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P M Patel

Publications and source records attributed to P M Patel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Isoflurane and pentobarbital reduce AMPA toxicity in vivo in the rat cerebral cortex.

BACKGROUND: Isoflurane and pentobarbital can reduce alpha-amino-d-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated toxicity in vitro. However, their effect on AMPA toxicity in vivo is not known. The present study was undertaken to evaluate the effects of isoflurane and pentobarbital on the in vivo neurotoxicity produced by AMPA. METHODS: Wistar-Kyoto rats were allocated to one of seven groups (n = 8 per group): isoflurane 1 minimum alveolar concentration, isoflurane electroencephalogram burst suppression (EEG-BS), low-dose pentobarbital, pentobarbital EEG-BS, NBQX, conscious, and sham groups. AMPA 30 nm was injected into the cortex. An equivalent volume of cerebrospinal fluid was injected into the cortex in the sham group. In the NBQX group, 200 nm NBQX was injected into the cortex with the AMPA. In the isoflurane and pentobarbital groups, anesthesia was maintained for a period of 5 h. Animals in the conscious, NBQX, and sham groups were allowed to awaken immediately after the AMPA injection. Injury to the cortex was evaluated 48 h later. RESULTS: Isoflurane reduced AMPA-induced cortical injury (4.5 +/- 1.9 mm3 and 1.7 +/- 0.8 mm3 in the 1 minimum alveolar concentration and EEG-BS groups, respectively) in comparison to the conscious group (7.2 +/- 0.8 mm3). Pentobarbital reduced cortical injury when administered in EEG-BS doses (2.2 +/- 0.7 mm3) but not when administered in sedative doses (8.6 +/- 0.9 mm3). NBQX reduced AMPA-induced cortical injury (1.2 +/- 0.5 mm3). CONCLUSIONS: Isoflurane and pentobarbital reduced cortical AMPA excitotoxicity. The magnitude of injury reduction was similar to that produced by NBQX when the anesthetics were administered in EEG-BS doses. These results are consistent with the previously demonstrated ability of isoflurane and pentobarbital to inhibit AMPA receptor responses.

Anesthetics, Inhalation↗
PubMed2000

Isoflurane delays but does not prevent cerebral infarction in rats subjected to focal ischemia.

BACKGROUND: Several investigations have shown that volatile anesthetics can reduce ischemic cerebral injury. In these studies, however, neurologic injury was evaluated only after a short recovery period. Recent data suggest that injury caused by ischemia is a dynamic process characterized by continual neuronal loss for a prolonged period. Whether isoflurane-mediated neuroprotection is sustained after a longer recovery period is not known. The current study was conducted to compare the effect of isoflurane on brain injury after short (2-day) and long (14-day) recovery periods in rats subjected to focal ischemia. METHODS: Fasted Wistar-Kyoto rats were anesthetized with isoflurane and randomly allocated to an awake (n = 36) or an isoflurane (n = 34) group. Animals in both groups were subjected to focal ischemia by filament occlusion of the middle cerebral artery. Pericranial temperature was servocontrolled at 37 degrees C throughout the experiment. In the awake group, isoflurane was discontinued and the animals were allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained at 1.5 times the minimum alveolar concentration. After 70 min of focal ischemia, the filament was removed. Animals were killed 2 days (awake, n = 18; isoflurane, n = 17) and 14 days (awake, n = 18; isoflurane, n = 17) after ischemia. The volumes of cerebral infarction and selective neuronal necrosis in the animals were determined by image analysis of hematoxylin and eosin-stained coronal brain sections. RESULTS: Cortical and subcortical volumes of infarction were significantly less in the isoflurane 2-day group (26 +/- 23 mm3 and 17 +/- 6 mm3, respectively) than in the awake 2-day group (58 +/- 35 mm3, P < 0. 01; and 28 +/- 12 mm3, P < 0.01, respectively). By contrast, cortical and subcortical volumes of infarction in the awake (41 +/- 31 mm3 and 28 +/- 16 mm3, respectively) and isoflurane (41 +/- 35 mm3 and 19 +/- 8 mm3, respectively) 14-day groups were not different (cortex, P = 0.99; subcortex, P = 0.08). The volume of cortical tissue in which selective neuronal necrosis was observed, however, was significantly less in the isoflurane 14-day group (5 +/- 4 mm3) than in the awake 14-day group (17 +/- 9 mm3, P < 0.01). The total number of necrotic neurons in the region of selective neuronal necrosis was significantly smaller in the isoflurane 14-day group than in the awake 14-day group (P < 0.01). CONCLUSION: Compared with the awake state, isoflurane reduced the extent of infarction assessed 2 days after focal ischemia in rats. At 14 days, however, only selective neuronal necrosis, but not infarction, was reduced by isoflurane. These results suggest that isoflurane delays but does not prevent cerebral infarction caused by focal ischemia. Isoflurane may attenuate the delayed development of selective neuronal necrosis in periinfarct areas in this animal model.

Anesthetics, Inhalation↗
PubMed2000

Effect of alpha-alpha diaspirin crosslinked hemoglobin (DCLHb) on the potency of sodium nitroprusside and nitroglycerine to decrease blood pressure in rats: a dose-response study.

The nitrovasodilators, sodium nitroprusside and nitroglycerine, effect a dose-dependent decrease in mean arterial blood pressure (MABP) by liberating nitric oxide. Alpha-alpha diaspirin crosslinked hemoglobin (DCLHb) is known to bind nitric oxide. We studied the effect of DCLHb on the potency of sodium nitroprusside (n=36) and nitroglycerine (n=36) to decrease MABP in rats which received 1, 10, 100, 1,000, or 10,000 mg/kg of the DCLHb, or normal saline as the Control. Six doses of sodium nitroprusside or nitroglycerine were given to each rat in a systematically varied sequence. For both drugs, in rats given 1, 10, or 100 mg/kg of DCLHb there were no between groups differences in the change in MABP compared to the Control group. For rats that received 1,000 or 10,000 mg/kg of DCLHb, the potency of nitroglycerine and sodium nitroprusside to decrease MABP was less (p<0.05) than the other groups. These data support the hypothesis that small doses of DCLHb effect a minimal change in the potency of nitrovasodilators to reduce blood pressure. However, they suggest that clinically relevant doses of DCLHb attenuate the vasodilatory ability of sodium nitroprusside and nitroglycerine.

Animals↗
PubMed1999

Fentanyl does not increase brain injury after focal cerebral ischemia in rats.

UNLABELLED: Recent reports have indicated that large-dose opiate anesthesia can increase neuronal injury in rats subjected to forebrain ischemia. However, most episodes of cerebral ischemia in the operating room setting are focal in nature, and the influence of large-dose opioid administration on the tolerance of the brain to focal cerebral ischemia has not been studied. Accordingly, we undertook the present study to evaluate the effect of fentanyl administration on outcome after focal cerebral ischemia. Three groups of fasted Wistar-Kyoto rats (awake, fentanyl, and isoflurane groups; n = 20 per group) were anesthetized with isoflurane (2.5% end-tidal). Pericranial temperature was servocontrolled at 37.0 degrees C. After surgical preparation fentanyl 50 microg/kg was administered IV over 10 min in the fentanyl group. Thereafter, an infusion was established at a rate of 50 microg x kg(-1) x h(-1). The end-tidal concentration of isoflurane was then reduced to 1.1%, one minimum alveolar anesthetic concentration (1 MAC) in all groups. Occlusion of the middle cerebral artery was achieved by advancing a 0.25-mm filament into the anterior cerebral artery via the common carotid artery. In the fentanyl and awake groups, isoflurane administration was then discontinued. In the isoflurane group, isoflurane anesthesia was maintained at 1.0 MAC. After 90 min of focal ischemia, the filament was removed, and the animals were allowed to recover. Seven days later, the volume of cerebral infarction in the animals was determined by image analysis of hematoxylin and eosin-stained coronal brain sections. There was no difference in the infarct volume between the fentanyl and awake groups. The infarct volume was the least in the isoflurane group. The results confirm the ability of isoflurane to reduce brain injury caused by focal cerebral ischemia. Fentanyl neither increased nor decreased brain injury compared with the awake unanesthetized state. IMPLICATIONS: Fentanyl is commonly used in surgical procedures in which there is a substantial risk of focal cerebral ischemia. Fentanyl did not affect cerebral injury produced by focal ischemia in the rat. The data suggest that, in doses that produce respiratory depression and muscle rigidity, fentanyl does not reduce the tolerance of the brain to a focal ischemic insult.

Analgesics, Opioid↗
PubMed1999

Isoflurane reduces N-methyl-D-aspartate toxicity in vivo in the rat cerebral cortex.

UNLABELLED: Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known. We conducted the present study to evaluate the effect of isoflurane on injury produced by cortical injection of NMDA in vivo and to compare it with dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were anesthetized with isoflurane. NMDA 50 nmoles (5-microL volume) were stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane groups, the end-tidal concentration of isoflurane was maintained at either electroencephalogram (EEG)-burst suppression (BS) doses (2.2%-2.3%, n = 12) or a 1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before the NMDA injection. In the awake group and the dizocilpine group, anesthesia was discontinued on completion of the NMDA injection, and the animals were allowed to awaken. In the animals in the control group (n = 10), 20 microL of artificial cerebrospinal fluid was injected into the cortex. Injury to the cortex was evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses, isoflurane reduced the injury produced by a cortical NMDA injection compared with the awake state (1.74+/-0.49 and 0.96+/-0.46 vs 2.34+/-0.56 mm3; P = 0.02). Dizocilpine reduced cortical injury (0.56+/-0.27; P = 0.01) compared with the awake state. Injury in the control group was limited to the trauma produced by cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury was not different from the control group. IMPLICATIONS: Isoflurane can reduce N-methyl-D-aspartate-mediated cortical injury in vivo in a dose-dependent manner. These data are consistent with the previously demonstrated ability of isoflurane to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.

Anesthetics, Inhalation↗
PubMed1999

Subarachnoid hemorrhage in rats: effect of singular or sustained hemodilution with alpha-alpha diaspirin crosslinked hemoglobin on cerebral hypoperfusion.

OBJECTIVE: To evaluate the effect of singular or sustained hemodilution, with alpha-alpha diaspirin crosslinked hemoglobin (DCLHb), on the area of hypoperfusion after subarachnoid hemorrhage. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Isoflurane anesthetized, mechanically ventilated rats. INTERVENTIONS: Subarachnoid hemorrhage was induced by injecting 0.3 mL of blood into the cisterna magna. The animals were randomly assigned to one of the following groups (n = 16 in each hemodilution group; eight animals received a single treatment of hemodilution after subarachnoid hemorrhage; and, for eight animals, treatment was sustained for 48 hrs): control group (n = 8), no hematocrit (45%) manipulation; DCLHb group (n = 16), hematocrit decreased to 30% with DCLHb; or Alb group (n = 16), hematocrit decreased to 30% with human serum albumin. After 48 hrs, the area of hypoperfusion (cerebral blood flow < 40 ml/100g/min) was determined with 14C-iodoantipyrine in five coronal brain sections. MEASUREMENTS AND MAIN RESULTS: For both singular and sustained treatment, the area of hypoperfusion was less in both hemodilution groups than in the control group (p<.05). For four of the five coronal brain sections, no differences were found between the DCLHb and Alb groups within a given hemodilution protocol. In addition, in four of the five coronal brain sections for the DCLHb hemodilution groups and in all five sections for the albumin hemodilution groups, the area of hypoperfusion was less for rats that received sustained hemodilution compared with their respective groups in the singular treatment protocol (p<.05). CONCLUSIONS: These data support the hypothesis that hemodilution with molecular hemoglobin decreases hypoperfusion after subarachnoid hemorrhage and that sustained hemodilution is more effective than singular treatment. The data do not support the notion that intravascular DCLHb has an adverse effect on cerebral ischemia after subarachnoid hemorrhage.

Animals↗
PubMed1998

Isoflurane and pentobarbital reduce the frequency of transient ischemic depolarizations during focal ischemia in rats.

UNLABELLED: Repetitive transient ischemic depolarizations (IDs) during focal cerebral ischemia are thought to contribute to ischemic damage. Isoflurane and pentobarbital reduce injury (versus the nonanesthetized state) after focal cerebral ischemia. The mechanism by which these drugs reduce injury is not known. This protective effect might be mediated by a reduction in the number of IDs. We measured the frequency of IDs during focal cerebral ischemia in animals anesthetized with isoflurane or pentobarbital and compared it with that in N2O/fentanyl anesthetized animals and in animals in which the N-methyl-D-aspartate receptor antagonist MK801 (dizocilpine) was given. Focal cerebral ischemia was induced by the occlusion of the middle cerebral artery for a period of 2 h. Cortical infarct volumes were determined after 3 h of reperfusion by image analysis of 2,3,5-triphenyl tetrazolium-stained coronal brain sections. The infarct volume was significantly greater in the N2O/fentanyl group than in the other three groups. Infarct volumes in the isoflurane, pentobarbital, and MK801 groups were similar. The frequency of IDs was significantly greater in the N2O/fentanyl group than in the other three groups, and was the least in the MK801 group. There was a direct correlation between the number of IDs and the volume of tissue injury. The data indicate that the protective effect of isoflurane and pentobarbital might, in part, be determined by their ability to reduce IDs during focal ischemia. However, the observation that the infarct volume was similar in the MK801, isoflurane, and pentobarbital groups, despite a greater frequency of IDs in the latter two groups, suggests that mechanisms other than a simple reduction in the number of IDs probably also play a role in anesthetic-mediated cerebral protection. IMPLICATIONS: Transient ischemic depolarizations during focal ischemia contribute to brain injury. Both isoflurane and pentobarbital reduced the frequency of these depolarizations. Isoflurane- and pentobarbital-mediated reduction in the frequency of depolarizations might, in part, mediate the previously documented neuroprotective effect of these drugs.

Adjuvants, Anesthesia↗
PubMed1998

The effect of the reduction of colloid oncotic pressure, with and without reduction of osmolality, on post-traumatic cerebral edema.

BACKGROUND: It has been asserted that reduction of colloid oncotic pressure (COP) can aggravate traumatic brain edema. To explore this issue, the authors measured the effect of COP reduction, with and without a simultaneous decrease in osmolality, on the development of brain edema after fluid percussion injury (FPI). METHODS: Isoflurane-anesthetized Wistar rats received a 2.7-atm right parasagittal FPI followed by isovolemic exchange with (1) normal saline (NS); (2) half-normal saline (0.5 NS); (3) whole blood (WB); or (4) hetastarch (Hespan, Dupont). Shed blood (16 ml) was replaced with donor erythrocytes suspended in the study fluid. The WB group received heparinized fresh donor WB. Central venous pressure was maintained with additional study fluid as required. The specific gravity (SG) of the cortex and subcortex near the impact site was determined 4.5 h after FPI. The water content of the hemispheres was also determined using the wet-dry method. To define the status of the blood-brain barrier in the non-FPI hemisphere, two additional groups (FPI, non-FPI) were studied. Both groups received 30 mg/kg Evans' blue and NS at 4 ml/kg(-1)/h(-1). Four hours after FPI, the concentration of Evans' blue in the hemispheres was determined. RESULTS: After exchange, COP (mmHg +/- SD) decreased in the NS (9.6 +/- 2.1) and 0.5 NS (8.5 +/- 0.5) groups and was unchanged in the WB (16.7 +/- 3.3) and hetastarch (18.9 +/- 1.1) groups. Osmolality was unchanged in the WB group (295 +/- 5 mOsm/kg), increased in the NS (304 +/- 3 mOsm/kg) and hetastarch (306 +/- 2 mOsm/kg) groups, and was decreased in the 0.5 NS group (261 +/- 6 mOsm/kg). The Evans' blue data indicated that FPI resulted in blood-brain barrier damage in both hemispheres. In all four exchange groups, the SG of both cortical and subcortical tissue was less (indicating greater water content) in the impact hemisphere than in the nonimpact hemisphere. The SG was less in both hemispheres, although it was less in both hemispheres in the NS and 0.5 NS groups than in the WB and hetastarch groups. The lowest SG values were observed in the 0.5 NS group. The wet-dry water content determinations yielded a similar pattern of edema formation. CONCLUSIONS: These data, while confirming the important edematogenic effect of decreased osmolality, indicate that COP reduction per se can also aggravate brain edema after a mild to moderate mechanical head injury.

Animals↗
PubMed1998

Subarachnoid molecular hemoglobin after subarachnoid hemorrhage in rats: effect on the area of hypoperfusion.

A previous study indicated that diaspirin-crosslinked hemoglobin (DCLHb) decreases cerebral ischemia after subarachnoid hemorrhage. However, the study was limited in that DCLHb was given to animals with an intact vasculature. As extravasated hemoglobin has been implicated in the pathogenesis of cerebral vasospasm, DCLHb in the subarachnoid space might in theory have a detrimental effect on cerebral perfusion after subarachnoid hemorrhage. In the current study, autologous blood was administered into the cistema magna of isoflurane-anesthetized rats. After 30 minutes, the animals received one of the following in the cistema magna (n=8 for each group): The control group received mock cerebral spinal fluid, the "blood" group received autologous blood, the "DCLHb" group received DCLHb, and the "Alb" group received human serum albumin. After 20 minutes, areas of reduced cerebral blood flow (CBF, 0-20 and 21-40 ml/100 g/min) were assessed in five coronal brain sections with 14C-iodoantipyrine. The data were evaluated by analysis of variance. The areas of 0-20 ml/100 g/min CBF were greater in all five brain sections in the Blood group than in the other three groups; were greater in four brain sections in the DCLHb group than in the Control group; and were greater in three brain sections in the Alb group than in the Control group (p < 0.05). The areas of 21-40 ml/100 g/min CBF were greater in three sections in the Blood group than in the other three groups; and were greater in two brain sections in the DCLHb group than in the Alb group (p < 0.05). These data support a hypothesis that subarachnoid blood induces cerebral hypoperfusion, and that although molecular hemoglobin decreases CBF, the potential adverse effects are less than those produced by blood.

Analysis of Variance↗
PubMed1997

Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors.

Previous studies have shown that expression of the immune co-stimulator B7.1 reduces the tumorigenicity of some, but not all, malignant cell lines. However, B7.1-expressing tumor cells are not very effective in inducing the rejection of established tumors. This may in part be due to induction of anergy in the potentially reactive T cells. Previous studies have shown that IL-2 can reverse the anergic state both in vitro and in vivo. Therefore, we have examined the effect of retrovirus-mediated delivery and expression of murine B7.1 and interleukin-2 on tumor formation and rejection of established MHC class I+/II- NC adenocarcinomas. Neither the expression of B7.1 nor IL-2 alone had a significant effect on NC tumorigenicity. In contrast, combined expression of B7.1 and IL-2 substantially decreased the tumorigenicity of these cells in the immunecompetent syngeneic hosts. T-cell depletion studies show this to be dependent primarily on the activation of CD4+ cells. Furthermore, distant subcutaneous injection of irradiated NC/IL-2/B7.1 can induce, much more effectively than NC/B7.1 or NC/IL-2, the rejection of small NC tumors, and prevent the recurrence of large surgically resected tumors. Together, these results suggest that tumor cells genetically modified to express B7.1 and IL-2 can induce the immune-mediated rejection of established class II- tumors by a mechanism involving CD4+ cells.

Adenocarcinoma↗
PubMed1997

Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain.

The mechanism by which platelets regulate the function of integrin alphaIIbbeta3 (or GPIIb/IIIa), the platelet fibrinogen receptor, is unknown but may involve the binding of proteins or other factors to integrin cytoplasmic domains. To identify candidate cytoplasmic domain binding proteins, we screened a human fetal liver cDNA library in the yeast two-hybrid system, using the alphaIIb cytoplasmic domain as "bait," and isolated a novel 855-base pair clone. The open reading frame encodes a novel 191-amino acid polypeptide (termed CIB for calcium- and integrin-binding protein) that appears to be specific for the cytoplasmic domain of alphaIIb, since it does not interact with the alphav, alpha2, alpha5, beta1, or beta3 integrin cytoplasmic domains in the yeast two-hybrid system. This protein has sequence homology to two known Ca2+-binding regulatory proteins, calcineurin B (58% similarity) and calmodulin (56% similarity), and has two EF-hand motifs corresponding to the two C-terminal Ca2+ binding domains of these proteins. Moreover, recombinant CIB specifically binds 45Ca2+ in blot overlay assays. Using reverse transcriptase-polymerase chain reaction and Western blot analysis, we detected CIB mRNA and protein ( approximately 25 kDa), respectively, in human platelets. An enzyme-linked immunosorbent assay performed using either immobilized recombinant CIB or monoclonal antibody-captured alphaIIbbeta3 indicates a specific interaction between CIB and intact alphaIIbbeta3. These results suggest that CIB is a candidate regulatory molecule for integrin alphaIIbbeta3.

Amino Acid Sequence↗
PubMed1997

Sarcoma cells engineered to secrete IFN-gamma or IL-2 acquire sensitization to immune cell killing via different mechanisms.

The murine fibrosarcoma FS29 can be more efficiently killed by syngeneic lymphocytes when it has been engineered to secrete either interferon gamma (IFN-gamma), or interleukin 2 (IL-2). The mechanisms by which the two cytokines enhance target sensitivity differ. Supernatant from IFN-gamma-secreting cells can enhance the sensitivity of unmodified cells. The enhanced sensitivity correlates with MHC upregulation observed on both the IFN-gamma-secreting and supernatant-treated cells. In contrast, supernatant from IL-2-secreting cells does not affect the sensitivity of unmodified cells. IL-2 can be detected, by a bioassay, bound to the extracellular matrix of the secreting tumour cells.

Animals↗
PubMed1997

Production and characterization of monoclonal antibodies to human interleukin-12.

Interleukin-12 is a cytokine that plays a central role in mediating cell mediated immunity via enhancement of a TH1 cell response. IL-12, unusually for a cytokine, has a heterodimeric structure made up of 35 kDa and 40 kDa subunits. The aim of this study was to produce and characterize monoclonal antibodies to recombinant human IL-12. Twenty-two monoclonal antibodies to IL-12 were successfully produced and subunit specificity determined using recombinant human IL-12 and chimeric murine/human IL-12. All antibodies were shown to react with the p40 subunit by ELISA and immunoblotting with three of the MAbs being found to cross-react with murine IL-12. Using two individual bioassays for IL-12, seven of the MAbs were shown to neutralize biological activity of IL-12. Ten of the antibodies were found to be of use in immunocytochemistry, reacting with LPS-stimulated peripheral blood monocytes. The approaches and difficulties encountered in characterizing antibodies to a heterodimeric cytokine are discussed together with possible reasons for the failure to generate antibodies to the p35 subunit.

Animals↗
PubMed1997

Transient neuronal depolarization induces tolerance to subsequent forebrain ischemia in rats.

BACKGROUND: Minor cortical injury has previously been shown to improve survival in animals subjected to ischemic insults. Although the mechanism by which an ischemia-tolerant state is achieved is not clear, transient neuronal depolarization is thought to play a central role in the development of the tolerance. One way of producing transient neuronal depolarization is by the induction of cortical spreading depression (CSD). The present study was conducted to evaluate the effect of preischemic transient depolarization, induced by CSD, on postischemic neuronal outcome in rats. METHODS: Unilateral CSD was induced by application of KCl to the frontal cortex (CSD hemisphere) in three groups of isoflurane-anesthetized rats (CSD groups; n = 8/group). Sham animals (n = 12) did not undergo CSD. In a fifth group (n = 8), ketamine was administered during KCl application to inhibit CSD. One, three, or seven days after CSD, animals were subjected to forebrain ischemia produced by bilateral carotid artery occlusion. Injury to the striatum, hippocampus, and cortex was evaluated in hematoxylin and eosin-stained brain sections 3 days after ischemia. RESULTS: Preischemic CSD reduced postischemic injury in the ipsilateral cortex. The ratio of the number of injured neurons in the CSD hemisphere to that in the non-CSD hemisphere was significantly less in the groups subjected to CSD 1 day (0.51 +/- 0.33), 3 days (0.56 /- 0.22), and 7 days (0.40 +/- 0.17) before ischemia than in the sham operated group (1.11 +/- 0.47). In the ketamine group (CSD inhibition), there were no differences in the extent of injury in the two hemispheres (ratio = 0.84 +/- 0.47). Injury to the striatum and hippocampus was similar among the groups. Within each group, injury to these subcortical structures in the CSD hemisphere was not different from that in the non-CSD hemisphere. CONCLUSIONS: The data suggest that preischemic depolarization induced by CSD results in an adaptive response that reduces the vulnerability of cortical neurons to subsequent ischemic injury (ischemic tolerance).

Animals↗
PubMed1997

Experimental subarachnoid hemorrhage in rats: effect of intravenous alpha-alpha diaspirin crosslinked hemoglobin on hypoperfusion and neuronal death.

BACKGROUND: Hemodilution with diaspirin crosslinked hemoglobin (DCLHb) ameliorates occlusive cerebral ischemia. However, subarachnoid hemoglobin has been implicated as a cause of cerebral hypoperfusion. The effect of intravenous DCLHb on cerebral perfusion and neuronal death after experimental subarachnoid hemorrhage was evaluated. METHODS: Rats (n = 48) were anesthetized with isoflurane and subarachnoid hemorrhage was induced by injecting 0.3 ml of autologous blood into the cistema magna. Each animal received one of the following regimens: Control, no hematocrit manipulation; DCLHb, hematocrit concentration decreased to 30% with DCLHb; or Alb, hematocrit concentration decreased to 30% with human serum albumin. The experiments had two parts, A and B. In part A, after 20 min, cerebral blood flow (CBF) was assessed with 14C-iodoantipyrine autoradiography. In part B, after 96 h, in separate animals, the number of dead neurons was determined in predetermined coronal sections by hematoxylin and eosin staining. RESULTS: Cerebral blood flow was greater for the DCLHb group than for the control group; and CBF was greater for the Alb group than the other two groups (P < 0.05). In one section, CBF was 45.5 +/- 10.9 ml x 100 g(-1) x min(-1) (mean +/- SD) for the control group, 95.3 +/- 16.6 ml x 100 g(-1) x min(-1) for the DCLHb group, and 138.1 +/- 18.7 ml x 100 g(-1) x min(-1) for the Alb group. The number of dead neurons was less in the Alb group (611 +/- 84) than in the control group (1,097 +/- 211), and was less in the DCLHb group (305 +/- 38) than in the other two groups (P < 0.05). CONCLUSIONS: These data support a hypothesis that hemodilution decreases hypoperfusion and neuronal death after subarachnoid hemorrhage. The data do not support the notion that intravascular molecular hemoglobin has an adverse effect on brain injury after subarachnoid hemorrhage.

Animals↗
PubMed1997

Hypervolemic-hemodilution during cerebral ischemia in rats: effect of diaspirin cross-linked hemoglobin (DCLHb) on neurologic outcome and infarct volume.

In a rat model of middle cerebral artery occlusion (MCAo) and reperfusion (120 min), previous studies have demonstrated that hemodilution with molecular hemoglobin decreases ischemic brain injury. However, long-term recovery data on the therapeutic efficacy of molecular hemoglobin for cerebral ischemia are lacking. Accordingly, we assessed the effect of hemodilution, with alpha-alpha diaspirin cross-linked hemoglobin (DCLHb, 10 g/dl) on neurologic outcome and infarct volume after 120 min of MCAo and 72 h of reperfusion. Ischemia was achieved by passing a 0.26-mm suture, via the external carotid artery, to internally occlude the middle cerebral artery. Immediately after MCAo, the rats were randomized to one of the following groups: Control-hematocrit not manipulated (44%); 30/Hct-hematocrit maintained at 30% with DCLHb; or 16/Hct-hematocrit maintained at 16% with DCLHb. After 120 min of MCAo, the suture was removed and the rats allowed to recover. Daily neurologic examinations were performed, and after 72 h, the brains were analyzed for infarct volume with TTC stain. Infarct volume (mm3) was less in the 30/Hct group (67 +/- 10; mean +/- SD) than in the Control group (141 +/- 17); and less in the 16/Hct group (40 +/- 12) than the other two groups (p < 0.05). Neurologic outcome was improved in both hemodilution groups versus the Control group (p < 0.05). These data are consistent with previous studies, performed in a model of short-term reperfusion, which indicate a dose-dependent decrease in ischemic injury by DCLHb.

Animals↗