PubMed Health⌕ Search

Biomedical subjects

G Z Feuerstein

Publications and source records attributed to G Z Feuerstein.

At least 55 records · Page 3Linked to original sources
PubMed1998

Staurosporine-induced apoptosis in cardiomyocytes: A potential role of caspase-3.

Cardiomyocyte apoptosis has been demonstrated in animal models of cardiac injury as well as in patients with congestive heart failure or acute myocardial infarction. Therefore, apoptosis has been proposed as an important process in cardiac remodeling and progression of myocardial dysfunction. However, the mechanisms underlying cardiac apoptosis are poorly understood. The present study was designed to determine whether the family of caspase proteases and stress-activated protein kinase (SAPK/JNK) are involved in cardiac apoptosis. Cultured rat neonatal cardiac myocytes were treated with staurosporine to induce apoptosis as evidenced by the morphological (including ultrastructural) characteristics of cell shrinkage, cytoplasmic and nuclear condensation, and fragmentation. Nucleosomal DNA fragmentation in myocytes was further identified by agarose gel electrophoresis (DNA ladder) as well as in situ nick end-labeling (TUNEL). Staurosporine-induced apoptosis in myocytes was a time- and concentration-(0.25-1 micro M)-dependent process. Staurosporine-induced apoptosis in myocytes was reduced by a cell-permeable, irreversible tripeptide inhibitor of caspases, ZVAD-fmk, but not by the ICE-specific inhibitor, Ac-YVAD-CHO. At 10, 50 and 100 muM of ZVAD-fmk, staurosporine-induced myocyte apoptosis was reduced by 5.8, 39.1 (P<0.01) and 53.8% (P<0.01), respectively. Staurosporine, at 0.25-1 micro M, increased caspase activity in cardiomyocytes by five- to eight-fold, peaking at 4-8 h after stimulation. Based on substrate specificity analysis, the major component of caspases activated in myocytes was consistent with caspase-3 (CPP32). Moreover, the appearance of the 17-kD subunit of active caspase-3 in staurosporine-treated myocytes was demonstrated by immunocytochemical analysis. In contrast, staurosporine induced a rapid and transient inhibition of SAPK/JNK in myocytes. The SAPK activity in myocytes was reduced by 68.3 and 58.3% (P<0.01 v basal) at 10 and 30 min after treatment with 1 micro M of staurosporine, respectively. Our results suggest that staurosporine-induced cardiac myocyte apoptosis involves activation of caspases, mainly caspase-3, but not activation of the SAPK signaling pathway.

Amino Acid Sequence↗
PubMed1998

Recent observations with beta-adrenoceptor blockade. Beneficial effects in hypertension and heart failure.

Carvedilol is a third-generation vasodilating beta-blocker initially approved for the treatment of hypertension. It lowers systemic arterial blood pressure without causing reflex tachycardia and preserves renal function. More recently, carvedilol has been shown to reduce morbidity and mortality in patients with congestive heart failure. This reduction may occur in part via beta-blockade and alpha 1-adrenoceptor blockade, the latter resulting in vasodilation. Importantly, carvedilol and several of its metabolites are potent antioxidants that may inhibit the oxidation of norepinephrine and the subsequent formation of toxic intermediates, such as reactive free radicals in the myocardium. As a result, carvedilol inhibits the expression of certain genes involved in myocardial damage, such as intracellular adhesion molecule-1, free-radical-induced activation of transcription factors, and programmed cell death or apoptosis. In this respect, carvedilol represents a new therapy for the treatment of hypertension and congestive heart failure and combines, in one molecule, a number of potentially beneficial properties.

Adrenergic beta-Antagonists↗
PubMed1998

Effects of a hydroxylated metabolite of the beta-andrenoreceptor antagonist, carvedilol, on post-ischaemic splachnic tissue injury.

1 Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new beta-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury. 2 Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg(-1) and 1.0 mg kg(-1), SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation. 3 Administration of 1 mg kg(-1) carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg(-1) carvedilol had no protective effects on post-ischaemic tissue injury. 4 Previous studies have shown that SB 211475 has virtually no beta-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.

Adrenergic beta-Antagonists↗
PubMed1998

Prolonged expression of interferon-inducible protein-10 in ischemic cortex after permanent occlusion of the middle cerebral artery in rat.

Focal cerebral ischemia elicits local inflammatory reaction as demonstrated by the accumulation of inflammatory cells and mediators in the ischemic brain. Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family that possesses potent chemoattractant actions for monocytes, T cells, and smooth muscle cells. To investigate a potential role of IP-10 in focal stroke, we studied the temporal expression of IP-10 mRNA after occlusion of the middle cerebral artery in rat by means of northern analysis. IP-10 mRNA expression after focal stroke demonstrated a unique biphasic profile, with a marked increase early at 3 h (4.9-fold over control; p < 0.01), a peak level at 6 h (14.5-fold; p < 0.001) after occlusion of the middle cerebral artery, and a second wave induction 10-15 days after ischemic injury (7.2- and 9.3-fold increase for 10 and 15 days, respectively; p < 0.001). In situ hybridization confirmed the induced expression of IP-10 mRNA and revealed its spatial distribution after focal stroke. Immunohistochemical studies demonstrated the expression of IP-10 peptide in neurons (3-12 h) and astroglial cells (6 h to 15 days) of the ischemic zone. To explore further the potential role of IP-10 in focal stroke, we demonstrated a dose-dependent chemotactic action of IP-10 on C6 glial cells and enhanced attachment of rat cerebellar granule neurons. Taken together, the data suggest that ischemia induces IP-10, which may play a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neuron attachment/sprouting after focal stroke.

Animals↗
PubMed1998

Use of suppression subtractive hybridization strategy for discovery of increased tissue inhibitor of matrix metalloproteinase-1 gene expression in brain ischemic tolerance.

Brief occlusion of the middle cerebral artery (i.e., ischemic preconditioning; PC) induces significant brain protection to subsequent severe ischemic events. In an effort to discover genes responsible for ischemic tolerance, we have applied a new technique, suppression subtractive hybridization (SSH), to identify genes that are upregulated by PC. Using this SSH approach, a cDNA that encodes tissue inhibitor of matrix metalloproteinase- (TIMP-1) was identified. Time course studies using Northern analysis revealed that TIMP-1 mRNA was significantly elevated at 24 hours (3.3-fold over controls, P < 0.05, n = 5) and 2 days (4.3-fold increase, P < 0.01) after PC, corresponding to the onset of significant ischemic tolerance. Our data not only demonstrate the utility of this new polymerase chain reaction-based SSH strategy for discovery of genes differentially expressed in PC, but also suggest a potential role of TIMP-1 in PC-induced ischemic tolerance.

Animals↗
PubMed1998

Carvedilol prevents severe hypertensive cardiomyopathy and remodeling.

BACKGROUND: Carvedilol (Coreg/Kredex) is an unselective vasodilating beta-blocker with potent antioxidant activity used in the treatment of hypertension, angina, and congestive heart failure. In previous studies, carvedilol has been demonstrated to confer significant cardiac protection in acute ischemic paradigms and reduction of left ventricle hypertrophy in spontaneously hypertensive rats. OBJECTIVE: To examine the effects of carvedilol on discrete histopathologic changes in the heart induced by severe hypertension in stroke-prone spontaneously hypertensive rats. DESIGN: Three groups of stroke-prone spontaneously hypertensive rats were maintained on 1% NaCl drinking solution and a high-fat (24.5%) diet (salt-fat diet). Two of these groups had their salt-fat diet supplemented by 1200 or 2400 ppm carvedilol. The third group had the same diet but it was not supplemented with drug and this group served as a control. We fed a fourth group of stroke-prone spontaneously hypertensive rats a normal diet and used this group to define cardiac changes induced by salt-fat diet. METHODS: In total, 33 stroke-prone spontaneously hypertensive rats from these four groups (n = 7-9 in each group) survived for 18 weeks under these treatment regimens and were evaluated in terms of cardiovascular parameters and several quantitative and semiquantitative histopathologic indices that we developed to identify and compare cardiac muscle and vascular pathology/remodeling. RESULTS: Administration of carvedilol had no effect on systolic blood pressure (range for all salt-fat diet groups 288 +/- 8 to 294 +/- 6 mmHg compared with the value for the normal diet group of 228 +/- 12 mmHg) whereas heart rate was slightly reduced (by 10-18%; P<0.05). Administration of carvedilol produced a significant (P<0.01) dose-related decrease in total cardiac histologic damage (i.e. the sum of several histopathologic indices) induced by the salt-fat diet (i.e. it reduced damage by 54 and 82% at low and high doses, respectively). Specifically, administration of carvedilol produced dose-dependent reductions in histopathologic indices of coronary artery hypertrophy (by up to 88%), hyperplasia (by up to 89%), degeneration of myofiber (by up to 91%), myocardial inflammation (by up to 100%), cardiac fibrosis (by up to 67%), arterial microthrombosis (by up to 95%), and myocardial microinfarction (by up to 100%; all P<0.01). Salt-fat diet induced an increase in total cardiac mass and left ventricle-intraventricular septum cross-sectional area that was completely eliminated by administration of carvedilol (P<0.01). CONCLUSIONS: These data indicate that carvedilol provides remarkable cardioprotection, by suppressing severe hypertension-induced cardiac remodeling and myopathies at doses that do not reduce systemic blood pressure.

Administration, Oral↗
PubMed1998

SB 209670 inhibits the arrhythmogenic actions of endothelin-1 in the anesthetized dog.

SB 209670 reduced basal mean arterial pressure (16%) without affecting left-circumflex coronary artery (LCX) flow, cardiac output, heart rate, or global/regional myocardial contractility. In vehicle-treated animals, i.e. endothelin (ET)-1 produced an initial hyperemic response in the LCX, followed by a secondary reduction in flow. This response was accomplished by decreases in LCX regional wall fractional shortening, +dP/dt and -dP/dt, but an increase in left anterior wall fractional shortening. ET-1 also produced dose-related, fatal ventricular fibrillation. Whereas SB 209670 administration did not inhibit the initial increase in coronary flow produced by ET-1, the secondary constrictor responses were markedly antagonized. SB 209670 also attenuated the reduction in LCX regional wall fractional shortening and converted the increase in left anterior wall contractility to a reduction in contractility. Although SB 209670 produced only a modest inhibition of the ET-1-mediated reductions in dP/dt, the induction of fatal ventricular arrhythmias was completely abolished. Therefore, the data are consistent with the hypothesis that the coronary ischemic and proarrythmic actions of ET-1 are distinct. Therefore, ET receptor antagonists may be useful in treatment of disturbances in cardiac rhythm.

Anesthesia, General↗
PubMed1998

Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure.

A variety of pathophysiologic processes are activated in patients with congestive heart failure (CHF), and some of these have been implicated in the progression of the disease. The most important processes to be activated in CHF are the neurohormonal systems, which include the renin-angiotensin system, the sympathetic nervous system, and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in patients with CHF. It has been postulated that stimulation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac remodeling, which is a hallmark of CHF. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis or programmed cell death, which may be responsible for a continued loss of myocardial cells, resulting in the progressive decrease in left ventricular function that occurs over time in patients with CHF. Carvedilol is a multiple-action neurohormonal antagonist that is effective in slowing the progression of CHF. In double-blind, placebo-controlled clinical trials, carvedilol decreased mortality by 65% (p <0.001) and significantly reduced hospitalization. Carvedilol is a nonselective beta-blocker and vasodilator, the latter activity resulting from alpha1-adrenoceptor blockade. The hemodynamic responses produced by carvedilol result primarily from the blockade of beta1-, beta2-, and alpha1-adrenoceptors. Carvedilol reduces total peripheral vascular resistance and preload without significantly compromising cardiac output or eliciting reflex tachycardia. Carvedilol is also a potent antioxidant that may protect the myocardium from damage produced by oxygen radicals and, as a consequence of its antioxidant activity, carvedilol also inhibits apoptosis in the myocardium. The ability of carvedilol to inhibit apoptosis in the heart may be responsible, in part, for the ability of the drug to reduce mortality and to inhibit the progression of CHF.

Adrenergic beta-Antagonists↗
PubMed1998

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure.

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Acrylates↗
PubMed1998

Subtractive cloning identifies tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) increased gene expression following focal stroke.

BACKGROUND AND PURPOSE: Differential gene expression has been reported following the onset of focal stroke. To identify de novo expression of ischemia-induced genes, we applied subtractive cDNA library strategy to identify the genes that are selectively upregulated by focal stroke. METHODS: Spontaneously hypertensive rats were subjected to permanent occlusion of the middle cerebral artery (MCAO). mRNAs prepared from ischemic and nonischemic cortex 2 and 12 hours after MCAO were subtracted, and a subtractive cDNA library was constructed. A cDNA that encodes for tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was identified in the subtractive cDNA library. The temporal expression of cortical TIMP-1 mRNA was further characterized in ischemic cortex subjected to permanent or temporary (160-minute) MCAO. RESULTS: A panel of genes isolated from the subtractive cDNA library was subjected to Southern analysis to confirm ischemia-induced gene expression. TIMP-1 demonstrated robust induction after ischemic injury. Time-course studies revealed that TIMP-1 mRNA was induced threefold over controls at 12 hours (P<.001, n=4 animals) and reached a peak level at 2 days after permanent MCAO (sevenfold increase, P<.001). Similar induction profile of TIMP-1 mRNA was observed in the ischemic cortex after temporary MCAO followed by reperfusion. CONCLUSIONS: This work demonstrated the utility of subtractive cDNA library strategy for discovery of genes differentially expressed in focal stroke. Furthermore, our data implicate TIMP-1 in ischemia-induced brain injury.

Animals↗
PubMed1998

Osteopontin and its integrin receptor alpha(v)beta3 are upregulated during formation of the glial scar after focal stroke.

BACKGROUND AND PURPOSE: Microglia and astrocytes in the peri-infarct region are activated in response to focal stroke. A critical function of activated glia is formation of a protective barrier that ultimately forms a new glial-limiting membrane. Osteopontin, a provisional matrix protein expressed during wound healing, is induced after focal stroke. The present study was performed to determine the spatial and temporal expression of osteopontin and its integrin receptor alpha(v)beta3 during formation of the peri-infarct gliotic barrier and subsequent formation of a new glial-limiting membrane. METHODS: Spontaneously hypertensive rats (n = 19) were subjected to permanent occlusion of the middle cerebral artery and killed 3, 6, and 24 hours and 2, 5, and 15 days after occlusion. The spatial and temporal expression of osteopontin mRNA was determined by in situ hybridization, and that of osteopontin ligand and its integrin receptor alpha(v)beta3 was determined by immunohistochemistry. RESULTS: Osteopontin mRNA was expressed de novo in the peri-infarct region from 3 to 48 hours; by 5 days osteopontin mRNA expression was restricted to the infarct. Osteopontin protein was expressed by peri-infarct microglia beginning at 24 hours and by microglia/macrophages at 48 hours in the infarct. Integrin receptor alpha(v)beta3 was expressed in peri-infarct astrocytes at 5 and 15 days. CONCLUSIONS: Early microglial/macrophage expression of osteopontin mRNA defines the borders and final infarct area at 24 hours. At 5 days osteopontin ligand is at a distance from the peri-infarct astrocytes expressing integrin receptor alpha(v)beta3. By 15 days astrocytes expressing integrin receptor alpha(v)beta3 are localized in an osteopontin-rich region concomitant with formation of the new glial-limiting membrane. The de novo expression and interaction of osteopontin ligand with its receptor integrin alpha(v)beta3 suggest a role in wound healing after focal stroke.

Animals↗
PubMed1998

Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression.

BACKGROUND AND PURPOSE: A short duration of ischemia (ie, ischemic preconditioning [PC]) can provide significant brain protection to subsequent ischemic events (ie, ischemic tolerance [IT]). The present series of studies was conducted to characterize the temporal pattern of a PC paradigm, to systematically evaluate the importance of protein synthesis in PC-induced IT, and to explore candidate gene expression changes associated with IT. METHODS: Temporary middle cerebral artery occlusion (MCAO) (10 minutes) was used for PC. Various periods of reperfusion (ie, 2, 6, and 12 hours and 1, 2, 7, 14, and 21 days) were allowed after PC and before permanent MCAO (PMCAO) (n=7 to 9 per group) to establish IT compared with non-PC (sham-operated) rats (n=22). Infarct size, forelimb and hindlimb motor function, and cortical perfusion (laser-Doppler flowmetry; n=9 per group) were measured after PMCAO. The effects of the protein synthesis inhibitor cycloheximide administered just before PC (n= 13 to 17) or administered long after PC but just before PMCAO (n=7 to 8) on IT were also determined. Interleukin- receptor antagonist mRNA (reverse transcriptase and polymerase chain reactions [n=20] and Northern analysis [n=50]) and protein expression (immunohistochemistry [n=16]) after PC and early response gene expression (Northern analysis [n=16]) after PMCAO in PC animals were determined. RESULTS: Hemispheric infarct was significantly (P<0.01) reduced only if PC was performed 1 day (decreased 58.4%), 2 days (decreased 58.1%), or 7 days (decreased 59.4%) before PMCAO. PC significantly (P<0.01) reduced neurological deficits (similar to reductions in infarct size). Cycloheximide eliminated ischemic PC-induced IT effects on both brain injury and neurological deficits if administered before PC (P<0.05) but not if administered long after PC but before PMCAO. PC did not produce any significant brain injury, alter cortical blood flow after PMCAO, or produce contralateral cortical neuroprotection. Interleukin-1 receptor antagonist mRNA and protein expression were increased significantly (P<0.01) only during the IT period. PC rats also exhibited a significant (P<0.01) reduction in c-fos and zif268 mRNA expression after PMCAO. CONCLUSIONS: PC is a powerful inducer of ischemic brain tolerance as reflected by preservation of brain tissue and motor function. PC induces IT that is dependent on de novo protein synthesis. New protein(s) that occurs at the PC brain site 1 to 7 days after PC contributes to the neuroprotection. Those proteins that are produced after the more severe PMCAO in PC animals apparently do not contribute to IT. The PC-induced IT is also associated with increased expression of the neuroprotective protein interleukin-1 receptor antagonist and a reduced postischemic expression of the early response genes c-fos and zif268. (Stroke. 1998;29:1937-1951.)

Animals↗
PubMed1998

Carvedilol: preclinical profile and mechanisms of action in preventing the progression of congestive heart failure.

Many pathophysiological processes are activated in patients with congestive heart failure, and several of these have been implicated in the progression of the disease. The most important processes to be activated in heart failure are the neurohormonal systems, which include the reninangiotensin system, the sympathetic nervous system and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in congestive heart failure. It has been proposed that the activation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac and vascular remodelling which are hallmarks of congestive heart failure. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis, or programmed cell death, which may contribute to the continued loss of myocardial cells resulting in progressive decreases in left ventricular function, while at the same time contributing to the cardiac remodelling process which subsequently creates a pro-arrhythmic environment in the myocardium. Carvedilol is a novel multiple-action neurohormonal antagonist that has been shown to be effective in the management of congestive heart failure. Carvedilol also possesses a number of additional activities which may inhibit many of the chronic pathophysiological processes that are involved in the progression of congestive heart failure.

Adrenergic alpha-Antagonists↗
PubMed1997

Protective effects of carvedilol in the myocardium.

Beta blockers have long been used in the treatment of systemic hypertension, where they effectively lower blood pressure and, in so doing, they decrease left ventricular hypertrophy. The sympathetic nervous system is activated in patients with congestive heart failure, and therefore it is logical that beta blockers may also provide benefit in these patients. As such, beta blockers are currently being evaluated in several large clinical trials in congestive heart failure. One particular drug, carvedilol, is a third-generation vasodilating beta blocker that is marketed for the treatment of hypertension. The drug lowers systemic arterial blood pressure without producing reflex tachycardia and preserves renal function. Carvedilol decreases mortality by 65% and decreases hospitalization by 29% in patients with congestive heart failure. The effects of carvedilol in heart failure may result, at least in part, from beta blockade as well as vasodilation, the latter resulting from alpha(1)-adrenoceptor blockade. Interestingly, carvedilol has a number of additional properties that may also provide benefit in these patients. Carvedilol and several of its metabolites are potent antioxidants that may inhibit catecholamine toxicity resulting from the oxidation of norepinephrine and the subsequent formation of toxic intermediates, including the generation of reactive oxygen free radicals in the myocardium. As a result of its antioxidant activity, carvedilol also blocks the expression of several genes involved in myocardial damage and cardiac remodeling, and the drug inhibits free radical-induced activation of transcription factors and programmed cell death (apoptosis). Carvedilol is a novel beta blocker that is highly effective in the treatment of hypertension and congestive heart failure, and combines in one molecule a number of important pharmacologic properties.

Adrenergic alpha-Antagonists↗
PubMed1997

Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets.

This review summarized evidence in support for the case that ischemia elicits an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils at the onset and later monocytes) and mediators (cytokines, chemokines, others). It is clear that de novo upregulation of proinflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain follow soon after the ischemic insult and at a time when the cellular component is evolving. The significance of the inflammatory response to brain ischemia is not fully understood. Evidence is emerging in support of the possibility that the acute inflammatory reaction to brain ischemia may be causally related to brain damage. This evidence includes: 1) the capacity of cytokines to exacerbate brain damage; 2) the capacity of specific cytokine antagonists such as IL-1ra to reduce ischemic brain damage; 3) that depletion of circulating neutrophils reduces ischemic brain injury; 4) and that antagonists of the endothelial-leukocyte adhesion interactions (e.g., anti-ICAM-1) reduce ischemic brain injury. However, it should be kept in mind that cytokines were also argued to provide beneficial effects in brain injury as inferred from studies with TNF-receptor knock-out mice (p55 and p75 knock-out), which display increased sensitivity to brain ischemia, and the capacity of IL-1 to elicit the state of ischemic tolerance upon repeated administration. Nevertheless, the recent revelation on the capacity of ischemia to induce acute inflammation in the brain provides a new and fertile ground for new explorations for novel therapeutic agents that could confine the neuronal damage that follows ischemia. Furthermore, many of the genes that are upregulated by ischemia have growth-promotion capacity and therefore raise the possibility that such gene products may be useful in counteracting brain damage by enhancing repair and establishing compensatory mechanisms that enhance histological and functional recovery.

Animals↗
PubMed1997

Brain cooling during transient focal ischemia provides complete neuroprotection.

A review of the effects of reducing brain temperature on ischemic brain injury is presented together with original data describing the systematic evaluation of the effects of brain cooling on brain injury produced by transient focal ischemia. Male spontaneously hypertensive rate were subjected to transient middle cerebral artery occlusion (TMCAO; 80, 120 or 160 min) followed by 24 h of reperfusion. During TMCAO, the exposed skull was bathed with isotonic saline at various temperatures to control skull and deeper brain temperatures. Rectal temperature was always constant at 37 degrees C. Initial studies indicated that skull temperature was decreased significantly (i.e. to 32-33 degrees C) just as a consequence of surgical exposure of the artery. Subsequent studies indicated that maintaining skull temperature at 37 degrees C compared to 32 degrees C significantly (p < 0.05) increased the infarct size following 120 or 160 min TMCAO. In other studies, 80 min TMCAO was held constant, but deeper brain temperature could be varied by regulating skull temperature at different levels. At 36-38 degrees C brain temperature, infarct volumes of 102 +/- 10 to 91 +/- 9 mm3 occurred following TMCAO. However, at a brain temperature of 34 degrees C, a significantly (p < 0.05) reduced infarct volume of 37 +/- 10 mm3 was observed. Absolutely no brain infarction was observed if the brain was cooled to 29 degrees C during TMCAO. Middle cerebral artery exposure and maintaining brain temperature at 37 degrees C without artery occlusion did not produce any cerebral injury. These data indicated the importance of controlling brain temperature in cerebral ischemia and that reducing brain temperature during ischemia produces a brain temperature-related decrease in focal ischemic damage. Brain cooling of 3 degrees C and 8 degrees C can provide dramatic and complete, respectively, neuroprotection from transient focal ischemia. Multiple mechanisms for reduced brain temperature-induced neuroprotection have been identified and include reduced metabolic rate and energy depletion, decreased excitatory transmitter release, reduced alterations in ion flux, and reduced vascular permeability, edema, and blood-brain barrier disruption. Cerebral hypothermia is clearly the most potent therapeutic approach to reducing experimental ischemic brain injury identified to date, and this is emphasized by the present data which demonstrate complete neuroprotection in transient focal stroke. Certainly all available information warrants the evaluation of brain cooling for potential implementation in the treatment of human stroke.

Animals↗
PubMed1997

The use of mRNA differential display for discovery of novel therapeutic targets in cardiovascular disease.

Recent advances in molecular biology techniques have provided powerful tools for discovery of novel genes relevant to both biological and pathological processes. mRNA differential display is an emerging technique for novel gene discovery and it has been successfully applied to many physiological and pathological conditions including normal development, cell differentiation, cancer, cardiovascular disease, inflammation and CNS disorders. In the present work, we briefly illustrate the critical procedure and highlight most recent technical improvements and modifications of this technology. Based upon the successful applications of this technique in cardiovascular research, it may provide a valuable and powerful investigational tool for the identification of novel therapeutic targets in cardiovascular diseases.

Cardiovascular Diseases↗