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Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 73 records · Page 4Linked to original sources
PubMed1992

Dehydroepiandrosterone protects mice inoculated with West Nile virus and exposed to cold stress.

The protective effect of pretreatment with dehydroepiandrosterone (DHEA) on stress-enhanced viral encephalitis was studied in mice exposed to cold following inoculation with West Nile virus (WNV). Exposure of WNV-inoculated mice to cold water (1 +/- 0.5 degrees C, 5 minutes/day for 8 days) resulted in a mortality rate of 83% as compared to 50% in nonstressed mice (p < 0.05). The effect of cold stress was more pronounced when mice were inoculated with WN-25, a noninvasive neurovirulent variant of WNV. Mice infected with WN-25 showed no mortality, whereas cold stressed mice inoculated with the same virus had a mortality rate of 67% (p < 0.05). The administration of DHEA (serial injections of 10-20 mg/kg with or without a loading dose of 1 gm/kg) resulted in a significant reduction in the mortality rate of stressed mice inoculated with either virus (p < 0.05). Virus levels in the blood and brain of the DHEA-treated mice, were significantly lower than in the control groups. DHEA also prevented the involution of lymphoid organs in stressed mice. The present study provides direct evidence of the protective effects of DHEA as an "anti-stress" agent. Its ability to prevent mortality associated with WNV or WN-25, and involution of lymphoid organs caused by stress-induced immunosuppression, supports the notion that its activity is based on the modulation of the host response.

Analysis of Variance↗
PubMed1992

Protein kinase C activator phorbol 12, 13-dibutyrate inhibits platelet activating factor-stimulated Ca2+ mobilization and phosphoinositide turnover in neurohybrid NG108-15 cells.

The protein kinase C (PKC) activator, phorbol 12, 13-dibutyrate (PDBu) dose-dependently inhibited platelet-activating factor (PAF)-induced [Ca2+]i elevation and inositol monophosphate (IP1) accumulation in neurohybrid NG108-15 cells with IC50 values of 162 nM and 35 nM, respectively. Pretreatment of NG108-15 cells with PKC inhibitor H-7 partially prevented the inhibitory effect of PDBu on PAF-induced [Ca2+]i elevation as well as PI metabolism in NG108-15 cells. Pretreatment of the cells with pertussis toxin (PTX) resulted in a dose-dependent inhibition of PAF-induced IP1 and IP3 accumulation but only slightly affected PAF-induced [Ca2+]i elevation in NG108-15 cells. The results reveal that PAF receptor-mediated Ca2+ mobilization and PI metabolism in NG108-15 cells are regulated by PKC while a PTX-sensitive G protein is coupled to PAF receptor for inducing activation of phospholipase C.

Animals↗
PubMed1992

Evidence for differential opioid mu 1- and mu 2-receptor-mediated regulation of heart rate in the conscious rat.

The possibility that mu-opioid-induced tachycardia and bradycardia could be mediated by different subtypes of the mu-receptor was studied in conscious Sprague-Dawley rats. The selective mu-receptor agonist dermorphin and its analog, TAPS (Tyr-D-Arg-Phe-sarcosine), a putative mu 1-receptor agonist, were given centrally. Tyr-D-Arg-Phe-sarcosine increased the heart rate, the response being inversely correlated to the dose (an increase of 71 +/- 22, 49 +/- 14 and 30 +/- 17 beats/min at doses of 0.3, 3 and 30 pmol, respectively). Dermorphin induced less clear changes in heart rate (maximum increase of 39 +/- 14 beats/min at the dose of 1 pmol). After treatment with the mu 1-selective antagonist naloxonazine (NAZ), TAPS 30 pmol and dermorphin 1 pmol decreased heart rate by -22 +/- 10 and -24 +/- 7 bpm, respectively. The bradycardiac effect of larger doses of dermorphin was potentiated by NAZ (from -25 +/- 8 to -97 +/- 22 bpm) but abolished by the non-selective antagonist naloxone. These data suggest that the high affinity mu 1-opioid receptors mediate tachycardic responses and mu 2-receptors mediate bradycardic responses.

Analgesics, Opioid↗
PubMed1992

Neuroprotective effects of carvedilol, a new antihypertensive agent, in cultured rat cerebellar neurons and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: Free radical generation mediates part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. Carvedilol, a novel multiple-action antihypertensive agent, has been shown to scavenge free radicals and inhibit lipid peroxidation in swine heart and rat brain homogenates. Therefore, we studied the neuroprotective effect of carvedilol on cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: Neuroprotective mechanisms were studied using an in vitro ischemia model of cultured rat cerebellar granule cell neurons exposed to either glutamate or oxygen free radical-generating systems. Prevention of lipid peroxidation by carvedilol was studied by measuring the formation of thiobarbituric acid-reactive substance. Gerbil CA1 neuron survival was examined by direct neuronal count 7 days after 6 minutes of global ischemia with reperfusion. RESULTS: Carvedilol protected cultured neurons in a dose-dependent manner against glutamate-mediated excitotoxicity (inhibitory concentration [IC50] = 1.1 microM) as well as against a 20-minute oxidative challenge (IC50 = 5 microM). The IC50 against the oxidative challenge was lowered to 1.3 microM by growing neurons for 24 hours in the presence of carvedilol. At 10 microM carvedilol inhibited lipid peroxidation 50% and 73% (n = 4, p < 0.001) in neurons exposed to two different free radical-generating systems. Neuroprotection of 52% (n = 22, p = 0.009 versus vehicle) of gerbil CA1 hippocampal neurons was achieved by pretreatment and posttreatment with subcutaneous injection of 3 mg/kg carvedilol twice a day for 4 and 3 days, respectively. CONCLUSIONS: Carvedilol provided neuroprotection in both in vitro and in vivo models of neuroinjury, where oxygen radicals are likely to play an important role. Therefore, carvedilol may reduce the risk of cerebral ischemia and stroke by virtue of both its antihypertensive action and its antioxidative properties.

Animals↗
PubMed1992

Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

BACKGROUND AND PURPOSE: We reported previously that stroke risk factors prepared the brain stem for the development of ischemia and hemorrhage and induced the production of tumor necrosis factor following an intrathecal injection of lipopolysaccharide, a prototypic monocyte-activating stimulus. This study evaluates whether blood or brain cells of hypertensive rats produce more proinflammatory and prothrombotic mediators than do blood or brain cells of normotensive rats. METHODS: Levels of tumor necrosis factor, platelet-activating factor, 6-ketoprostaglandin F1 alpha, and thromboxane B2 in the cerebrospinal fluid and blood of spontaneously hypertensive and normotensive Wistar-Kyoto rats were monitored before and after a challenge with lipopolysaccharide. RESULTS: Little or no activity from these mediators was found in the cerebrospinal fluid or blood of saline-injected control animals. Intravenous administration of lipopolysaccharide (0.001, 0.1, and 1.8 mg/kg) produced dose-dependent increases in blood levels of all mediators in hypertensive rats. In normotensive rats the levels were less than in hypertensive rats and were not clearly dose-related. When lipopolysaccharide was injected intracerebroventricularly, more tumor necrosis factor was measured in the cerebrospinal fluid than in the blood, suggesting local synthesis of this cytokine. Levels of tumor necrosis factor and platelet-activating factor in the cerebrospinal fluid were higher in hypertensive than in normotensive rats. The thromboxane A2/prostacyclin ratio was not altered significantly between the two rat strains. CONCLUSIONS: It is suggested that the higher incidence of brain stem ischemia and hemorrhage after the intrathecal injection of lipopolysaccharide in hypertensive rats than in normotensive rats might be related to the higher levels of the two cytotoxic factors tumor necrosis factor and platelet-activating factor produced in response to such challenge.

Animals↗
PubMed1992

Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia.

BACKGROUND AND PURPOSE: Delayed deterioration of neurological function after central nervous system ischemia is a well-documented clinical problem. The purpose of our study was to elucidate the role of spinal cord blood flow and spinal cord-blood barrier integrity in the evolution of delayed neurological deterioration after transient spinal cord ischemia in rabbits. METHODS: Anesthetized rabbits were subjected to lumbar spinal cord ischemia (25 minutes) and variable periods of reperfusion (30 minutes to 48 hours after ischemia). Regional spinal cord blood flow was monitored by carbon-14-labeled iodoantipyrine autoradiography; vascular permeability was assessed by quantitative microhistofluorescence of Evans blue-albumin in frozen sections of spinal cord. Hindlimb motor function was assessed by standard scoring system and tissue edema by wet/dry weight method. RESULTS: Hindlimb motor function indicated complete paralysis during ischemia and partial gradual recovery upon reperfusion (up to 8 hours), followed by progressive deterioration to severe deficits over 48 hours. Severe vascular permeability disruption was noticed early (30 minutes) after reperfusion, but almost complete recovery reestablished at 8 hours was followed by a secondary progressive increase in vascular permeability. Blood flow was reduced by 20-30% (p less than 0.01) 4 hours after ischemia in the gray matter, but hyperemia (200-300%, p less than 0.01) was observed 12-24 hours after ischemia. Spinal cord water content increased by 5.7% (p less than 0.05) 24 hours after ischemia. CONCLUSIONS: This study demonstrates that delayed neurological and motor deterioration after spinal cord ischemia is associated with severe progressive breakdown of spinal cord-blood barrier integrity that develops late (hours) after the injury. Our data suggest that no ischemic insult in early or late reperfusion is associated with delayed motor deterioration.

Animals↗
PubMed1992

Neuroprotective effects of SKF 10,047 in cultured rat cerebellar neurons and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: Excitatory amino acids and their receptors are involved in mediating ischemic neuronal damage. The sigma-agonists are believed to interact with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective, hypothermic, and motor deficit effects of the sigma-agonist SKF 10,047 and the N-methyl-D-aspartate antagonist MK-801. METHODS: Neuroprotective effects were compared using an in vitro ischemia model of cultured rat cerebellar granule cells and the gerbil model of global brain ischemia induced by 5 minutes of bilateral carotid artery occlusion followed by 7 days of reperfusion. RESULTS: In vitro, (+)MK-801 protected against 100 microM glutamate with a 50% protective concentration of 30 nM, followed by (-)MK-801 (150 nM), cyclazocine (0.5 microM), (+)SKF 10,047 (3.3 microM), pentazocine (5 microM), and (-)SKF 10,047 (10 microM). In vivo, (+)SKF 10,047 pretreatment (60 mg/kg) or multiple postischemic treatments provided neuroprotection comparable with MK-801 pretreatment (10 mg/kg). When ischemic animals were administered the multiple dosing regimen of (+)SKF 10,047, no hypothermic effect was noted in the temporalis muscle over 4 hours' postischemia. Motor deficits monitored by a swing grid test showed that 50% recovery from (+)SKF 10,047 was 5.5 times faster than recovery from MK-801. CONCLUSIONS: These results are the first to report a hypothermia-free, in vivo neuroprotective effect of (+)SKF 10,047, a prototypical drug of the sigma-agonist class.

Animals↗
PubMed1992

Neuroprotective mechanism of (+)SKF 10,047 in vitro and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: The N-methyl-D-aspartate receptor is believed to mediate part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. (+)SKF 10,047, the prototypic sigma-agonist, interacts with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective effect of (+)SKF 10,047 on cultured rat cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: Mechanisms of neuroprotection were studied in vitro by measuring calcium influx into cultured rat cerebellar granule cells loaded with fura 2-AM. In vivo neuroprotection of gerbil CA1 hippocampal neurons was studied in a posttreatment regimen following 5 minutes of bilateral carotid artery occlusion and 7 days of reperfusion. RESULTS: In primary cultured rat cerebellar granule cell neurons, (+)SKF 10,047 in a dose-dependent manner diminished intracellular calcium levels of N-methyl-D-aspartate-stimulated neurons by a maximum of 87% (n = 8), with a 50% inhibitory concentration of 0.8 microM. (+)SKF 10,047 did not prevent subsequent calcium influx stimulated by kainic acid or KCl, nor did it interfere with modulation of the kainate response by quisqualic acid. Neuroprotection of 64% (p = 0.006, n = 15) of gerbil CA1 hippocampal neurons was achieved by posttreatment injection followed by minipump infusion. CONCLUSIONS: Neuroprotection by (+)SKF 10,047 most likely involves interaction at the N-methyl-D-aspartate receptor. These results suggest that the benzomorphan class of sigma-agonists may provide neuroprotection in cerebral ischemia and stroke.

Animals↗
PubMed1992

Platelet activating factor mediates interleukin-2-induced lung injury in the rat.

Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10(5)-10(6) U/rat (n = 7-9) dose-dependently elevated lung water content (27 +/- 1%, P less than 0.01), myeloperoxidase activity (+84 +/- 23%, P less than 0.05), and serum thromboxane B2 (990 +/- 70%, P less than 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-alpha, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P less than 0.05) and thromboxane B2 production (P less than 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18 +/- 16%, P less than 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy.

Animals↗
PubMed1992

Platelet-activating factor stimulates phosphoinositide turnover in neurohybrid NCB-20 cells: involvement of pertussis toxin-sensitive guanine nucleotide-binding proteins and inhibition by protein kinase C.

Platelet-activating factor (PAF) is an unusually potent phospholipid known to be produced by neuronal cells and to modulate cerebral blood flow and metabolism. In previous studies with NCB-20 cells, we reported that PAF induced a significant mobilization of intracellular free Ca2+ ([Ca2+]i), which was inhibited by PAF antagonists. The increase was the result of release from intracellular stores and influx from extracellular sources. The present study was designed to characterize further PAF receptor-mediated cellular signal-transduction mechanisms in myo-[3H]inositol-labeled cells. PAF induced a concentration-dependent increase in phosphatidylinositol (Pl) metabolism, with EC50 values of 1.96 +/- 0.62 nM and 1.12 +/- 0.50 nM for inositol trisphosphate (IP3) and inositol monophosphate (IP1) formation, respectively (four experiments). The maximal production of IP3 and IP1 induced by 50 nM PAF was 254 +/- 34% and 178 +/- 25% over the basal, respectively (four experiments). PAF-induced Pl metabolism was concentration-dependently inhibited by the PAF antagonist BN50739, with an IC50 value of 6.48 +/- 0.52 nM (four experiments). The protein kinase C (PKC) activator phorbol 12,13-dibutyrate concentration-dependently inhibited PAF-induced Pl metabolism and [Ca2+]i mobilization in NCB-20 cells, of NCB-20 cells with pertussis toxin (PTX) resulted in a concentration-dependent inhibition of PAF-induced IP3 production and intracellular Ca2+ release, with a maximal reduction of 66.9 +/- 3.5% and 63 +/- 6.1%, respectively, at 300 ng/ml PTX. PTX in the presence of [32P]NAD specifically [32P]ADP-ribosylated a 38-kDa protein in membranes prepared from NCB-20 cells. Pretreatment of the cells with PTX resulted in a concentration-dependent inhibition of subsequent 32P-labeling of the toxin substrate in the membranes and correlated with the uncoupling of PAF-induced IP3 formation. PAF (0.01-10 nM) elicited a concentration-related stimulation in guanosine 5'-O-(3-[35S]) triphosphate ([35S]GTP gamma S) binding to G alpha i(1,2) proteins, which was inhibited by the PAF antagonist BN50739. PAF at 10 nM also increased [35S]GTP gamma S binding to G alpha s and G alpha o. PAF-evoked activation of G alpha i(1,2) and G alpha o was reduced by preincubation with PTX. Our results reveal that neuronal cells possess PAF receptors linked through guanine nucleotide-binding proteins to phospholipase C and receptor-operated Ca2+ channels that are regulated by PKC. Both PTX-sensitive and -insensitive guanine nucleotide-binding proteins appear to couple the PAF receptor to activation of phospholipase C and the increase in [Ca2+]i. These results contribute to the further understanding of the mechanisms behind PAF actions on neuronal cells.

Adenosine Diphosphate↗
PubMed1992

Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger.

The antioxidant effect of carvedilol, a new vasodilating, beta adrenoceptor blocker was studied and compared with five other beta blockers. Carvedilol rapidly inhibited Fe(++)-initiated lipid peroxidation, measured as thiobarbituric acid reactive substance (TBARS), in rat brain homogenate with an IC50 of 8.1 microM. Under the same conditions, the IC50 values of atenolol, pindolol propranolol, celiprolol and labetalol were over 1.0 mM. Carvedilol protected against Fe(++)-induced alpha-tocopherol depletion in rat brain homogenate with an IC50 of 17.6 microM; propranolol, celiprolol and labetalol, up to 200 microM, did not show any effect. Using dihydroxyfumarate/Fe(++)-ADP as a OH.radical generating system and 5,5-dimethyl pyrroline-N-oxide (DMPO) as a trapping agent, the characteristic DMPO-OH signals were monitored by electron paramagnetic resonance. Carvedilol dose-dependently decreased the intensity of the DMPO-OH signal, with an IC50 of 25 microM, whereas propranolol, at 500 microM, and U74500A, a 21-aminosteroid, at 100 microM, had no effect. The antioxidant effect of carvedilol mainly resides in the carbazole moiety, and the substitution of a hydroxyl group at certain positions on the phenyl ring of either carbazole or the ortho-substituted phenoxylethylamine part of carvedilol resulted in an increase in antioxidant activity. Furthermore, the protective effect of carvedilol analogs against OH.-mediated neuronal death positively correlated to their antioxidant effect. We conclude that carvedilol is a far more potent antioxidant than other commonly used beta blockers. The apparent mechanism of carvedilol's inhibition of lipid peroxidation is mainly via scavenging free radicals. This novel property of carvedilol may contribute to the known cardioprotective activity of this compound.

Adrenergic beta-Antagonists↗
PubMed1992

Hemodynamic, hematologic and eicosanoid mediated mechanisms in 7.5 percent sodium chloride treatment of uncontrolled hemorrhagic shock.

Hypertonic saline solution (HTS) (7.5 percent sodium chloride [NaCl]) treatment (5 milliliters per kilogram) of rats subjected to uncontrolled hemorrhagic shock (n = 7) caused an initial partial recovery of blood pressure (+38 +/- 5 percent, p<0.05) and cardiac index (+48 +/- 6 percent, p<0.01) followed by increased bleeding (+53 +/- 5 percent versus rats treated with 0.9 percent NaCl, p<0.05), secondary shock (mean arterial pressure [MAP] 23 +/- 7 millimeters of mercury, p<0.01) and decreased survival (-54 +/- 15 minutes versus control, p<0.05). The increased blood loss resulted from: 1, increased vascular pressure and vasodilatation (total peripheral resistance index -27 +/- 5 percent, p<0.05), as initial bleeding occurred when MAP and cardiac index are increased compared with the control group (+88 +/- 10 percent, p<0.05 and +82 +/- 7 percent, p<0.01, respectively) and as the concomitant infusion of angiotensin II, a potent vasoconstrictor, delayed the HTS-induced bleeding (resumed at 60 minutes), and 2, a defect in platelet aggregation reflected by decreased adenosine diphosphate (ADP)-induced maximal aggregation (-79 percent versus rats treated with 0.9 percent NaCl, p<0.05) and increased EC50 of ADP (+159 percent, p<0.05). These hemodynamic and hematologic responses might be mediated at least in part by prostacyclin, a vasodilator and antiplatelet aggregator, as HTS-treated rats markedly elevated the 6-keto-PGF1 alpha per thromboxane B2 ratio (+140 +/- 12 percent, p<0.01) and pretreatment with indomethacin decreased blood loss and improved MAP and survival. These data point out potential untoward hemodynamic and hematologic consequences of HTS treatment in traumatic injury in which control of bleeding cannot be confirmed.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effects of coronary angioplasty on plasma platelet-activating factor in man.

Platelet activating factor (PAF) is a mediator of ischemia and reperfusion-induced tissue damage which was found to be synthesized in culture by endothelial cells. We hypothesized that PAF levels may be increased in the coronary system following coronary angioplasty. PAF levels were measured in the great cardiac vein of 16 patients before, during and following angioplasty of the left anterior coronary artery. PAF concentration was significantly higher in the cardiac vein than in the peripheral circulation at all time points. Interestingly, while PAF levels tended to decrease in the periphery they tended to increase in the coronary system over time. We conclude that PAF levels are higher in the coronary system than in the peripheral circulation in patients undergoing coronary angioplasty and that PAF may be released into the coronary artery following the procedure.

Adult↗
PubMed1992

Biological responses to exchange transfusion with liposome-encapsulated hemoglobin.

The present study evaluates the biological responses to 10% blood volume infusion ("top-loading," n = 7) or 50% blood volume exchange transfusion (n = 8) with a new preparation of liposome-encapsulated hemoglobin (LEH) in the conscious rat. Top-loading did not affect systemic hemodynamic variables but induced transient thrombocytopenia (-36% +/- 7%; P less than 0.05) and elevation of plasma thromboxane B2 (12.4 +/- 3.8 pg/100 microliters vs. undetectable levels at the control; P less than 0.05). Rats exchanged with LEH maintained mean arterial pressure (MAP) during the 3 hr observation period, whereas control (0.9% NaCl or lactated Ringer's solution) animals developed hypotension (-23 +/- 5 mm Hg, P less than 0.05). The maintenance of MAP in the LEH group resulted from the opposing effects of LEH-induced increase in total peripheral resistance index (TPRI; +0.06 +/- 0.01 mm Hg/ml/min/kg; P less than 0.05), and decreased cardiac index, (Cl, -25 +/- 6 ml/min/kg, P less than 0.05). In contrast, the decline in MAP in the control groups could be attributed to the lower Cl (-65 +/- 8 ml/min/kg; P less than 0.05). All rats developed metabolic acidosis (base excess of -9.7 +/- 0.6 mmol/liter; P less than 0.05), which was transient in the LEH group but progressive in the control groups. These data support the possible use of LEH as a blood substitute when massive transfusions are needed.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Lipopolysaccharide-induced production of tumor necrosis factor activity in rats with and without risk factors for stroke.

Rats produced more TNF activity in cerebrospinal fluid (CSF) than in blood after intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). After intravenous (i.v.) LPS, blood TNF levels exceeded CSF levels. Thus, brain cells appear to produce TNF in response to LPS. Rats with the stroke-risk factors hypertension or combined hypertension and genetic stroke-proneness produce more TNF in response to a provocative dose of LPS i.v. than control animals free of these risk factors. The possible relevance to stroke vulnerability is discussed.

Animals↗
PubMed1991

Platelet-activating factor in stroke and brain injury.

Platelet-activating factor, an endogenous phospholipid of proinflammatory, hemostatic, and vasoactive properties, is synthesized by neurons and in injured brain. Platelet-activating factor is released together with eicosanoids such as thromboxane A2, prostacyclin, and leukotrienes. Its effects in neurons are mediated through a specific receptor coupled to phospholipase C and phosphoinositol metabolism. The cerebrovascular effects of platelet-activating factor include disruption of the blood-brain barrier, edema formation, and vasospasm. It has also been described to possess direct toxicity to neuronal cells in culture. Discovery and development of several highly potent and selective antagonists to platelet-activating factor receptors facilitated experimental studies underscoring the role of this factor as an endogenous mediator in cerebral disorders, particularly cerebral ischemia and trauma. Significant biochemical, microvascular, functional, and behavioral recovery has been demonstrated using these antagonists in an array of experimental models of focal and global ischemia in the central nervous system (CNS). Clearly, studies of platelet-activating factor in experimental models of CNS ischemia and reperfusion injury open a new perspective on phospholipid metabolism in stroke and offer an exceptionally promising therapeutic prospect. Data supporting this factor as a mediator of specific pathological sequelae in stroke and neuroinjury are surveyed in this review. We discuss the mechanisms and significance of platelet-activating factor-mediated effects and propose directions for future studies.

Animals↗