Therapeutic effects of JLX001 on cerebral ischemia through inhibiting platelet activation and thrombus formation in rats.

(3ß,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX001), a derivative of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effect of JLX001 on cerebral ischemia and researchits antiplatelet and antithrombosis activities via thromboxane (TXA2)/phospholipase C-ß-3(PLCß3)/protein kinase C (PKC) pathway suppression. The therapeutic effects of JLX001 was evaluated by infarct sizes, brain edema and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Brain TXA2 and prostacyclin (PGI2) were measured by enzyme-linked immunosorbentassay (ELISA). P-PLCß3and activated PKC were detected by immunohistochemical method. Adenosine diphosphate (ADP) or 9, 11-dieoxy-11α, 9α-epoxymethanoeprostaglandin F2α (U46619) was used as platelet agonist in the in vivo and in vitro platelet aggregation experiments. Clotting time and bleeding time were determined. Besides, two whole-animal experiments including arteriovenous shunt thrombosis and pulmonary thromboembolism model were conducted. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, and neurological scores in permanent middle cerebral artery occlusion (pMCAO) rats. Brain TXA2 level, p-PLCß3and activated PKC were decreased, while PGI2level had no significant change. Besides, JLX001 inhibited platelet aggregation induced by ADP or U46619 and exhibited anti-coagulation effects with a minor bleeding risk. In the two whole-animal experiments, JLX001 inhibited thrombus formation. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms relate to inhibiting platelet activation and thrombus formation via TXA2/PLCß3/PKC pathway suppression.

Protective effects of allicin against ischemic stroke in a rat model of middle cerebral artery occlusion.

Allicin, a molecule predominantly responsible for the pungent odor and the antibiotic function of garlic, exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of various disorders. The present study aimed to elucidate the effect of allicin in cerebral ischemia/reperfusion (I/R) injury in rats. Rats were subjected to 1.5 h of transient middle cerebral artery occlusion (MCAO), followed by 24 h of reperfusion. Rats were randomly assigned to the sham surgery group, the MCAO group and the MCAO + allicin group. Neurological score, cerebral infarct size, brain water content, neuronal apoptosis, serum tumor necrosis factor (TNF)­α and myeloperoxidase (MPO) activity were measured. The results suggested that allicin reduced cerebral infarction area, brain water content, neuronal apoptosis, TNF­α levels and MPO activity in the serum. The results of the present study indicated that allicin protects the brain from cerebral I/R injury, which may be ascribed to its anti­apoptotic and anti­inflammatory effects.

[Effect of xingnaojing injection combined with minimally invasive percutaneous drainage in treating brain edema and content of serum AQP4 in patients with moderate hypertensive basal ganglia hemorrhage].

OBJECTIVE: To observe the effect of Xingnaojing Injection combined with minimally invasive percutaneous drainage on brain edema and content of serum aquaporin-4 (AQP4) in patients with moderate hypertensive basal ganglia hemorrhage, and discuss the treatment mechanism of Xingnaojing injection combined with minimally invasive percutaneous drainage for cerebral hemorrhage. METHOD: Forty-two patients with moderate (25-50 mL) hypertensive basal ganglia hemorrhage (< 24 h) were selected and randomly divided into two groups: the observation group (n = 22) and the control group (n = 20). The neurological severity score were evaluated by the NIHSS (national institutes of health stroke scale), the volume of brain edemas were measured by head CT, the serum levels of AQP4 were determined by ELISA method on admission and 1 and 2 weeks after treatment. RESULT: On admission, there was no significant difference in the scores of NIHSS, the volume of brain edemas and the level of serum AQP4 between the observation group and the control group. At the end of the first week after the treatment, the score of NIHSS of the observation group were lower than that of the control group, with significant different (P < 0.05); the observation group showed reduced volume of brain edemas than that on admission (P < 0.05), whereas the control group the control group showed increased volume of brain edemas than that on admission; the control group displayed increased level of serum AQP4 than that on admission, but without significant difference; the observation group displayed decreased level of serum AQP4 than that on admission (P < 0.05). At the end of the second week after the treatment, the control group showed decreased score of NIHSS than that on admission and at the end of the first week after treatment (P < 0.05). Compared with the control group, the observation group showed a much lower score of NIHSS (P < 0.01), the control group displayed reduced volume of brain edemas than that on admission and at the end of the first week after treatment, but the observation group was even lower than the control group. Both of observation and control groups displayed significantly reduced level of AQP4 (P < 0.05), but the observation group showed a lower AQP4 level than that of the control group (P < 0.05). CONCLUSION: The therapy of Xingnaojing injection combined with minimally invasive percutaneous drainage could remarkably reduce brain edema, and promote neural functional recovery, thus could be selected as a therapeutic regimen for patients with moderate hypertensive basal ganglia hemorrhage.

Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury.

Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI.

Quercetin as a prophylactic measure against high altitude cerebral edema.

The present study was undertaken to elucidate the intervention of quercetin against high altitude cerebral edema (HACE) using male Sprague Dawley rats as an animal model. This study was also programmed to compare and correlate the effect of both quercetin (flavonoid) and dexamethasone (steroid) against HACE. Six groups of animals were designed for this experiment, (I) normoxia, (II) hypoxia (25,000 ft, 24 h), (III) normoxia+quercetin (50 mg/kg body wt), (IV) normoxia+dexamethasone (4 mg/kg body wt), (V) hypoxia+quercetin (50 mg/kg body wt), (VI) hypoxia+dexamethasone (4 mg/kg body wt). Quercetin at 50 mg/kg body wt, orally 1h prior to hypoxia exposure, was considered as the optimum dose, due to a significant reduction in the level of brain water content and cerebral transvascular leakage (P < 0.001), as compared to control (24 h hypoxia). Dexamethasone was administered at 4 mg/kg body wt, orally, 1h prior to hypoxia exposure. Both drugs (quercetin and dexamethasone) could efficiently reduce the hypoxia-induced hematological changes. Quercetin was observed to be a more potent antioxidative and anti-inflammatory agent. It blocks nuclear factor kappa-beta (NFκB) more significantly (P < 0.05) than the dexamethasone-administered hypoxia-exposed rats. Histopathological findings demonstrate the absence of an edema and inflammation in the brain sections of quercetin-administered hypoxia-exposed rats. The present study reveals quercetin to be a potent drug against HACE, as it efficiently attenuates inflammation as well as cerebral edema formation without any side effects of steroid therapy (dexamethasone).

Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: We investigated the role of thrombin in early brain injury after subarachnoid hemorrhage (SAH). METHODS: The standard intravascular perforation model was used to produce experimental SAH in Sprague Dawley rats. Low-dose (0.3 mg/h) and high-dose (0.9 mg/h) argatroban, a direct thrombin inhibitor, were evaluated for effects on brain edema, blood-brain barrier (BBB) disruption, apoptotic cell death, inflammatory marker, and neurological outcomes after SAH. RESULTS: Both doses of argatroban attenuated BBB disruption; however, only high-dose was effective in lowering edema in all brain regions, reducing cell death, and inflammatory marker expression, and improving neurological outcomes. CONCLUSIONS: Thrombin inhibition by argatroban improves neurological outcomes and provides neuroprotection against acute events after SAH such as BBB disruption, brain edema, and cell death.

The effect of mannitol on intracranial pressure in relation to serum osmolality in a cat model of cerebral edema.

OBJECTIVE: To determine whether intravenous mannitol administration reduces intracranial pressure (ICP) in a cat model of brain edema by changing serum osmolality. DESIGN: Prospective, controlled study. SETTING: Pediatric intensive care unit laboratory in a university hospital. INTERVENTIONS: Intraparenchymal ICP monitors were placed in 12 adult cats which subsequently underwent 60 min of continuous arteriovenous hemofiltration with countercurrent dialysis (CAVH-D), using sterile water with potassium chloride as a dialysate. The ultrafiltrate was replaced with a hypotonic solution causing a rapid reduction in serum osmolality while maintaining a euvolemic state. In six cats (control group) no further interventions were instituted, while in the six other cats (mannitol group) 1g/kg mannitol was administered intravenously immediately after CAVH-D had been discontinued. ICP was monitored continuously, and serum osmolality was determined at 15-min intervals during CAVH-D and for 30 min thereafter. RESULTS: ICP increased significantly in both the control and mannitol groups during 60 min of CAVH-D. After CAVH-D, ICP was reduced in the mannitol group while ICP remained significantly higher in the control group. An inverse linear correlation was demonstrated between serum osmolality and ICP values in the control group throughout the experiment, as well as during the first 60 min in the mannitol group. However, no such correlation existed in the mannitol group after mannitol administration, as no significant changes in serum osmolality were observed while a marked reduction in ICP values occurred. CONCLUSION: Mannitol is effective in reducing increased ICP in this model of euvolemic brain edema. However, 15 min after mannitol administration, no relationship between a continued decrease in ICP and a change in serum osmolality could be established. We postulate that the beneficial effect on ICP by mannitol outlasts its possible instantaneous and short-lived effect on serum osmolality.