Baicalin treats cerebral ischemia reperfusion-induced brain edema in rats by inhibiting TRPV4 and AQP4 of astrocytes / 中国中药杂志

This study aims to explore the pharmacodynamic effect of baicalin on rat brain edema induced by cerebral ischemia reperfusion injury and discuss the mechanism from the perspective of inhibiting astrocyte swelling, which is expected to serve as a refe-rence for the treatment of cerebral ischemia with Chinese medicine. To be specific, middle cerebral artery occlusion(suture method) was used to induce cerebral ischemia in rats. Rats were randomized into normal group, model group, high-dose baicalin(20 mg·kg~(-1)) group, and low-dose baicalin(10 mg·kg~(-1)) group. The neurobehavior, brain index, brain water content, and cerebral infarction area of rats were measured 6 h and 24 h after cerebral ischemia. Brain slices were stained with hematoxylin and eosin(HE) for the observation of pathological morphology of cerebral cortex after baicalin treatment. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the content of total L-glutathione(GSH) and glutamic acid(Glu) in brain tissue, Western blot to measure the content of glial fibrillary acidic protein(GFAP), aquaporin-4(AQP4), and transient receptor potential vanilloid type 4(TRPV4), and immunohistochemical staining to observe the expression of GFAP. The low-dose baicalin was used for exploring the mechanism. The experimental results showed that the neurobehavioral scores(6 h and 24 h of cerebral ischemia), brain water content, and cerebral infarction area of the model group were increased, and both high-dose and low-dose baicalin can lower the above three indexes. The content of GSH dropped but the content of Glu raised in brain tissue of rats in the model group. Low-dose baicalin can elevate the content of GSH and lower the content of Glu. According to the immunohistochemical staining result, the model group demonstrated the increase in GFAP expression, and swelling and proliferation of astrocytes, and the low-dose baicalin can significantly improve this situation. The results of Western blot showed that the expression of GFAP, TRPV4, and AQP4 in the cerebral cortex of the model group increased, and the low-dose baicalin reduce their expression. The cerebral cortex of rats in the model group was severely damaged, and the low-dose baicalin can significantly alleviate the damage. The above results indicate that baicalin can effectively relieve the brain edema caused by cerebral ischemia reperfusion injury in rats, possibly by suppressing astrocyte swelling and TRPV4 and AQP4.

Agmatine Attenuates Brain Edema and Apoptotic Cell Death after Traumatic Brain Injury

Traumatic brain injury (TBI) is associated with poor neurological outcome, including necrosis and brain edema. In this study, we investigated whether agmatine treatment reduces edema and apoptotic cell death after TBI. TBI was produced by cold injury to the cerebral primary motor cortex of rats. Agmatine was administered 30 min after injury and once daily until the end of the experiment. Animals were sacrificed for analysis at 1, 2, or 7 days after the injury. Various neurological analyses were performed to investigate disruption of the blood-brain barrier (BBB) and neurological dysfunction after TBI. To examine the extent of brain edema after TBI, the expression of aquaporins (AQPs), phosphorylation of mitogen-activated protein kinases (MAPKs), and nuclear translocation of nuclear factor-kappaB (NF-kappaB) were investigated. Our findings demonstrated that agmatine treatment significantly reduces brain edema after TBI by suppressing the expression of AQP1, 4, and 9. In addition, agmatine treatment significantly reduced apoptotic cell death by suppressing the phosphorylation of MAPKs and by increasing the nuclear translocation of NF-kappaB after TBI. These results suggest that agmatine treatment may have therapeutic potential for brain edema and neural cell death in various central nervous system diseases.

Effects of dexamethasone in primary intracerebral hemorrhage in the south west of Iran

Previous study revealed the value of dexamethasone in the treatment of vasogenic edema associated with brain tumor and abscess. However there are poor documented studies about its usefulness in primary intracerebral hemorrhage. In this study we evaluated dexamethasone effects in primary intracerebral hemorrhage. In a double blind randomized placebo-controlled clinical trial we evaluated 200 intracerebral hemorrhage cases between 40 to 80 years old whom were admitted at Golestan Hospital [Ahwaz, IR] between March 2002 And March 2003. They were divided in two groups; dexamethasone [N=100] and placebo [N=100]. Then mortality, GI bleeding, fever, electrolytes disturbances, hypertension and hyperglycemic status were analyzed in two groups. Ethical considerations were employed and subjects were followed by appropriate statistical methods for 21 days to assess the major outcomes. Mortality was much higher in the dexamethasone group; Dexamethasone group [49.3%] and placebo [23.4%] and also fever was higher seen in the dexamethasone group; dexamethasone group [40.2%] and placebo group [24.7%] but there was not any significant statistical difference between two groups as regards other complications. Dexamethasone is widely used for cerebral edema associated conditions but in this study we saw that it's complications in intracerebral hemorrhage such as increasing fever and mortality are significantly higher. Hence it use for treatment of primary intracerebral hemorrhage should be reconsidered

[ effect of enalapril on brain edema and cytokine production following transient focal cerebral ischemia in mice]

Cytokines production as one of the inflammatory pathways in CNS is responsible for most brain damages following ischemia. On the other hand, during inflammation and brain ischemia, most of the renin- angiotensin components [RAS] increase locally. While it is established that blockade of RAS especially AT1 receptors has a protective effect on ischemia, the interaction of cytokines and angiotensin II is not well understood. This study was designed to investigate the effect of angiotensin II inhibitor on cytokine production as well as brain edema. Fifty-four male mice were randomly divided into 5 groups of normal, Sham operated, ischemia, Pretreatment with enalapril [high dose], and Pretreatment with enalapril [low dose] for the measurement of IL-IB and TNF-alpha in the brain and blood serum by ELIZA method. Ischemia caused a significant increase in water content and neurological deficit scores as well as cytokine levels. Treatment with enalapril had paradoxical effect on ischemia. In high dose, 85% of the animals showed convulsion after reperfusion. The IL-1 beta in serum and neurological deficit scores of this group were high, in accordance with clinical signs. In contrast, the low dose of enalapril, had protective effect on ischemia. It caused a significant reduction in brain concentration of both IL-1 beta and TNF- alpha [P<0.05] and improved significantly the neurological deficit scores and brain water content as well. [P<0.05]. Enalapril as an ACE inhibitor, has a dual effect on stroke. At low dose, it has a protective role at least in part by suppressing the local production of pro-inflammatory cytokines while, at high dose, it increases the inflammation by an unknown mechanism

[ effect of sex steroid hormones on brain edema and intracranial pressure after experimental traumatic brain injury in rats]

We investigated the role of sex hormones on changes in brain edema intracranial pressure [ICP], cerebral perfusion pressure [CCP] after trauma brain injury [TBI] in ovarectomized female [OVX] rats. In this study female rats are divided into five groups. Control group [Intact] sham group and other groups include: vehicle, estrogen group [1mg/kg] and progesterone group [8 mg/kg] which on all groups TBI was induced by Marmarou method. 30 minutes after TBI, drugs were injected i.p. ICP was measured in spinal cord using a standard procedure. CPP was calculated by the mean arterial pressure [MAP] - ICP. Neurologic scores were measured by motor, eye and respiratory reflex. The results showed after TBI, water content was significantly lower in estrogen and progesterone groups [P<0.001] compared with vehicle group. Analysis showed a stable ICP up to 24 hours. The ICP in estrogen and progesterone groups was significantly decreased at 4 and 24 hours as compared to vehicle group [P<0.001in both cases]. The CPP at 24 hours after TBI, significantly increased in estrogen and progesterone groups compared with vehicle [P<0.001]. Also after TBI, neurologic scores was significantly higher in estrogen and progesterone groups as compared with vehicle [at 1 hours P<0.05, and at 24hours P<0.001 for estrogen], [at 1 hours P<0.01 for progesterone]. Our findings indicated an improvement of ICP, CPP and neurologic scores produced by pharmacologic doses of estrogen and progesterone after TBI in OVX rat. These effects may be contribute to neuroprotective effects of these hormones

[Comparison of the effects of progesterone, allopregnanolone and gender on suppressing edema formation after traumatic brain injury in rats]

Brain edema is one of the most important causes of death within the first few days following head trauma. In this study we investigated the role of gender as well as the effects of progesterone and allopregnanolone one hour after diffuse traumatic brain injury on edema formation in rats. This interventional-experimental study was performed on 12 groups of female and male rats. They were divided into 12 groups as follows: 1 and 2: intact female and male rats, 3 and 4: trauma male and female rats, 5: vehicle of progesterone [benzyl alcohol with sesame oil], 6: sham [ovariectomized female rats: ovx], 7: sham [no ovx], 8: sham[male], 9 and 10: low dose [4mg/kg] and high dose [8mg/kg] of progesterone, 11: allopregnanolone and 12: vehicle of allopregnanolone [water]. Hormones were injected i. p one hour after diffuse traumatic brain injury through Marmarou model. The results showed a significant increase of 5.32 times in Evans blue and 2.42% in water content in trauma male group comparing to control groups, while in female rats the difference was significant just for Evans blue [4.68 times]. Evans blue and water content were also significantly greater in traumatic males than female rats [1.57 times and 2.04% respectively]. After injection of low and high doses of progesterone, there was a significant decrease in water content [2.21% and 2.30%] and Evans blue content [2.55 and 2.98 times]. Allopregnanolone significantly decreased these parameters [2.36% and 1.82 times respectively]. Moreover, the injection of progesterone in both low and high doses increased the serum progesterone of female ovarectomized rats as compared to vehicle group. Based on these results, it can be concluded that the rate of edema formation in traumatic male rats is higher compared to traumatic female rats. Moreover, both progesterone and allopregnanolone decrease edema formation in ovariectomized female rats

Hypertonic saline treatment in children with cerebral edema.

OBJECTIVE: To compare the efficacy and side effects of hypertronic saline and mannitol use in cerebral edema. DESIGN: Retrospective study. SETTING: Pediatric intensive care unit. SUBJECTS: 67 patients with cerebral edema. METHODS: Patients with cerebral edema treated with either mannitol or hypertronic saline (HS) (Group II: n = 25), and both mannitol and HS (Group III: n = 20) were evaluated retrospectively. Cerebral edema and increased intracranial pressure were based on the clinical and/or radiological (CT, MR) findings. When treating with both mannitol and HS (Group IIIA), if patients serum osmality was greater than 325 mosmol/L, mannitol was stopped and patients were treated with only HS (Group IIIB). All patients were closely monitored for fever, pulse, blood pressure, central venous pressure (CVP), oxygen saturation, volume of fluid intake and urine output. Mannitol was given at a dose of 0.25-0.5 g/kg while the hypertonic saline was given as 3% saline to maintain the serum-Na within the range of 155-165 mEq/L. RESULTS: There was no statistically significant difference in terms of Glasgow coma scale, age, gender, and etiologic distribution between the groups. And also distribution of the other treatments given for cerebral edema is not significiant. Mannitol was given for a total dose of 9.3 +/-5.0 (2-16) doses in Group I, and 6.5 +/-2.8 (2-10) doses in Group III. Hypertonic saline was infused for 4-25 times in Group II. Although there was no statistically significant difference in the highest serum Na and osmolarity levels of the groups, duration of comatose state and mortality rate were significantly lower in Group II and Group III A B. Patients who received only HS were subdivided according to their serum Na concentrations into 2 groups as those between 150-160 mEqL and those between 160-170 mEqL. The duration of comatose state and mortality was not different in patients with serum-Na of 150-160 mEqL and in patients with 160-170 mEqL in the hypertonic saline receiving patients. Four patients in the group II developed hyperchloremic metabolic acidosis and 2 patients in the group I had hypotension. As two patients in group II had diabetes insipidus and one patient had renal failure in group I, the treatment was terminated. The causes of death were septic shock, ventilator associated pneumonia with acute respiratory distress syndrome, progressive cerebral edema and cerebral edema with pulmonary edema. Multivariate analysis showed that age, gender, cause of cerebral edema, electrolyte imbalance, hyperglycemia and hyper-ventilation had no significant impact on outcome. CONCLUSION: Hypertonic saline seems to be more effective than mannitol in the cerebral edema.

Hipertensión endocraneana secundaria a edema cerebral y la utilización de soluciones salinas hipertónicas y manitol en su tratamiento / Intracranial hypertension secondary to cerebral edema, and the use of saline hypertonic and mannitol

Este artículo es una revisión de la información de los últimos años, relacionados con las terapias utilizadas en el manejo y tratamiento de hipertensión endocraneana. Se inicia recordando los conceptos básicos de la neurofisiología y neuropatología; en los que se han basado los fundamentos, para las guías terapéuticas. También se comparan las opciones terapéuticas que brinden mejores y más efectivos resultados en el manejo de esta patología. Se explican algunas de las medidas generales del manejo del edema cerebral, dando énfasis en las ventajas y desventajas de los tratamientos tradicionales versus los que se han incorporado en los últimos años. Todo esto basados en el manejo de Soluciones Hiperosmolares versus la utilización de manitol.

Dexametasona en meningitis bacteriana aguda del niño: un análisis métrico / Dexamethasone in acute bacterial meningitis in children: a metric analysis

Recientemente se ha puesto en duda la utilidad en el manejo de la meningitis bacteriana aguda en niños, planteando un serio problema de desición clínica. Ya que el uso de dexametasona no sólo tiene bases empíricas, se revisaron los respaldos biológicos de su empleo, así como ensayos clínicos controlados en niños. 5 estudios cumplieron los criterios de inclusión. Los resultados respaldan el empleo de dexamentasona en la prevención de secuelas neurológicas (RR= 2,37; IC: 95 por ciento= 1,34 a 4,22; p <0,004) y audiológicas (RR= 2,25; IC: 95 por ciento= 1,59 a 3,2; p <0,00003). Las diferencias entre los resultados de los estudios pueden explicarse por la falta de compatibilidad (desigualdades en la duración de la enfermedad antes del diagnóstico, tratamientos y etiología). Aunque los efectos de la dexametasona no son de la magnitud esperada de los fundamentos biológicos, el esteroide disminuye los impactos globales neurólogicos y audiológicos en los sobrevivientes y debería considerarse como terapia adjunta en meningitis bacteriana aguda, para emplearla con la debida cautela a las interrogantes sobre covariables tales como la etiología

Prognostic study of different antioedema medications in cases of cerebrovascular accidents

We studied 38 [20 females and 18 mates] consecutive selected cases diagnosed as acute stroke with a mean age of 57.86 years. The patients were randomly allocated to one of three antioedema agents; 16 on furosemide, 12 on mannitol, and 10 on dexamethasone treatments. They were clinically assessed on alternate days till the end of 21-day period of the study and scored according to a clinical scoring system. CT was done pre-medication for all cases. Mortality rate was 53% in the furosemide treated group, 25% in the mannitol group, and 30% in the dexamethasone group. In the three groups, the survivors showed improvement in postmedication and final scores. The initial level of consciousness in our cases was a good predictive of antioedema drug. Cases with better level of consciousness had better scores at the end of the study. Cases presented with midline shift had poor prognosis. We found no difference between the three antioedema drugs as regards improvement of the clinical course in the survivors

Edema cerebral en traumatismo craneoencefálico severo en niños tratados con y sin dexametasona: estudio comparativo U.T.I. Hospital de Niños J.M. De Los Rios, Caracas / Brain edema in severe head injury on children treated instead in not dexametasone: comparative study U.T.I. Hospital de Niños J.M. De Los Rios, Caracas

Se realizó un estudio prospectivo de los resultados obtenidos al tratar con y sin Dexametasona a niños con traumatismo craneoencefálico severo, que ingresaron a la U.T.I. del Hospital de Niños "J.M. De Los Rios", durante el período comprendido en los meses de Enero a Mayo de 1986. Se dividieron en dos grupos de cinco cada uno distribuídos al azar simple por el método de la lotería. Ambos grupos fueron comparables estadísticamente. Se distribuyeron por fecha de ingreso, edad, sexo, procedencia, peso, escala de Glasgow de ingreso y salida. Se comparó la vigilancia hemodinámica, metabólica, respiratoria, hematológica e infecciosa. Llamó la atención 4 hechos importantes: 1) La evolución en ambos grupos estudiados fue igual con el uso o no de Dexametasona, si se mantiene una vigilancia hemodinámica, respiratoria y metabólica adecuada. 2) La mortalidad fue discretamente mayor en el grupo con dexametasona, 20%. 3) La función pulmonar se encontró más deteriorada en el grupo que recibió Dexametasona. 4) El porcentaje de hemocultivos sin desarrollo bacteriano (SDB) fue menor en el grupo que recibió Dexametasona

Influence of ambient temperature and drug treatments on brain oedema induced by impact injury on skull in rats.

The progression and persistence of oedema development following impact-injury on closed skull was studied in anaesthetised as well as in unanaesthetised rats. The degree and rate of oedema development, following trauma, was aggravated in anaesthetised hypothermic animals but was reduced/or delayed by maintenance of body temperature at euthermic level. In general, the unanaesthetised animals showed a greater accumulation of oedema fluid than the corresponding anaesthetised group. The development of oedema corresponded more or less with the accumulation of 5-HT level in plasma and brain. This development of oedema was completely prevented following pretreatment with p-CPA, indomethacin paracetamol and aminophylline in unanaesthetised animals; whereas these drugs were able only to partially reduce the oedema development in euthermic anaesthetised animals. On the other hand the cyproheptadine pretreatment aggravated the oedema development which was more pronounced in unanaesthetised animals. The probable mechanism of the action of these drugs has been discussed.

Cerebral oedema and blood-brain and blood-CSF barriers in experimental brain trauma: effect of indomethacin-A prostaglandin synthetase inhibitor.

Cerebral oedema often occurs following trauma to the brain. Recently several biogenic amines have been suggested for their possible mediation in the pathophysiology of traumatic brain oedema. The present investigation indirectly indicates that prostaglandins of E series are also involved in the etiology of cerebral oedema, since administration of a potent PG synthetase inhibitor, indomethacin significantly diminished oedematous swelling of traumatised rat brain.