carbomer (CP), which served as the bioactive adhesive compound. The release behavior of systems containing 30 mg of morphine sulfate and various amounts of the two polymers was found to be non-Fickian. The adhesion force was significantly affected by the mixing ratio of HPMC and CP in the tablet, and the weakest adhesion force was observed at a ratio of 1:1 (HPMC:CP). Interpolymer complex formation was confirmed between HPMC and CP in acidic medium by turbidity, viscosity, and FT-IR measurements. The amount absorbed (percentage of the drug loaded) of the controlled-release buccoadhesive tablets in six healthy volunteers and was 30 +/- 5%.

Absorption↗
PubMed1994

The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia.

Nitrogen monoxide (NO) has recently emerged as an important mediator of cellular and molecular events which impacts the pathophysiology of cerebral ischemia. Although tempting to ask whether NO is "good or bad" for cerebral ischemia, the question underestimates the complexities of NO chemistry and physiology as well as oversimplifies the pathophysiology of focal cerebral ischemia. Important vascular and neuronal actions of NO have been defined which both enhance tissue survival and mediate cellular injury and death, and these will be reviewed. Strategies which modify NO synthesis and/or metabolism may someday assume therapeutic importance, but not until the tissue compartments generating NO, the activities of the enzymes that are inducibly and constitutively expressed, and the redox state of NO during the stages of ischemic injury, are defined with greater precision. Our knowledge of these processes is rudimentary. This review will summarize the evidence from animal models which supports an emerging role for NO in ischemic pathophysiology. Important aspects of NO synthesis and inhibitors of this process will also be discussed.

Amino Acid Oxidoreductases↗
PubMed1994

Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia.

The reduction in focal infarct volume after L-arginine has been attributed to an increase in regional cerebral blood flow (rCBF) within ischemic tissue. We tested the hypothesis that L-arginine-induced rCBF increases precede the recovery of spontaneous electrical activity [electrocorticogram (ECoG)] in spontaneously hypertensive rats subjected to middle cerebral artery (MCA) occlusion. ECoG was recorded from the penumbral region of parietal cortex by a glass microelectrode inserted into 1-mm3 cortical tissue from which blood flow was sampled by laser-Doppler flowmetry. rCBF dropped to 21 +/- 8% of the preischemic level, and ECoG was depressed by 64 +/- 13% after distal MCA occlusion. L-Arginine infusion (300 mg/kg i.v.) increased rCBF in 14 out of 18 rats, and ECoG significantly recovered in seven rats in which rCBF exceeded 31% of preischemic flow. Increases in rCBF anticipated the functional improvement in every case. Saline (n = 6) or D-arginine (n = 5) administration was ineffective. These data demonstrate that increasing rCBF can promote functional recovery in the ischemic brain and suggest that early administration of L-arginine or other vasodilators may enhance tissue survival by increasing rCBF.

Animals↗
PubMed1994

L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat.

BACKGROUND AND PURPOSE: We previously reported that L-arginine infusion increased pial vessel diameter by nitric oxide-dependent mechanisms, improved regional cerebral blood flow (rCBF) distal to middle cerebral artery (MCA) occlusion, and reduced infarction volume in spontaneously hypertensive rats when administered intraperitoneally before and after MCA occlusion. In this report we extend our findings (1) by examining the time course of L-arginine on rCBF and pial vessel diameter under basal conditions and on rCBF after MCA occlusion and (2) by reproducing the protective effect of L-arginine on infarct volume when given intravenously immediately after the onset of MCA occlusion in both normotensive and hypertensive models of focal cerebral ischemia. METHODS: Changes in pial vessel diameter (closed cranial window) and rCBF (laser-Doppler flowmetry) were measured over time after L-arginine infusion into anesthetized Sprague-Dawley rats. rCBF was also measured distal to MCA occlusion in a brain region showing rCBF reductions in the range of 80% of baseline. The effects of infusing L-arginine (300 mg/kg for 10 minutes beginning 5 minutes after occlusion) were assessed on infarction volume in Sprague-Dawley rats after proximal MCA occlusion and in spontaneously hypertensive rats after common carotid artery plus distal MCA occlusion. RESULTS: L-Arginine (300 mg/kg IV) elevated rCBF by 20% when measured in the dorsolateral cortex of Sprague-Dawley rats and caused L-nitroarginine-methyl ester-inhibitable increases in pial vessel diameter. L-Arginine (> or = 30 mg/kg IV) increased blood flow distal to MCA occlusion by 50%. These effects were sustained throughout the observation period (70 to 105 minutes). Changes in mean arterial blood pressure were not observed. L-Arginine (300 mg/kg IV) reduced infarction volume by 35% and 28% in Sprague-Dawley and spontaneously hypertensive rats, respectively, when examined 24 hours after vessel occlusion. CONCLUSIONS: These studies extend our previous findings by demonstrating that exogenous L-arginine induces sustained rCBF increases in normal brain as well as in a marginally perfused brain region distal to MCA occlusion. Our data in Sprague-Dawley rats support the conclusion that L-arginine-induced increases in rCBF can decrease infarction volume. We conclude that nitric oxide-mediated mechanisms increase rCBF and decrease infarction volume after MCA occlusion in both normotensive and hypertensive animals.

Amino Acid Oxidoreductases↗