The experimental study of the effects about rhEPO on brain edema and HIF-1α in rats with intracerebral hemorrhage
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Objective:To explore the effects of rhEPO on brain edema and HIF-1α in rats intracerebral hemorrhage(ICH) .Method:A total of 152 rats were randomly divided into sham operation group,and 18 groups of the 3rd,6th,12th,24th,48th,72ndh and 7th,14th,21std after ICH and ICH+rhEPO respectively. There were 8 rats in each group. The model of ICH was established in rats by intracerebral injection of autogenous blood.In ICH +rhEPO groups rhEPO was injected(IP) everyday after ICH. The expressions of HIF-1α in rats brain tissue around hematoma were detected with SP immunohistochemical method. The expressions of HIF-1α were compared with the degree of brain edema at different time points after ICH and ICH +rhEPO.Result:The water contents of brain tissue in ICH+rhEPO group were lower than that in ICH groups. The rates of HIF-1α in ICH+rhEPO groups were less than that in ICH groups.Conclusion:rhEPO can significantly reduce brain edema and the HIF-1α rhEPO can protect the brain after intracerebral hemorrhage.Keywords:
Brain Edema
Brain tissue
Autologous blood
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To explore the effect of mild hypothermia on inflammatory response and angiogenesis in brain tissues of rats with intracerebral hemorrhage (ICH) and its possible mechanism for improving behavioral deficits of the rats After ICH.A total of 120 healthy male SD rats were randomly divided into sham operation group, ICH group and mild hypothermia group. Rat models of ICH were established in the latter two groups by stereotactic injection of autogenous blood in the brain, and the rats in the sham operation group received injection of normal saline in the same manner. At 15 min after modeling, the rats in hypothermia group were subjected to mild hypothermia (30-32 ℃) for 8 h followed by rewarming (37-38 ℃); the body temperature was maintained at 37-38 ℃ in the other two groups. At 2, 4, 7, 14 and 21 days after the treatment, Longa scoring, balance beam scoring and Berderson scoring were used to evaluate the behavioral deficits of the rats. Immunohistochemical staining was used to detect the protein expressions of tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) in the brain tissue of the rats, and the mRNA expressions of α subunit of hypoxia-inducible factor 1 (HIF1-α) and vascular endothelial growth factor (VEGF) were detected using RT- PCR.At 2, 4, 7, 14 and 21 days after the treatment, the behavioral scores of the rats were significantly higher in ICH group and mild induced hypothermia group than in the sham operation group (P < 0.05 or 0.01). The protein expressions of TNF-α and NF-κB and mRNA expressions of HIF1-α and VEGF were significantly higher in ICH group and mild hypothermia group than in the sham operation group (P < 0.01). The behavioral scores were significantly lower in mild hypothermia group than in ICH group (P < 0.05), and the protein expressions of TNF-α and NF-κB were lower and the mRNA expressions of HIF1- α and VEGF were higher in mild hypothermia group than in ICH group (P < 0.05 or 0.01).Mild hypothermia can improve behavioral deficits in rats with ICH possibly by antagonizing brain inflammation and promoting angiogenesis.
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Objective: To study the expression of aquaporin4(AQP4) protein in perihematomal tissue after intracerebral hemorrhage(ICH) in rats. Methods: The experimental ICH m odel was established in rats by injecting quantitative collagenase into the left caudate nuclei of the rats. The changes of brain water content(BWC) were measur e d by the wet and dry weight methods. Immunohistochemistry was used to determine the change of expression of AQP4 protein during different periods after ICH. Results: BWC and AQP4 protein expression in perihematomal tissue were increased at 6 ho urs after ICH and reached peak at 72 hours. In one week following ICH, it was st il l higher than normal level. In addition, the expression of AQP4 was positively c orrelated with BWC(r=0 985 7,P0 01). Conclusion: AQP4 has a relevant relationship with the formation of brain edema after ICH.
Brain Edema
Brain tissue
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Objective:To study the effects of hyperbaric oxygen(HBO) on brain edema and expression of aquaporin-4(AQP-4) surrounding brain tissue of hemorrhagic focus following experimental intracerebral hemorrhage(ICH) in two kinds of rat models.Method:A total of 126 rats were randomly divided into five groups:sham-operated group(SHG,6 rats);control-1 group(autologous blood induced intracerebral hemorrhage model,A-ICH,30 rats),control-2 group(collagenase-induced intracerebral hemorrhage model,C-ICH,30 rats),trial-1 group(A-ICH+HBO,30 rats),trial-2 group(C-ICH+ HBO,30 rats).HBO therapy was intervened at 24h after operation,once a day.All rats were sacrificed at 24h,48h,72h,5d,7d post operation(each time point 6 rats).Brain edema and expression of AQP-4 were tested.Result:The success rates of A-ICH model and C-ICH model were 65% and 75% respectively.Brain edema content of A-ICH,C-ICH,A-ICH+HBO and C-ICH+HBO groups were significant higher than that of SHG group(P 0.05).The cerebral edema of A-ICH+HBO and C-ICH+HBO groups alleviated obviously compared with A-ICH and C-ICH groups,and the difference was significant respectively at 48h,72h,5d,7d and 48h,5d post operation(P 0.05).The brain edema of A-ICH+HBO group alleviated more early and obviously than that of C-ICH+HBO group,especially at 72h post operation(P0.05).The expression of AQP-4 appeared in all rats brain tissue,but expression of AQP-4 in SHG group was lower.That of A-ICH and C-ICH groups started rising at 24h post operation,the peak appeared at 48h,then dropped at 72h,but there were still significant different compared with SHG group at 7d post operation(P0.05).The difference between A-ICH group and C-ICH group was significant at 72h post operation(P0.05),and the difference between A-ICH+HBO group and A-ICH group was significant at all time points post operation(P0.05).but the difference between C-ICH+HBO group and C-ICH group was significant only at 48h and 72h post operation(P0.05).Compared with C-ICH +HBO group,expression of AQP-4 in A-ICH+HBO group was more obvious and early,especially at 48h and 72h post operation(P0.05).Conclusion:HBO might play neuroprotection role by relieving brain edema and down-regulating AQP-4 expression.A-ICH model was more fit for brain edema study of ICH rat.
Brain Edema
Brain tissue
Cerebral edema
Autologous blood
Aquaporin 4
Rat model
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Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and hyperglycemia worsens the clinical and neurological outcomes of patients with ICH. In this study, we utilized proteomic approaches to investigate the role of hyperglycemia in ICH. Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ) in adult Sprague-Dawley male rats; ICH was induced by stereotaxic infusion of collagenase/heparin into the right striatum. It was observed that the size of induced hemorrhage was significantly larger in the hyperglycemic group (n=6 in each group). On the first day after ICH, an apparent decrease in the bilateral grasp was also observed for the lesioned hyperglycemic rats compared with normoglycemic ones. When employing 2-DE and MS to examine the proteomes of perihematomal and control regions in individual hyperglycemic and normoglycemic rats, eight differentially expressed protein targets were identified. Most noteworthy, in response to ICH significant increase of albumin was ubiquitously observed in the brains of normoglycemic rats but not in the brains of hyperglycemic rats. Coincidentally, more significant neuronal apoptosis were found in the perihematomal regions of hyperglycemic rats. These observations described suggest the protection role of albumin in acute stage of ICH, which may be dependent on different blood sugar levels.
Intraperitoneal injection
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To explore the protective effects of hirudin on acute experimental intracerebral hemorrhage (ICH) by observing the changes of histologic pathology and brain water content as well as GFAP-positive cells in the perihematomal brain regions.The models of rat ICH were made with infusion of autologous blood into the right neucleus caudatus. The rats were divided randomly into control group, intracerebral hemorrhage group and treating group with hirudin. Brain water content was measured, and pathological and GFAP changes were observed.The pathological impairation after ICH were gradually deteriorated and peaked at the third day. Brain water content after ICH was gradually increased and obviously after one day(P < 0.05) and peaked at the third day. GFAP-positive cells were gradually increased and peaked at the seventh day after ICH. In the treating groups, the pathological impairation and brain water content as well as the GFAP-positive cells were decreased as compared to those in the intracerebral hemorrhage group and the control group. And the positive correlation between GFAP-positive cell numbers and brain water content were shown by linear regression.The local administration of hirudin, a special inhibitor of thrombin, has protective effects within the first week after ICH.
Hirudin
Pulmonary hemorrhage
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Treadmill
Sham surgery
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Objective: Spontaneous intracerebral hemorrhage (ICH) accounts for 10%–15% of all strokes and causes high mortality and morbidity. In the previous study, we demonstrated that ethanol could aggravate the severity of brain injury after ICH by increasing neuroinflammation and oxidative stress. In this study, we further investigate the acute effects of ethanol on brain injury within 24 h after ICH. Materials and Methods: Totally, 66 male Sprague-Dawley rats were assigned randomly into two groups: saline pretreatment before ICH (saline + ICH), and ethanol pretreatment before ICH (ethanol + ICH). Normal saline (10 mL/kg) or ethanol (3 g/kg, in 10 mL/kg normal saline) was administered intraperitoneally 1 h before induction of experimental ICH. Bacterial collagenase VII-S (0.23 U in 1.0 μL sterile saline) was injected into the right striatum to induce ICH in the rats. We evaluated the hematoma expansion, hemodynamic parameters (heart rate and blood pressure), activated partial thromboplastin time (aPTT), prothrombin time (PT), and striatal matrix metallopeptidase 9 (MMP-9) expressions at 3, 6, 9, and 24 h after ICH. Results: The ethanol + ICH group exhibited decreased hematoma at 3 h after ICH; nevertheless, there was a larger hematoma compared with the saline + ICH group at 9 and 24 h after ICH. The ethanol + ICH group had lower blood pressure at 3, 6, and 9 h post-ICH, but both groups maintained similar heart rates after ICH. There was no significant difference in the aPTT and PT between the two groups. Incremental ethanol concentrations had no influence on collagenase VII-S activity at 120 min in vitro. MMP-9 expression was upregulated in the right striata of the ethanol + ICH group, especially at 3 and 9 h after ICH. Conclusion: Ethanol delayed hematoma formation in the first 3 h due to a hypotensive effect; however, the accelerated growth of hematomas after 9 h may be a sequela of ethanol-induced MMP-9 activation.
Prothrombin time
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Objective
To investigate the effect of hypertonic saline (HS) on the permeability of blood-brain barrier in a rat model of intracerebral hemorrhage (ICH).
Methods
Sixty healthy male Sprague-Dawley rats, aged 8 weeks, weighing 260-300 g, were randomly divided into 4 groups (n=15 each) using a random number table: sham operation group (group S), sham operation+ HS group (group HS), ICH group, and ICH+ HS group.ICH was commonly induced in anesthetized rats by intraparenchymal injection of autologous blood 50 μl.The equal volume of normal saline was given instead in group S. The neurologic deficits were scored on a five-point scale, and a score of 1-3 indicated successful establishment of the model.At 48 h after establishment of the model, the rats were sacrificed, and brains were removed for determination of brain water content, expression of occludin in brain tissues (by Western blot), and Evans blue content.
Results
Compared with group S, the brain water content and Evans blue content were significantly increased, and the expression of occludin was down-regulated in ICH and ICH+ HS groups, and no significant change was found in the indices mentioned above in group S+ HS.Compared with group ICH, the brain water content and Evans blue content were significantly decreased, and the expression of occludin was up-regulated in group ICH+ HS.
Conclusion
HS can inhibit increase in the permeability of blood-brain barrier, and reduce the cerebral edema in a rat model of ICH.
Key words:
Cerebral hemorrhage; Saline solution, hypertonic; Blood-brain barrier
Evans Blue
Occludin
Hypertonic saline
Cerebral edema
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Objective To investigate the effect of mild therapeutic hypothermia for different lengths of time on cerebral edema and hypoxia-inducible factor 1 α (HIF-1α),vascular endothelial growth factor (VEGF) expressions following intracerebral hemorrhage (ICH) so as to explore possible mechanism for better application of mild hypothermia.Methods ICH models were made in rats by stereotaxically injecting autologous artery blood into right caudate nucleus.Forty male Sprague-Dawley (SD) rats were randomly (random number) divided into 5 groups (n =8 each):sham-operated (sham),normothermic (NT),hypothermic-1 hour (MH1),hypothermic-2 hours (MH2),hypothermic-4 hours (MH3).Normothermic and sham-operated animals were kept at (37.0-± 0.2) ℃ of body temperature.Animals in the hypothermic groups received immediately and rapid cooling after ICH and kept at (33.0 ± 0.5) ℃ of body temperature for 1,2 and 4 hours respectively.Rats were sacrificed at 48 hours after cerebral hemorrhage.Then brain water content and BBB permeability were determined.Quantitative real-time PCR and Western blot were used to analyze the expression of HIF-1α and VEGF.Results The content of brain water,Evans blue concentration in brain,and the mRNA expression and protein levels of HIF-1α and VEGF were noticeably higher in NT group than those in sham group (P ＜0.01).There were statistically significant difference in the expression of HIF-lα mRNA and protein but little difference in other indicators between MH1 group and NT group.Compared with NT group,MH2 group and MH3 group brought about an improvement in BBB permeability and remarkable down-regulation of protein levels and expression of HIF-1 α and VEGF mRNA,whereas there were no statistically significant difference in expression of indicators between the two groups.Conclusions Mild therapeutic hypothermia induced rapidly and immediately after ICH could limit the development of brain edema in rats by down-regulating expression and protein levels of HIF-1 α mRNA,and in turn suppressing the evaluation of VEGF mRNA and protein expression.The brain edema was effectively reduced in animals treated with hypothermia for 2 hours' or 4 hours ' duration with little difference in magnitude of reduction in brain edema between these two modalities of hypothermia.
Key words:
Cerebral hemorrhage; Cerebral edema; Hypothermia; Hypoxia-inducible factor 1 α ; Vascular endothelial growth factor
Evans Blue
Hypoxia
Cerebral edema
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