Biomedical subjects

F C Barone

Publications and source records attributed to F C Barone.

At least 73 records · Page 4Linked to original sources

PubMed1995

Time-related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke.

In previous studies, we have used histological methods to characterize cellular changes, and validated the use of the myeloperoxidase (MPO) activity assay to quantitate increased neutrophil infiltration in ischemic stroke. We also identified increased leukotriene B4 (LTB4) binding sites as a potential marker for neutrophil infiltration into focal ischemic tissue. However, these studies were conducted at only one time-point, 24 h after ischemia. In the present study, we examined the full time-course of MPO activity and LTB4 receptor binding following middle cerebral artery occlusion (MCAO) made permanently (PMCAO) or transiently (160 min followed by reperfusion; TMCAO) in spontaneously hypertensive rats, and compared the results to previously characterized histologic changes in these models. Ischemic and contralateral (control) cortical tissue samples were assayed for MPO (U/g wet wt) and [3H]LTB4 receptor binding (fmol/mg protein). Following PMCAO, MPO activity significantly increased as early as 12 h and continued to increase over the next 5 d (p < 0.05). Following TMCAO, MPO activity was significantly elevated already after only 6 h of reperfusion and also continued to increase over the next 5 d of reperfusion (p < 0.05). LTB4 receptor binding and MPO activity were highly correlated during periods when both measures increased together (i.e., 0.5-5 d; p <0.01). However, by 15 d post-MCAO, LTB4 receptor binding remained elevated after MPO activity levels had returned to normal. This persistent LTB4 binding was associated with the significant gliosis that was characterized previously to persist in these models. The time-course of increased MPO activity and initially increased LTB4 binding post-MCAO correspond very well to our previous histological data that characterized the time-course for leukocyte infiltration under these conditions. Therefore, the increased MPO activity over time was associated with initial neutrophil and later mononuclear cell infiltration into ischemic tissue in these models. In addition, the present studies utilized histochemical analysis to demonstrate peroxidase activity in macrophages within the cerebral infarct following MCAO, thus validating that MPO activity originates from the later infiltrating mononuclear cells in addition to the early infiltrating neutrophils that had been previously characterized in the same manner. TMCAO produces a significantly larger and earlier increase in ischemic cortex MPO activity and a similar later increase in MPO activity compared to PMCAO treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗

PubMed1995

Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain.

Cytokines have been shown to be induced following a variety of central nervous system (CNS) insults, and may play a role in the pathophysiological sequelae of CNS injury. In the present study, we characterized the regional expression of interleukin-1 beta (IL-1 beta) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injury of moderate severity (2.4 atm.) centered over the left parietal cortex, or 'sham' treatment (anesthesia and surgery without injury). Animals were sacrificed at 1, 6 and 24 h post injury, brains were removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH) were prepared. Total RNA was isolated and Northern blot hybridization was performed and the quantity of brain tissue IL-1 beta mRNA is presented as percent relative radioactivity of IL-1 beta positive macrophage RNA which was loaded on same gel.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Transforming growth factor-beta 1 exhibits delayed gene expression following focal cerebral ischemia.

Transforming growth factor-beta 1 (TGF-beta 1) is a pleiotropic peptide growth factor. The expression of TGF-beta 1 mRNA in the focal ischemic cortex of rats was studied by means of Northern hybridization. A moderately low level of constitutively expressed TGF-beta 1 mRNA was detected following sham-surgery or in the contralateral (nonischemic) cortex. A significant increase of TGF-beta 1 mRNA level in the ischemic cortex was observed at 2 days (3.2-fold increase compared to sham-operated animals, p < 0.01, n = 4) following permanent occlusion of the middle cerebral artery (PMCAO). The elevated TGF-beta 1 mRNA expression was plateaued for up to 15 days (3.6-fold increase, p < 0.01) following PMCAO. This temporal profile for TGF-beta 1 mRNA expression in focal stroke was significantly delayed compared to that of TNF-alpha, IL-1 beta and IL-6 mRNA expressions as demonstrated previously which peaked at 12 h and decreased to almost basal levels by 5 days following PMCAO. Interestingly, the TGF-beta 1 mRNA expression profile was remarkably parallel with that of monocyte/macrophage accumulation in the ischemic cortex, as well as with the increased formation of extracellular matrix in the focal ischemic brain. These data suggest that TGF-beta 1 may play a role in anti-inflammatory process and in tissue remodeling following ischemic brain injury.

Analysis of Variance↗

PubMed1995

Gastric distension modulates hypothalamic neurons via a sympathetic afferent path through the mesencephalic periaqueductal gray.

The effects of gastric distension on extracellularly recorded single neuronal activity in the lateral hypothalamuslateral preoptic area-medial forebrain bundle (LPA-LH-MFB), other areas of the hypothalamus, mesencephalic periaqueductal gray (PAG), and other areas associated with the mesencephalic reticular formation were determined in the anesthetized rat. Gastric distension was produced by filling a gastric balloon with water using a calibrated infusion pump. Experimental conditions were based on previous studies that simulated gastric distension during fluid consumption in the rat. The effects of stomach distension using water at body temperature and room temperature were compared. Neurons in both the hypothalamus and mesencephalon were modulated by gastric distension. Hypothalamic neurons exhibited responses associated with gastric distension and exhibited interactions between distension and temperature stimulation of the stomach. Neurons in the mesencephalic periaqueductal gray (PAG) and associated reticular formation also were modulated by these gastric stimuli. When the PAG was electrically stimulated, similar responses to gastric distension and PAG stimulation were observed for hypothalamic neurons. The effects of gastric distension on hypothalamic neurons were reduced or eliminated when the PAG stimulating electrode site was destroyed by electrocoagulation. In addition, the microiontophoretic application of horseradish peroxidase at hypothalamic neuronal recording sites where gastric distension effects were observed resulted in the retrograde labeling of neurons in the PAG. These gastric stimulation-induced effects on hypothalamic and mesencephalic neuronal activity were attenuated but were not permanently eliminated by bilateral cervical vagotomy. However, these effects were significantly reduced or eliminated by bilateral transection of the cervical sympathetic chain or spinal transection at the first cervical level. Because the filling of balloons placed into the abdominal cavity close to the stomach had no similar effects on neural activity, these results can be attributed primarily to the activation of gastric mechano-and temperature-sensitive receptors. These results indicate that the effects of gastric temperature/distension stimulation under these conditions are mediated to a large degree by sympathetic afferents. The PAG is clearly involved as one of the mesencephalic relays for gastric afferent input to the hypothalamus.

Adrenergic Fibers↗

PubMed1995

GABA receptors in the dorsal motor nucleus of the vagus influence feline lower esophageal sphincter and gastric function.

Gamma-aminobutyric acid (GABA) antagonist (bicuculline methiodide, BIC; picrotoxin, PIC) or agonist (muscimol, MUS) microinjections were made into the dorsal motor nucleus of the vagus nerve (DMV), and effects on lower esophageal sphincter pressure (LESP), gastric motility, and gastric acid secretion were determined in chloralose-anesthetized cats. Right or left DMV sites were microinjected with BIC, PIC, MUS, or isotonic tonic saline (140 nl) through a glass micropipette having a tip diameter of 15-21 microns. Esophageal body, LESP, and gastric fundic pressures were measured manometrically. Circular smooth muscle contractions of the antrum and pylorus were recorded with strain-gauge force transducers. Gastric acid secretion was measured every 15 min through a gastric cannula and titrated to pH 7.0. DMV microinjection sites were verified histologically. Direct BIC microinjections (0.275 or 0.550 nmol) into the DMV primarily produced a decrease in LESP (71% of all sites tested), with mean LESP changing from 23.2 +/- 1.7 mmHg to 3.7 +/- 0.7 mmHg (p < 0.01). Tonic LESP increases and phasic LESP contractile activity occurred less frequently. BIC-induced LESP responses were abolished by vagotomy or by microinjections of MUS (0.5 to 10 nmol) into the DMV. Direct PIC microinjection (0.232 nmol) into the DMV produced a pattern of responses similar to those observed with BIC (which were also abolished by vagotomy or by MUS microinjections into the DMV). The antrum and pylorus were also responsive to DMV microinjections of both GABA antagonists. Microinjections of BIC or PIC into the DMV produced increases in gastric circular muscle activity that occurred less frequently than LESP effects, but also were eliminated by vagotomy. The high (0.550 nmol) dose of BIC increased gastric motility significantly more often than the low dose of BIC (p < 0.05). In addition, BIC (0.550 nmol) microinjections into the DMV increased gastric secretory volume (from 0.6 +/- 0.2 to 6.0 +/- 2.5 ml/15 min; p < 0.01) and total titratible acid (from 34.4 +/- 8.9 to 86.0 +/- 19.1 mEq/15 min; p < 0.01), and decreased gastric pH (from 4.63 +/- 0.44 to 3.50 +/- 0.49; p < 0.05). Vagotomy also eliminated the gastric secretory effects of DMV BIC. Direct microinjections of MUS into the DMV also blocked BIC- or PIC-induced changes in gastric motility and/or gastric acid secretion. Isotonic saline microinjected into the DMV did not increase basal or decrease stimulated gastric esophageal motility or gastric secretion. These data indicate that LESP, gastric motility, and gastric secretion are influenced by a tonic DMV inhibition mediated by GABAA receptor stimulation of the DMV. Because disinhibition of these receptors clearly activates the upper gut, future work should focus on identifying the nuclei providing this synaptic input to the DMV that might be involved in the functional regulation of upper gut motor and secretory function.

Animals↗

PubMed1995

Expression of interleukin-6, c-fos, and zif268 mRNAs in rat ischemic cortex.

The expression of interleukin-6 (IL-6) mRNA in the focal ischemic rat cortex was studied by means of Northern hybridization. IL-6 mRNA was induced after permanent occlusion of the middle cerebral artery, reached a significant level at 3 h, and peaked at 12 h, i.e., approximately 10-fold increase in the ischemic zone compared with the nonischemic cortex or sham-operated controls. The increased IL-6 mRNA was elevated for at least 24 h. Low levels of IL-6 mRNA were detected in sham-operated rats or in the contralateral nonischemic cortex. The expression of c-fos and zif268 mRNAs, two early response genes, was rapid (increased by 1 h postischemia) and transient (returned to basal levels by 24 and 12 h, respectively), clearly having different kinetic patterns from that of IL-6 mRNA. The early response kinetic pattern of c-fos and zif268 mRNAs in focal ischemia suggests their transcriptional regulatory roles in response to ischemic insult, while the delayed induction pattern of IL-6 mRNA suggests a role for this pleiotropic cytokine in the inflammatory response to the focal ischemic damage of the brain.

Animals↗

PubMed1995

Differential calcitonin gene-related peptide (CGRP) and amylin binding sites in nucleus accumbens and lung: potential models for studying CGRP/amylin receptor subtypes.

Calcitonin gene-related peptide (CGRP), a 37-amino-acid peptide, is a member of a small family of peptides including amylin or islet amyloid polypeptide and salmon calcitonin. These related peptides have been shown to display similar effects on in vitro and in vivo carbohydrate metabolism. The present study was initiated to identify and characterize the binding sites for these peptides in lung and nucleus accumbens membranes prepared from pig and guinea pig. Both tissues in either species displayed high-affinity (2-[125I]iodohistidyl10)humanCGRP alpha ([125I]hCGRP alpha) binding (IC50 = 0.4-7.7 nM), which was displaced by hCGRP8-37 alpha with equally high affinity (IC50 = 0.4-7.3 nM). High-affinity binding for [125I]Bolton-Hunter human amylin ([125I]BH-h-amylin) was also observed in these tissues (IC50 = 0.2-6.0 nM). In membranes from the nucleus accumbens of both species, salmon calcitonin competed for amylin binding sites with high affinity (IC50 = 0.1 nM) but was poor in competing for amylin binding in lung membranes. Rat amylin8-37 competed for [125I]hCGRP alpha binding with higher affinity (IC50 = 5.4 nM) compared with [125I]BH-h-amylin binding (IC50 = 200 nM) in porcine nucleus accumbens, whereas in guinea pig nucleus accumbens, the IC50 values for rat amylin8-37 were 117 and 12 nM against [125I]hCGRP alpha and [125I]BH-h-amylin, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1995

Therapeutic effects of endothelin receptor antagonists in stroke.

The presence of the endothelin isopeptides and endothelin receptors on neurons, glial cells and brain capillary endothelium suggests that endothelins may play a significant role in neuromodulation, astrocytic function and in regulation of cerebral blood flow. Furthermore, endothelins may play a significant role in the central regulation of neuroendocrine and autonomic nervous system functions (i.e., plasma volume, cardiovascular and respiratory control). Endothelin has potent cerebrovascular and proliferative effects suggesting a pathogenic role in cerebrovascular diseases. Endothelin receptors may represent important therapeutic targets for the treatment of both hemorrhagic and ischemic stroke. A review of the available data on endothelin levels and the effects of endothelin antagonists in cerebrovascular diseases is provided in the present report. Most notably is evidence in support of increased brain endothelin levels in hemorrhagic and ischemic stroke both in animal models and in humans. Also, endothelin receptor antagonists exert significant efficacy in animal models of cerebrovascular disease. For example, SB 209670, a rationally designed, potent, nonpeptide endothelin receptor antagonist, exerts therapeutic efficacy in reducing vasospasm following subarachnoid hemorrhage and neuroprotection following ischemic stroke. Certainly the available data warrants further evaluation of novel, selective endothelin receptor antagonists or endothelin converting enzyme inhibitors in cerebrovascular diseases.

Animals↗

PubMed1995

Monocyte chemoattractant protein-1 messenger RNA expression in rat ischemic cortex.

BACKGROUND AND PURPOSE: Previously we demonstrated that focal cerebral ischemia results in an increased expression of several cytokines/chemokines that precede the infiltration of leukocytes into the ischemic cortex after focal stroke induced by occlusion of the middle cerebral artery (MCAO). Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant specific for monocytes. The aim of the present study was to examine whether MCP-1 messenger RNA (mRNA) is expressed in ischemic brain tissue after MCAO. METHODS: The expression of MCP-1 mRNA in the ischemic cortex was first identified by means of a sensitive reverse transcription and polymerase chain reaction technique. The time course of expression of MCP-1 mRNA in the ischemic and nonischemic cerebral cortex after both permanent MCAO and temporary MCAO (160 minutes) with reperfusion was then examined by means of Northern blot analysis. RESULTS: Almost no expression of MCP-1 mRNA was found in the sham-operated or nonischemic (contralateral) cortex. A significant increase in MCP-1 mRNA expression in the ischemic cortex was observed after either permanent or temporary MCAO. MCP-1 mRNA was elevated at 6 hours (4.4-fold increase over sham; n = 4), reached its highest expression from 12 hours to 2 days (22.7-fold at the peak level; P < .01), and remained elevated up to 5 days (5.6-fold; P < .01) after permanent MCAO. The profile of MCP-1 mRNA expression in the ischemic cortex after MCAO with reperfusion was similar to that of permanent MCAO except that MCP-1 mRNA was increased earlier (ie, 12.5-fold increase at 3 hours; n = 4; P < .01). Also, MCP-1 mRNA expression in the ischemic cortex after permanent MCAO was significantly greater in hypertensive rats than in two normotensive rats (n = 4; P < .05). CONCLUSIONS: The demonstration of induced MCP-1 mRNA expression early after focal ischemia suggests that MCP-1 may represent a locally expressed monocyte chemoattractant that plays an important role in monocyte infiltration into ischemic tissue and therefore may contribute to the tissue injury in ischemic stroke. Further studies must concentrate on identifying the induced expression of MCP-1 and its cellular localization in the ischemic brain when the appropriate antibodies become available.

Animals↗

PubMed1995

Demonstration of increased endothelial-leukocyte adhesion molecule-1 mRNA expression in rat ischemic cortex.

BACKGROUND AND PURPOSE: Leukocyte infiltration from circulating blood into ischemic brain tissue contributes significantly to ischemic injury. The role of adhesion molecules in leukocyte attachment and infiltration in ischemic tissue has been emphasized. The aim of the present study was to evaluate whether endothelial-leukocyte adhesion molecule-1 (ELAM-1 or E-selectin) mRNA expression is upregulated in focal brain ischemia. METHODS: Northern blot analysis with the use of poly(A) RNA isolated from the ischemic and nonischemic rat cortex at 2 and 12 hours after permanent occlusion of the middle cerebral artery (PMCAO) was used to examine ELAM-1 mRNA expression. The temporal expression profile of ELAM-1 mRNA in the ischemic cortex was further evaluated with the use of a quantitative reverse transcription and polymerase chain reaction technique. RESULTS: A very low level of ELAM-1 mRNA was detected in the sham-operated cortex or in the nonischemic cortex. The expression of ELAM-1 mRNA in the focal ischemic cortex was significantly induced by PMCAO, reaching a peak level at 12 hours (6.9-fold increase compared with sham surgery cortical samples, P < .01) and remained elevated for up to 2 days (3.3-fold increase, P < .01) after PMCAO. CONCLUSIONS: The demonstration of upregulated ELAM-1 mRNA expression after focal stroke suggests that ELAM-1 may play an important role in leukocyte infiltration into the ischemic brain and that ELAM-1 may provide a potential therapeutic target in ischemic stroke. However, the demonstration of translated ELAM-1 and its cellular localization in the ischemic tissue is required when specific antibodies become available.

Animals↗

PubMed1995

SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

BACKGROUND AND PURPOSE: Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. METHODS: Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. RESULTS: In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. CONCLUSIONS: These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Animals↗

PubMed1995

The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury.

Previously, we demonstrated that cerebral focal ischemic tissue exhibits a significant increase in immunoreactive endothelin (ET). Because increased ET might exacerbate the consequences of cerebral ischemia, we evaluated the effects of the orally active ETA/B receptor antagonist SB 217242 on middle cerebral artery occlusion (MCAO) in the spontaneously hypertensive rat (SHR). SHRs were treated b.i.d. with vehicle or with 3 or 15 mg/kg SB 217242 p.o. for 7 days. Permanent MCAO was performed on day 7 and animals were sacrificed on day 8. Forebrains were stained and the extent of cerebral (i.e., cortical) infarction was determined using image analysis. Hemispheric swelling (%), hemispheric infarct (%), and infarct volume (mm3) were quantitated for each animal. SB 217242 treatment produced a significant decrease in ischemic brain injury. Hemispheric infarction and infarct volume were reduced after the 15 mg/kg treatment (12.0 +/- 1.1% and 69 +/- 6 mm3) compared to vehicle (17.3 +/- 1.5% and 99 +/- 8 mm3) (p < 0.05). No significant effects on hemispheric swelling were observed. This is the first demonstration of an ET receptor antagonist exhibiting efficacy in cerebral focal ischemia. The fact that a 30% reduction in ischemic brain injury can be demonstrated after oral administration of SB 217242 suggests that ET antagonists may be of therapeutic utility in focal stroke.

Animals↗

PubMed1994

Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role in cerebroprotection.

The antioxidant activities of carvedilol have been demonstrated in a wide variety of test systems, including (i) physicochemical (EPR studies), (ii) biochemical (measurement of lipid peroxidation and endogenous antioxidant depletion), (iii) cellular, and (iv) in vivo. The antioxidant activity of carvedilol clearly emanates from the carbazole moiety which is unique to carvedilol. The antioxidant activity resides equally in both of the enantiomers of carvedilol, as well as in some of its metabolites which are devoid of either the alpha 1-adrenoceptor blocking activity or beta-adrenoceptor blocking activity. This novel antioxidant property of carvedilol may account, at least in part, for its cerebroprotection. The data discussed in this article suggest that carvedilol may not only provide effective and safe antihypertensive therapy and therefore reduce a major risk factor for stroke, but will also be better able to provide additional benefits to patients by protecting against oxygen free radicals generated during cerebral ischemia and stroke.

Animals↗

PubMed1994

Pharmacological profile of a novel neuronal calcium channel blocker includes reduced cerebral damage and neurological deficits in rat focal ischemia.

Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage following ischemia. Therefore, blocking voltage-operated calcium channels on nerve cells should provide significant neuroprotection in ischemia. We now report on a novel neuronal calcium channel blocker, NNC 09-0026, in terms of its selective effects on neuronal calcium current and its efficacy in reducing infarct size and neurological deficits in a rat model of focal stroke. In the present studies, the effects of NNC 09-0026 on neuronal calcium influx, calcium channel binding, and cardiovascular parameters were determined. Also, phencyclidine, NNC 09-0026, or vehicle were administered i.v. to rats subjected to permanent middle cerebral and common carotid artery occlusions. Infarct volumes and contralateral forepaw and hindlimb neurological deficits were assessed at 24 and 48 h after onset of stroke. NNC 09-0026 exhibited a pharmacological profile suggesting selectivity at neuronal calcium channels. It inhibited potassium-stimulated calcium uptake into rat synaptosomes with an IC50 of 13 microM. Voltage-operated calcium currents measured from cultured rat dorsal root ganglion cells using the patch clamp technique were blocked by 43% at 10 microM (p < 0.05). The compound showed only weak effects on smooth muscle from the guinea pig taenia coli and was relatively inactive at displacing nitrendipine and omega-conotoxin in receptor-binding studies. Single, bolus injections of NNC 09-0026 as high as 10 mg/kg i.v. produced only 12% reduction in heart rate and a 28% decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex.

The expression of intercellular adhesion molecule 1 (ICAM-1) was studied in rat focal ischemic cortex. A significant increase in ICAM-1 mRNA expression in the ischemic cortex over levels in contralateral (nonischemic) site was observed by means of Northern blot analysis following either permanent or temporary occlusion with reperfusion of the middle cerebral artery (PMCAO or MCAO with reperfusion) in spontaneously hypertensive rats. In the ischemic cortex, levels of ICAM-1 mRNA increased significantly at 3 h (2.6-fold, n = 3, P < 0.05), peaked at 6 to 12 h (6.0-fold, P < 0.01) and remained elevated up to 5 days (2.5-fold, P < 0.05) after PMCAO. The profile of ICAM-1 mRNA expression in the ischemic cortex following MCAO with reperfusion was similar to that following PMCAO, except that ICAM-1 mRNA was significantly increased as early as 1 h (6.3-fold, n = 3, P < 0.05) and then gradually reached a peak at 12 h (12-fold, P < 0.01) after reperfusion. ICAM-1 mRNA expression in ischemic cortex following PMCAO was significantly greater in hypertensive rats than in two normotensive rat strains. Immunostaining using anti-ICAM-1 antibodies indicated that upregulated ICAM-1 expression was localized to endothelial cells of intraparenchymal blood vessels in the ischemic but not contralateral cortex. The data suggest that an upregulation of ICAM-1 mRNA and protein on brain capillary endothelium may play an important role in leukocyte migration into ischemic brain tissue.

Animals↗

PubMed1994

Peptidic endothelin-1 receptor antagonist, BQ-123, and neuroprotection.

Endothelin-1 (ET-1) is a potent cerebrovascular constrictor that has been implicated in brain ischemia. Utilizing the ETA receptor antagonist, BQ-123, the role of ET-1 in ischemic neuronal death following global ischemia was studied. BQ-123, administered ICV, either before and after ischemia or only after ischemia, increased hippocampal CA1 neuron survival in gerbils subjected to transient global ischemia. This study suggests that ETA receptor antagonists might be useful in neuronal salvage following stroke.

Animals↗

PubMed1994

Reticular thalamic inhibitory input to lateral hypothalamic neurons: a functional and histochemical determination.

Both the lateral hypothalamus (LH) and reticular thalamus (RT) have been implicated in the integration of a variety of vital functions. To determine relevant connections more specifically between cells of these two regions in the rat, functional neurophysiological and horseradish peroxidase (HRP) histochemical techniques were utilized. Single pulse electrical stimulation of the RT modified the discharge frequency of the majority of LH neurons tested. LH neuronal responses to RT stimulation included; inhibition (66.32%), excitation followed by inhibition (6.12%), and excitation (7.14%). Because RT stimulation resulted primarily in the inhibition of LH neuronal activity with a relative short mean latency of 1.87 +/- 0.23 ms, the existence of a possible direct inhibitory pathway from the RT to LH also was evaluated using HRP histochemistry. Retrogradely HPR labeled soma were identified in the RT after HRP was ejected extracellularly onto LH neurons, which exhibited a decrease in spontaneous activity in response to RT stimulation. These data demonstrate direct projections from the RT to the LH. In addition, HRP labeling of neurons and axons in the zona incerta-LH area following LH HRP ejections suggest this route as a synaptic pathway from RT to LH.

Action Potentials↗

PubMed1994

Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue.

Previously, we described cellular changes following Permanent Middle Cerebral Artery Occlusion (PMCAO) in spontaneously hypertensive rats. Ischemic changes following PMCAO included a time-related focal pan necrosis, inflammatory cell infiltration, gliosis, and eventual loss of necrotic tissue post PMCAO. We have now characterized changes which occur after Temporary Middle Cerebral Artery Occlusion (TMCAO; 80 or 160 min) followed by reperfusion and compared these changes to those which occur following PMCAO. TMCAO with reperfusion results in cortical infarcts which vary in size in an occlusion-time-dependent manner. After 1 h of reperfusion, ischemic changes were observed histologically, including microhemorrhages and the beginning of a slight inflammatory infiltration in and around the meningeal vasculature. This infiltrate consisted primarily of neutrophils, which by 6 h of reperfusion was significant with infiltration from deep blood vessels into brain tissue, including the presence of some monocytes adhering within blood vessels. Neutrophil infiltration occurred sooner and to a greater extent in reperfused tissues than in permanently occluded tissues, where it only began at 12 h post PMCAO. As occurred following PMCAO, increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity indicating astrogliosis was first observed at 12 h postTMCAO. Over 1-3 days of reperfusion, a heavy macrophage infiltrate was observed in the reperfused tissues in addition to a continued influx of neutrophils. Following 5 days of reperfusion, the lesion was completely replaced with inflammatory cells, of which macrophages predominated. Unlike PMCAO, which resulted in focal spots of neutrophil accumulation, neutrophils were more distributed throughout the infarcted cortex following TMCAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗