benzofurans and Brain-Edema

Concussive head injury (CHI) is quite prevalent in military personnel leading to lifetime disability in more than 85% of cases. Other reasons of CHI include motor vehicle accident, fall or blunt trauma under various conditions. In United States of America (USA) alone more than 150k cases of head injury are added every year for which no suitable therapeutic strategies are still available. Thus, there is a need to expand our knowledge in treating CHI cases with novel therapeutic measures to enhance the quality of life of head injury victims. With recent advancements in nanodelivery of drugs for superior neuroprotective effects in neurological diseases, our laboratory is engaged in understanding the role of nanowired delivery of suitable drugs in treating CHI and other neurodegenerative diseases. DL-3-n-butylphthalide (NBP) is an extract of Chinese celery and is able to induce profound neuroprotection following ischemic stroke and other related neurological dysfunction. Thus, it is quite likely that synthetic NBP could have pronounced neuroprotective effects in CHI as well. We believe that nanodelivery of NBP have superior neuroprotection in CHI. In this review neuroprotective effects of nanowired delivery of NBP in CHI induced brain pathology is described. Our experimental observations show that nanowired delivery of NBP results in superior neuroprotection than the regular NBP in CHI. The probable mechanisms and functional significance of our finding in relation to military medicine is discussed based on our own investigations.

Topics: Animals; Benzofurans; Brain Concussion; Brain Edema; Humans; Nanomedicine; Nanowires; Neuroprotective Agents

Damage to the blood-brain barrier (BBB) is an important factor leading to intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Krüppel-like transcription factor 2 (KLF2) plays an important role in the maintenance of the BBB. This study aims to detect the changes of KLF2 after ICH and evaluate the potential effects of fraxinellone on ICH-induced SBI and its correlation with KLF2. An ICH model was established by injecting autologous blood into the right basal ganglia of Sprague-Dawley (SD) rats. First, after ICH induction, the protein levels of KLF2 were reduced. Then, we found that the decrease of KLF2 protein levels induced by ICH could be effectively reversed with the treatment of fraxinellone in vascular endothelial cells. Furthermore, fraxinellone treatment effectively alleviated brain edema, decreased the levels of TNF-α and IL-1β, and improved neuronal cell degeneration induced by ICH. Meanwhile, fraxinellone ameliorated neurobehavioral disorders, motor and sensory impairments, and neurobehavioral disorders and memory loss caused by ICH. Collectively, these findings reveal that KLF2 may be a potential target for fraxinellone to exert neuroprotective effects after ICH, and fraxinellone could be a potential therapeutic agent for SBI after ICH.

Topics: Animals; Benzofurans; Brain Edema; Brain Injuries; Cerebral Hemorrhage; Disease Models, Animal; Endothelial Cells; Kruppel-Like Transcription Factors; Rats; Rats, Sprague-Dawley

Topics: Animals; Anti-Inflammatory Agents; Apium; Benzofurans; Blood-Brain Barrier; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Humans; Infusions, Intraventricular; Male; Matrix Metalloproteinase 9; Neuroprotective Agents; Permeability; Rats; Signal Transduction; Tumor Necrosis Factor-alpha

The lack of inclusion of comorbidities in animal models of stroke may underlie the limited development of therapy in stroke. Previous studies in mice deficient of CD36, an immune receptor, indicated its contribution to stroke-induced inflammation and injury in hyperlipidemic conditions. The current study, therefore, tested whether pharmacological inhibition of CD36 provides neuroprotection in hyperlipidemic stroke. The hyperlipidemic mice subjected to stroke showed an exacerbation of infarct size and profound brain swelling. However, post-stroke treatment with CD36 inhibitors did not reduce, and in some cases worsened, acute stroke outcome, suggesting potential benefits of elevated CD36 in the post-stroke brain in a hyperlipidemic condition. On the other hand, chronic treatment of a CD36 inhibitor prior to stroke significantly reduced stroke-induced brain swelling. There was a trend toward infarct reduction, although it did not reach statistical significance. The observed benefit of preventative CD36 inhibition is in line with previously reported smaller infarct volume and swelling in CD36 KO mice. Thus, the current findings suggest that insights gained from the genetic models should be carefully considered before the implementation of pharmacological interventions, as a potential therapeutic strategy may depend on preventative treatment or a post-stroke acute treatment paradigm.

Topics: Animals; Apolipoproteins E; Benzofurans; Brain Edema; CD36 Antigens; Disease Models, Animal; Drug Administration Schedule; Drugs, Chinese Herbal; Hyperlipidemias; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Protective Agents; Stroke

Ischemic stroke occurs following arterial occlusion and subsequent blood flow cease, and restoration of blood supply by thrombolytic therapy may cause cerebral ischemic reperfusion (IR) injury resulting in breakdowns of blood-brain barrier (BBB). Dl-3-n-butylphthalide (NBP) is an extraction from Chinese celery Apium graveolens Linn seeds and has neuroprotective effects in ischemic stroke. This study explored effects of NBP on BBB disruption caused by cerebral IR and transformation of tight junctions (TJs)-associated proteins and caveolae. Our results demonstrated that NBP alleviated cerebral IR-induced deterioration of vascular permeability by up-regulating TJ-associated proteins but down-regulating caveolin-1. NBP significantly improved neurological function and cerebral blood flow but reduced cerebral edema and infarct volume after IR. In conclusion, NBP exerts neuroprotective effects through attenuating cerebral infarct volume and neurological deficit score, reducing cerebral edema and BBB permeability. The neuroprotective effect of NBP is possibly related to its ability to improve blood flow in cerebral ischemic areas. NBP may turn into a novel treatment drug to prevent BBB dysfunction in ischemic stroke.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Capillary Permeability; Caveolin 1; Cerebrovascular Circulation; Disease Models, Animal; Male; Mice; Neuroprotective Agents; Random Allocation; Reperfusion Injury; Tight Junctions

We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia.. Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting.. 2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 ± 5.4% vs 56.1 ± 7.9%, p < 0.05). Significant decreased of brain water content (79.5 ± 2.6% vs 84.62 ± 2%, p < 0.05) and Evans Blue extravasation (1.2 ± 0.5 vs 2.5 ± 0.41 µg/g, p < 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP-9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups.. These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU.

Topics: Animals; Apoptosis; Benzofurans; Brain; Brain Edema; Brain Ischemia; Capillary Permeability; Disease Models, Animal; Imidazoles; Male; Motor Activity; Neurons; Neuroprotection; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley

Silent information regulator 1 (SIRT1), a histone deacetylase, has been suggested to be effective in ischemic brain diseases. Salvianolic acid B (SalB) is a polyphenolic and one of the active components of Salvia miltiorrhiza Bunge. Previous studies suggested that SalB is protective against ischemic stroke. However, the role of SIRT1 in the protective effect of SalB against cerebral ischemia has not been explored. In this study, the rat brain was subjected to middle cerebral artery occlusion (MCAO). Before this surgery, rats were intraperitoneally administrated SalB with or without EX527, a specific SIRT1 inhibitor. The infarct volume, neurological score and brain water content were assessed. In addition, levels of TNF-α and IL-1β in the brain tissues were detected by commercial ELISA kits. And the expression levels of SIRT, Ac-FOXO1, Bcl-2 and Bax were detected by Western blot. The results suggested that SalB exerted a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema and increased neurological scores. SalB also exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-1β levels in the brain tissue. Moreover, SalB upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FOXO1 and Bax. These effects of SalB were abolished by EX527 treatment. In summary, our results demonstrate that SalB treatment attenuates brain injury induced by ischemic stoke via reducing apoptosis and inflammation through the activation of SIRT1 signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Benzofurans; Brain; Brain Edema; Brain Ischemia; Carbazoles; Central Nervous System Agents; Disease Models, Animal; Infarction, Middle Cerebral Artery; Inflammation; Male; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Severity of Illness Index; Sirtuin 1; Stroke; Treatment Outcome

The aim of this study was to explore the effect of butylphthalide on the brain edema, blood-brain barrier of rats of rats after focal cerebral infarction and the expression of Rho A. A total of 195 sprague-dawley male rats were randomly divided into control group, model group, and butylphthalide group (40 mg/kg, once a day, by gavage). The model was made by photochemical method. After surgery 3, 12, 24, 72, and 144 h, brain water content was done to see the effect of butylphthalide for the cerebral edema. Evans blue extravasation method was done to see the changes in blood-brain barrier immunohistochemistry, and Western blot was done to see the expression of Rho A around the infarction. Compared with the control group, the brain water content of model group and butylphthalide group rats was increased, the permeability of blood-brain barrier of model group and butylphthalide group rats was increased, and the Rho A protein of model group and butylphthalide group rats was increased. Compared with the model group, the brain water content of butylphthalide group rats was induced (73.67 ± 0.67 vs 74.14 ± 0.46; 74.89 ± 0.57 vs 75.61 ± 0.52; 77.49 ± 0.34 vs 79.33 ± 0.49; 76.31 ± 0.56 vs 78.01 ± 0.48; 72.36 ± 0.44 vs 73.12 ± 0.73; P < 0.05), the permeability of blood-brain barrier of butylphthalide group rats was induced (319.20 ± 8.11 vs 394.60 ± 6.19; 210.40 ± 9.56 vs 266.40 ± 7.99; 188.00 ± 9.22 vs 232.40 ± 7.89; 288.40 ± 7.86 vs 336.00 ± 6.71; 166.60 ± 6.23 vs 213.60 ± 13.79; P < 0.05), and the Rho A protein of butylphthalide group rats was decreased (western blot result: 1.2230 ± 0.0254 vs 1.3970 ± 0.0276; 1.5985 ± 0.0206 vs 2.0368 ± 0.0179; 1.4229 ± 0.0167 vs 1.7930 ± 0.0158;1.3126 ± 0.0236 vs 1.5471 ± 0.0158; P < 0.05). The butylphthalide could reduce the brain edema, protect the blood-brain barrier, and decrease the expression of Rho A around the infarction.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Cortex; Cerebral Infarction; Disease Models, Animal; Immunohistochemistry; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; rhoA GTP-Binding Protein; Time Factors; Water

Salvianolic acid B (SalB), a bioactive compound isolated from the Chinese medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in in vitro and in vivo studies. Here, we investigated the protective effects of SalB on traumatic brain injury (TBI) in mice. When administered within 2 h after TBI onset, SalB (25 mg/kg) reduced brain edema, lesion volume and motor functional deficits, and improved spatial learning and memory abilities. Moreover, SalB treatment inhibited the neutrophil infiltration and microglial activation at 48 h after TBI. Enzyme-linked immunosorbent assay (ELISA) for brain tissue homogenates was performed at 24 h after TBI to evaluate the expression of inflammation-related cytokines. The results showed that SalB suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1β, whereas enhanced the expression of anti-inflammatory cytokines IL-10 and TGF-β1. All of these findings extended the protective role of SalB in the model of TBI and suggested that these protective effects might be associated with its anti-inflammatory activities. Thus SalB may have therapeutic potential for patients with TBI and perhaps other forms of acute brain injury.

Topics: Animals; Benzofurans; Brain Edema; Brain Injuries; Inflammation; Interleukin-10; Interleukin-1beta; Learning; Male; Memory; Mice; Mice, Inbred C57BL; Molecular Structure; Space Perception; Tumor Necrosis Factor-alpha

Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10 mg/kg). Animals were randomized to receive either IRFI 042 (20 mg/kg i.p.), a lipid peroxidation inhibitor, or its vehicle (NaCl 0.9% DMSO 10% 1 ml/kg i.p.) 30 min before KA administration. A first set of animals was sacrificed 6 h after KA injection to measure malondialdehyde (MDA) content, glutathione-reduced (GSH) levels and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the hippocampus. A second set of animals was sacrificed 48 h after KA administration for histological analysis. All animals were observed for monitoring the behavioral sequelae and for evaluating latency of convulsions. Sham brain injury rats were used as controls. Intraperitoneal administration of IRFI 042 significantly decreased brain MDA (cortex: KA + vehicle = 0.285 +/- 0.04 nmol/mg protein; KA + IRFI 042 = 0.156 +/- 0.02 nmol/mg protein, P < 0.005; hippocampus: KA + vehicle = 0.350 +/- 0.03 nmol/mg protein; KA + IRFI 042 = 0.17 +/- 0.04 nmol/mg protein, P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 7.81 +/- 1 micromol/g protein; KA + IRFI 042 = 12.1 +/- 1 micromol/g protein; P < 0.005) and hippocampus (KA + vehicle = 5 +/- 0.8 micromol/g protein; KA + IRFI 042 = 9.4 +/- 1.8 micromol/g protein; P < 0.005), reduced both brain IL-1beta mRNA expression and oedema, and increased latency of convulsions. Histological analysis showed a reduction of cell damage in IRFI 042-treated samples. The present data indicate that lipid peroxidation inhibition reduces IL-1beta gene expression and protects against kainic acid-induced brain damage.

Topics: Animals; Behavior, Animal; Benzofurans; Brain Edema; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Glutathione; Hippocampus; Interleukin-1; Kainic Acid; Lipid Peroxidation; Male; Malondialdehyde; Nerve Degeneration; Neurotoxins; Oxidative Stress; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

To investigate the protective effect of dl-3-n-butylphthalide (NBP) as an anti-cerebral ischemic drug on brain damage 24 h after closed head injury in mice.. Closed head injury was induced by dropping a 50-g weight from a height of 18 cm on a metal impounder resting on the parietal bone in mice.. The neurotraumatic model induced impairment of memory function, significant cerebral edema, and disruption of the blood-brain barrier. dl-3-n-butylphthalide (50 mg.kg-1) given intraperitoneally 5 minutes and 60 minutes after the onset of closed head injury was found to attenuate the impairment of memory function (P < 0.05), alleviate brain edema in the injured cerebral cortex (P < 0.05), and reduce extravasation of plasma protein bound to Evans blue dye by 63.5% (P < 0.01). NBP was also shown to increase the activity of choline acetyltransferase in the injured cortex to 0.83 +/- 0.21 ng.min-1.mg-1 (P < 0.01, compared with 0.48 +/- 0.14 ng.min-1.mg-1 of vehicle group).. NBP provides therapeutic response in experimental closed head injury.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Brain Edema; Brain Injuries; Head Injuries, Closed; Male; Mice; Neuroprotective Agents

The present study evaluated the effect of dl-3-n-butylphthalide(NBP), a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (MCAO), producing permanent focal ischemia in the right cerebral hemisphere, which developed ipsilateral brain edema reproducibly. Edema was assessed 24 h after MCA occlusion by determining the brain water content from wet and dry weight measurements, and the sodium, potassium concentrations with ion-selective electrodes. In this model, NBP at the dose of 80, 160 and 240 mg/kg p.o. 15 min after MCAO prevented from brain edema in a dose-dependent manner. A significant reduction of sodium content and an increase in potassium level were observed in all drug-treated groups. It showed that NBP strongly attenuated brain water entry, sodium accumulation and potassium loss. Nimodipine treatment (5 mg/kg s.c.) also reduced brain edema (P < 0.05). The results suggest that a strong anti-edema activity of NBP may play an important role to contribute to the treatment of ischemic damage.

Topics: Animals; Benzofurans; Brain Edema; Drugs, Chinese Herbal; Hypoxia-Ischemia, Brain; Male; Neuroprotective Agents; Rats; Rats, Wistar

Oxygen derived free radicals have been proposed to be in part responsible for the cerebral oedema resulting from head injury. In the present study the effects of free radical suppression with MDL 74,180 (2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methylpiperazino)-methyl-1 - benzofuran-5-ol dihydrochloride), an alpha-tocopherol analogue free radical scavenger, on the development of cerebral oedema resulting from head injury has been assessed. Fluid percussion head injury in rats caused a regional oedema 48 h after injury. Infusion of MDL 74,180 for 2 h after the injury significantly attenuated oedema development in a dose-related manner. Using magnetic resonance imaging, cerebral oedema development was monitored in head injured mice. Oedema was apparent 4 h after head injury and was greatest in the vicinity of the olfactory bulb and surrounding the ventricles. Treatment with MDL 74,180 (1-10 micrograms/kg intravenously, administered 3-5 min after the injury) significantly reduced the oedema development. MDL 74,180 is a potential treatment for the oedema caused as a result of head injury.

Topics: Animals; Benzofurans; Brain Edema; Brain Injuries; Free Radical Scavengers; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred Strains; Piperazines; Rats; Rats, Inbred Strains

The neuroprotective efficacy of the kappa-opioid agonist enadoline (CI-977) was examined in two acute rat models of focal cerebral ischaemia [non-recovery (4 h) and recovery (24 h)]. In the non-recovery model, Sprague-Dawley rats were anaesthetized throughout the study period. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA). The amount of early ischaemic damage was assessed in coronal sections at nine pre-determined stereotaxic planes. Enadoline at doses of 0.1, 0.3 and 1.0 mg/kg (n = 8), administered s.c. 30 min prior to ischaemia, produced dose-dependent amelioration of cortical damage. Importantly, enadoline had no significant effect on any of the physiological parameters monitored (blood pressure, blood gases, glucose, pH). In the recovery model the left MCA was permanently occluded under isoflurane anaesthesia. Animals were allowed to recover and were killed 24 h later. The amount of ischaemic brain damage and swelling was assessed histologically. In this model pretreatment with enadoline at either 0.1, 0.3, or 1.0 mg/kg s.c. was followed by continuous s.c. infusion at 0.017, 0.05 or 0.17 mg/kg/h respectively (n = 8-17). Enadoline produced dose-dependent reductions in the volumes of infarction and brain swelling; the greatest reductions were seen at 1.0 mg/kg plus 0.17 mg/kg/h in both infarction (reduced by 37.4% from controls) and swelling (reduced by 47.8%). Therefore the kappa-opioid agonist enadoline affords dose-dependent neuroprotection in both the non-recovery and recovery models of focal cerebral ischaemia in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Brain; Brain Edema; Brain Ischemia; Cerebral Infarction; Dose-Response Relationship, Drug; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA) during a brief period of halothane anaesthesia. The animals were sacrificed 24 h after MCA occlusion and the amount of ischaemic brain damage and swelling was assessed in coronal sections at 8 predetermined stereotactic planes. Treatment with CI-977 (0.03, 0.3 or 3 mg/kg), initiated 30 min prior to MCA occlusion (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling, with the most marked reductions being noted with CI-977 (0.3 mg/kg) in both infarction (reduced by 38% from controls; P less than 0.02) and swelling (reduced by 31%; P less than 0.002). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar with saline-treated and CI-977-treated animals (overall correlation coefficient r = 0.896). These results indicate that CI-977 is effective in reducing infarction in a model of focal cerebral ischaemia, and that the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.

Topics: Animals; Benzofurans; Brain Edema; Cerebral Infarction; Disease Models, Animal; Ischemic Attack, Transient; Male; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa