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OBJECTIVE: Previously, we have successfully purified and synthesized viscolin, an agent derived from Viscum coloratum extract, which has shown significant potential in the treatment of stroke. Our study aimed to evaluate the neuroprotective effects of viscolin. METHODS: We first assessed the cytotoxicity of viscolin on primary neuronal cultures and determined its antioxidant and radical scavenging properties. Subsequently, we identified the optimal dose-response of viscolin in protecting against glutamate-induced neurotoxicity. RESULTS: Our results demonstrated that viscolin at a concentration of 10 µM effectively reduced neuronal cell death up to 6 hours after glutamate-induced neurotoxicity. Additionally, we investigated the therapeutic window of opportunity and the potential of viscolin in preventing necrotic and apoptotic damage in cultured neurons exposed to oxygen glucose deprivation-induced neurotoxicity. Our findings showed that viscolin treatment significantly reduced DNA breakage, prevented the release of cytochrome c from mitochondria to cytosol, increased the expression of anti-apoptotic protein Bcl-2, decreased the expression of pro-apoptotic protein Bax, and reduced the number of TUNEL-positive cells. Additionally, our in vivo investigation demonstrated a reduction in brain infarction following middle cerebral artery occlusion. CONCLUSION: Viscolin has potential utility as a therapeutic agent in the treatment of stroke.
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In posterior spine surgery, retractors exert pressure on paraspinal muscles, elevating intramuscular pressure and compromising blood flow, potentially causing muscle injury during ischemia-reperfusion. Ginkgo biloba extract (EGb 761), known for its antioxidant and free radical scavenging properties and its role in treating cerebrovascular diseases, is investigated for its protective effects against muscle ischemia-reperfusion injury in vitro and in vivo. Animals were randomly divided into the control group, receiving normal saline, and experimental groups, receiving varying doses of EGb761 (25/50/100/200 mg/kg). A 2-h hind limb tourniquet-induced ischemia was followed by reperfusion. Blood samples collected pre-ischemia and 24 h post-reperfusion, along with muscle tissue samples after 24 h, demonstrated that EGb761 at 1000 µg/mL effectively inhibited IL-6 and TNF-α secretion in RAW 264.7 cells without cytotoxicity. EGb761 significantly reduced nitric oxide (NO) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, and increased glutathione (GSH) levels compared to the control after 24 h. Muscle tissue sections revealed more severe damage in the control group, indicating EGb761's potential in mitigating inflammatory responses and oxidative stress during ischemia-reperfusion injury, effectively protecting against muscle damage.
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Antiinflamatorios , Antioxidantes , Ginkgo biloba , Miembro Posterior , Músculo Esquelético , Extractos Vegetales , Daño por Reperfusión , Animales , Ginkgo biloba/química , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Extractos Vegetales/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/irrigación sanguínea , Ratones , Miembro Posterior/irrigación sanguínea , Masculino , Ratas , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Interleucina-6/metabolismo , Ratas Sprague-Dawley , Extracto de GinkgoRESUMEN
The level of G2/M-phase can represent tumor grading to discriminate benign from atypical meningiomas using flow cytometric analysis. In this study, we compare two tumor DNA prepared methods using fresh and frozen samples for flow cytometric analysis. The specimens were obtained from tumoral tissues of 28 microsurgically resected meningiomas as approved by the institutional review board. Single-cell suspensions were prepared from fresh and frozen tumor tissues using fresh and frozen isolation methods. The coefficient of variation (CV) of DNA and the level of G2/M-phase were assessed by flow cytometric analysis. For fresh samples prepared using the fresh isolation method, atypical meningiomas had significantly higher G2/M-phase levels than those of benign meningiomas. In contrast, for fresh samples prepared using the frozen isolation method, the levels of G2/M-phase in benign and atypical meningiomas were severely interfered. Benign meningiomas could not be discriminated from atypical meningiomas based on the level of G2/M-phase. Additionally, frozen samples prepared using the frozen isolation method had significantly higher values of G2/M-phase in benign and atypical meningioma than those of fresh samples using fresh isolation method. CV was used to estimate the quality of DNA fixation. The diploid G0/G1 peak determined from fresh samples obtained using the fresh isolation method had a smaller CV than those for frozen samples obtained using the frozen isolation method. DNA prepared from fresh samples obtained using fresh isolation method is more suitable for discriminating benign from atypical meningiomas using flow cytometric analysis.
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BACKGROUND: Meningiomas have classically been considered to include benign and atypical/anaplastic tumors. Despite the availability of clinical and pathologic parameters for prognostic prediction prognosis, the behavior of each meningioma may be difficult to predict. Here, we used DNA flow-cytometric studies to predict biological tumor behaviors of intracranial meningiomas. METHODS: The specimens were obtained from fresh tumoral tissues of 43 microsurgically resected meningiomas as approved by the institutional review board. The presence of G2/M-phase and S+G2/M-phase fractions were analyzed and correlated with the proliferation index of Ki-67 and the World Health Organization grading. The check point of G2/M-phase fraction, cyclin B, and pCdk1 (Y15), were analyzed by Western blotting. RESULTS: Our results showed that there were significant differences in Ki-67, G2/M-phase, S+G2/M-phase fractions, and cyclin B between benign and atypical/anaplastic meningiomas. The optimal cutoff point of G2/M-phase and S+G2/M-phase fractions were 5.12 and 7.52%, respectively, and this can be used to discriminate those cases with benign or atypical/anaplastic meningiomas. Besides, both the G2/M-phase and S+G2/M-phase fractions were correlated well with Ki-67 and the histopathological features such as focal necrosis, infiltration of dura mater and mitotic activity. In addition, the occurrence of tumor recurrence and patient age were correlated to the G2/M-phase and S+G2/M-phase fractions, respectively. The G2/M-phase and S+G2/M-phase fractions, however, did not correlate well with histologic invasion to adjacent bone, sinus, or brain tissues. CONCLUSIONS: The use of flow cytometry facilitates additional information for G2/M-phase and S+G2/M-phase fractions represent tumoral grading and risk of recurrence in patients with meningiomas.
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Biomarcadores de Tumor/genética , ADN de Neoplasias/genética , Citometría de Flujo , Puntos de Control de la Fase G2 del Ciclo Celular , Neoplasias Meníngeas/genética , Meningioma/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Western Blotting , Proteína Quinasa CDC2 , Proliferación Celular , Ciclina B/análisis , Quinasas Ciclina-Dependientes/análisis , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Masculino , Neoplasias Meníngeas/química , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/cirugía , Meningioma/química , Meningioma/patología , Meningioma/cirugía , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Breast cancer is one of the most common origins of metastatic lesions in the central nervous system. Many patients with a breast cancer and concurrent brain tumor(s) were diagnosed to have a metastatic lesion or lesions in the brain, based exclusively on their image findings without further pathologic verification, and received radiotherapy alone thereafter. It is, however, possible that a different pathology such as primary brain malignancy, which actually warrants a specific treatment modality, may occur in such patients with an already known malignancy. We, herein, reported a 61-year-old female patient who suffered from an anaplastic oligodendroglioma 1 year after her diagnosis of breast cancer. Demographic data, characteristic imaging findings, treatment, and outcome of the patient were discussed.
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Neoplasias Encefálicas/patología , Carcinoma Ductal de Mama/patología , Neoplasias Primarias Múltiples/patología , Oligodendroglioma/patología , Femenino , Humanos , Persona de Mediana Edad , Clasificación del TumorRESUMEN
Recent evidence shows that the NMDAR postsynaptic density-95 (PSD-95), growth-associated protein-43 (GAP-43), and matrix metalloproteinase-9 (MMP-9) protein enhance neuroplasticity at the subacute stage of stroke. Here, we evaluated whether melatonin would modulate the PSD-95, GAP-43, and MMP-9 proteins in cultured neurons exposed to glutamate excitotoxicity and in rats subjected to experimental stroke. Adult male Sprague-Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Animals were euthanized for Western immunoblot analyses for the PSD-95 and GAP-43 proteins and gelatin zymography for the MMP-9 activity at 7 days postinsult. Another set of animals was sacrificed for histologic and Golgi-Cox-impregnated sections at 28 days postinsult. In cultured neurons exposed to glutamate excitotoxicity, melatonin significantly upregulated the GAP-43 and PSD-95 expressions and improved dendritic aborizations (P<0.05, respectively). Relative to controls, melatonin-treated stroke animals caused a significant improvement in GAP-43 and PSD-95 expressions as well as the MMP-9 activity in the ischemic brain (P<0.05). Consequently, melatonin also significantly promoted the dendritic spine density and reduced infarction in the ischemic brain, and improved neurobehaviors as well at 28 days postinsult (P<0.05, respectively). Together, melatonin upregulates GAP-43, PSD-95, and MMP-9 proteins, which likely accounts for its actions to improve neuroplasticity in cultured neurons exposed to glutamate excitotoxicity and to enhance long-term neuroprotection, neuroplasticity, and brain remodeling in stroke rats.
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Isquemia Encefálica/metabolismo , Proteína GAP-43/metabolismo , Ácido Glutámico/toxicidad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Melatonina/farmacología , Proteínas de la Membrana/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Células Cultivadas , Homólogo 4 de la Proteína Discs Large , Masculino , Neuronas , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Neuroprotective efficacy of magnolol, 5,5'-dially-2,2'-dihydroxydiphenyl, was investigated in a model of stroke and cultured neurons exposed to glutamate-induced excitotoxicity. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Magnolol or vehicle was administered intraperitoneally, at 1 hr pre-insult or 1-6 hrs post-insult. Brain infarction was measured upon sacrifice. Relative to controls, animals pre-treated with magnolol (50-200 mg/kg) had significant infarct volume reductions by 30.9-37.8% and improved neurobehavioral outcomes (P<0.05, respectively). Delayed treatment with magnolol (100 mg/kg) also protected against ischemic brain damage and improved neurobehavioral scores, even when administered up to 4 hrs post-insult (P<0.05, respectively). Additionally, magnolol (0.1 µM) effectively attenuated the rises of intracellular Ca(2+) levels, [Ca(2+)](i), in cultured neurons exposed to glutamate. Consequently, magnolol (0.1-1 µM) significantly attenuated glutamate-induced cytotoxicity and cell swelling (P<0.05). Thus, magnolol offers neuroprotection against permanent focal cerebral ischemia with a therapeutic window of 4 hrs. This neuroprotection may be, partly, mediated by its ability to limit the glutamate-induced excitotoxicity.
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Compuestos de Bifenilo/uso terapéutico , Encéfalo/efectos de los fármacos , Calcio/metabolismo , Infarto Cerebral/tratamiento farmacológico , Lignanos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Compuestos de Bifenilo/farmacología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Células Cultivadas , Infarto Cerebral/patología , Infarto Cerebral/fisiopatología , Relación Dosis-Respuesta a Droga , Ácido Glutámico/farmacología , Infarto de la Arteria Cerebral Media , Inyecciones Intraperitoneales , Lignanos/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fármacos Neuroprotectores/farmacología , Pruebas Neuropsicológicas , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
OBJECTIVE: Cerebellar hemorrhage remote from the site of surgery may complicate neurosurgical procedure. The exact pathophysiology of this type of hemorrhage is poorly understood. We retrospectively compared 16 patients who had remote cerebellar hemorrhage (RCH) with a case-matched control cohort, to determine the significance of perisurgical and surgical factors that may predispose patients to such bleeding events. METHODS: From 1 June 2005 to 31 December 2008, postoperative routine head computed tomographic (CT) scan was performed in our institution and 16 patients with RCH after supratentorial neurosurgical procedure were identified. The medical charts of these 16 cases and a control cohort of 64 patients were recorded. All parameters were analyzed with regards to various variables. RESULTS: The incidence RCH after supratentorial craniotomy increased after postoperative computed tomographic scan. The mechanism of cerebellar hemorrhage in this series of patients is most likely multifactorial. Several variables showed a significant association with the occurrence of RCH. Multivariate analysis indicated that the following two factors independently correlated with occurrence of RCH: (1) postoperative epidural drainage amount; and (2) history of previous cerebrovascular accident (CVA) with cerebral atrophy. All cases with RCH underwent medical treatment and no neurological sequelae associated with RCH. CONCLUSIONS: Postoperative epidural drainage amount and history of previous CVA with cerebral atrophy can reliably predict the occurrence of cerebellar hemorrhage after supratentorial craniotomy. One of the most important strategies to minimize hazardous complications is to be aware of these potential risk factors and to take action to prevent them.
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Cerebelo/patología , Cerebelo/cirugía , Craneotomía/efectos adversos , Hemorragia Posoperatoria/etiología , Adolescente , Adulto , Anciano , Cerebelo/diagnóstico por imagen , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hemorragia Posoperatoria/diagnóstico por imagen , Estudios Retrospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
We explored anti-inflammatory potential of melatonin against the lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro. RAW 264.7 and BV2 cells were stimulated by LPS, followed by the treatment with melatonin or vehicle at various time intervals. In a mouse model of meningitis induced by LPS, melatonin (5mg/kg) or vehicle was intravenously injected at 30min postinsult. The activity of matrix metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) was determined by gelatin zymography. Nuclear factor-kappa B (NFκB) translocation and binding activity were determined by immunocytochemistry and electrophoretic mobility shift assay (EMSA). Our results showed that either pretreatment or cotreatment with melatonin at 50-500 µm effectively inhibited the LPS-induced proMMP-9 activation in the RAW 264.7 and BV2 cells, respectively (P<0.05). This melatonin-induced proMMP-9 inhibition remained effective when treatment was delayed up to 2 and 6hr postinsult for RAW 264.7 and BV2 cells, respectively (P<0.05 for both groups). Additionally, melatonin significantly attenuated the rises of circulatory and cerebral MMP-9 activity, respectively (P<0.05) and reduced the loss of body weight (P<0.05) in mice with meningitis. Moreover, melatonin (50µm) effectively inhibited nuclear factor-kappa B (NFκB) translocation and binding activity in the LPS-treated RAW 264.7 and BV2 cells, respectively (P<0.05). These results demonstrate direct inhibitory actions of melatonin against postinflammatory NFκB translocation and MMP-9 activation and highlight its ability to inhibit systemic and cerebral MMP-9 activation following brain inflammation.
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Lipopolisacáridos/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Meningitis/tratamiento farmacológico , Meningitis/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Activación Enzimática/efectos de los fármacos , Inmunohistoquímica , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , FN-kappa B/metabolismoRESUMEN
We sought to determine the optimal Percoll concentration for ischemic rat brain prepared for flow cytometric (FC) measurements. Animals were subjected to the right middle cerebral artery (MCA) occlusion, and were euthanized at 3, 12, 24, and 72 h after reperfusion onset. The brains were processed by different concentrations (unisolated, 20, 25, 30, or 40%) of Percoll and stained with annexin V/propidium iodine (PI). Ischemic brain damage was evaluated by FC analysis and image analysis for histologic sections. The relative susceptibility of different phenotypes of cells to necrotic and apoptotic damage were evaluated by the FC analyses for the immunohistochemistry, PI, and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-processed brain tissues. Our results showed that FC analysis effectively detected the extent and maturation of apoptotic/necrotic brain damage, and the results were consistent with those determined from histologic brain sections. Neuron was more vulnerable to apoptosis than glia, whereas both cellular phenotypes were compatible in susceptibility for necrotic cell death. Percoll at a low concentration (20%) could effectively remove tissue debris without affecting membranous integrity of the injured neurons. Conversely, high percentages of Percoll (30-40%) substantially increased membranous damage for the injured cells. These results supported the application of FC to determine the extent and progression in time, as well as relative phenotypes of apoptotic/necrotic cell deaths following ischemic damage. We highlighted the use of Percoll at low percentages to facilitate the removal of tissue debris and to improve membrane integrity preservation for the injured neurons.
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Citometría de Flujo/métodos , Infarto de la Arteria Cerebral Media/patología , Neuroglía/patología , Neuronas/patología , Animales , Anexina A5/química , Apoptosis/fisiología , Modelos Animales de Enfermedad , Ataque Isquémico Transitorio/patología , Masculino , Necrosis , Neuroglía/metabolismo , Neuronas/metabolismo , Povidona/química , Propidio/química , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/química , Coloración y Etiquetado/métodosRESUMEN
BACKGROUND: Calcified chronic subdural hematoma (CCSDH), or "armored brain," is a rare disease entity. The optimal surgical procedure for CCSDH has not been established because it is hard to obtain brain re-expansion after surgery. In particular, a large CCSDH is difficult to completely extirpate, and the residual rigid inner and outer membranes facilitates dead space retention and hematoma recurrence. METHODS: We introduce the use a multiple suturing technique to tent the residual outer and inner membranes onto the dura matter so as to obliterate dead space after surgical treatment for CCSDH. Neuroimaging and surgical reports with illustrative images from two cases are shown. RESULTS: Two patients were admitted to our intensive care unit more than 10 years apart from their ventriculoperitoneal (V-P) shunt placements. The first patient presented with clinical signs of increased intracranial pressure. The second patient had a large CCSDH as a concomitant finding with ruptured aneurysmal subarachnoid hemorrhage. Computerized cranial tomography demonstrated large hematoma cavities with thick calcified inner membranes. After neurosurgical intervention by craniotomy and optimal resection of calcified membranes and muddy blood clot, we tented the residual calcified inner and outer membranes onto the dura matter by multiple sutures to reduce dead space accumulation. Postoperatively, the two patients had improved clinical symptoms along with much reduced hematoma cavity in imaging examinations. CONCLUSIONS: We reported an alternative technique using multiple tenting procedures to improve dead space obliteration after surgical treatment for patients with a large CCSDH presenting as a late complication after V-P shunting.
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Calcinosis/patología , Calcinosis/cirugía , Hematoma Subdural Crónico/patología , Hematoma Subdural Crónico/cirugía , Procedimientos Neuroquirúrgicos/métodos , Adulto , Calcinosis/diagnóstico por imagen , Niño , Femenino , Hematoma Subdural Crónico/diagnóstico por imagen , Humanos , Masculino , Procedimientos Neuroquirúrgicos/instrumentación , RadiografíaRESUMEN
Melatonin (5-15 mg/kg) protects male animals against ischemic stroke. We explored the potential interactions and synergistic neuroprotection of melatonin and estrogen using a panel of lipid peroxidation and radical-scavenging assays, primary neuronal cultures subjected to oxygen-glucose deprivation (OGD), and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Neuroprotective efficacy of melatonin was also evaluated in both reproductively active and ovariectomized female rats subjected to transient focal cerebral ischemia. Relative to melatonin or estradiol (E2) alone, a combination of the two agents exhibited robust, synergistic antioxidant and radical-scavenging actions (P<0.05, respectively). Additionally, the two agents, when combined at large doses, showed synergistic inhibition in the production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in the LPS-stimulated RAW 264.7 cells (P<0.05, respectively). Alternatively, co-treatment with melatonin and E2 independently, but not combined, showed a U-shaped dose-responsive (hormetic) cytoprotection for neuronal cultures subjected to OGD. When combined at a dosage either positively or negatively skewed from each optimal dosage, however, co-treatment caused synergistic neuroprotection. Relative to vehicle-injected controls, melatonin given intravenously at 1-5 mg/kg, but not 0.1 or 15 mg/kg, significantly reduced brain infarction and improved neurobehavioral outcomes (P<0.05, respectively) in reproductively active female rats. In ovariectomized stroke rats, melatonin was only effective at a large dosage (15-50 mg/kg). These results demonstrate complex interactions and synergistic antioxidant, radical-scavenging, and anti-inflammatory actions between estradiol and melatonin, and highlight the potential need to rectify the melatonin's hormetic dose-response by the level of circulating estradiol in the treatment of female stroke patients.
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Estrógenos/metabolismo , Ataque Isquémico Transitorio/tratamiento farmacológico , Melatonina/uso terapéutico , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Línea Celular , Células Cultivadas , Estrógenos/deficiencia , Femenino , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Nitratos/metabolismo , Nitritos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
We report a 75-year-old man with two spinal tumors, primary epidural lymphoma and metastatic carcinoma of the prostate, which caused thoracic spinal cord compression, with a long symptom free interval between episodes. The patient presented with back pain and progressive weakness and numbness in his lower limbs for 3 months. Eleven years earlier, he had a symptomatic T8-10 primary spinal epidural lymphoma that was treated successfully with surgery and he made a full recovery. Magnetic resonance imaging of the thoracic and lumbar spines revealed multiple thoracic and lumbar vertebral osteolytic lesions. Extraosseous extension of a lesion at T1-4 resulted in severe spinal cord compression. In consideration of recurrent lymphoma, emergent cord decompression was achieved via posterior T1-4 decompressive laminectomy, and the patient's neurological status improved rapidly after surgery. Pathological examination confirmed metastatic carcinoma of the prostate. After several courses of chemotherapy, the patient improved neurologically and could walk independently. Three years after surgery, magnetic resonance imaging showed complete resolution of cord edema at T1-4 and T8-9, and the high signal intensity at unoperated levels largely regressed. This report emphasizes that other newly developed lesions should be included in the differentiation of recurrent primary spinal epidural lymphoma, especially in patients who have long-term, disease-free intervals between episodes.
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Carcinoma/complicaciones , Linfoma/complicaciones , Neoplasias de la Próstata/complicaciones , Compresión de la Médula Espinal/etiología , Anciano , Carcinoma/patología , Descompresión Quirúrgica , Humanos , Linfoma/patología , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata/secundario , Compresión de la Médula Espinal/cirugíaRESUMEN
We have shown that melatonin attenuated matrix metalloproteinase-9 (MMP-9) activation and decreased the risk of hemorrhagic transformation following cerebral ischemia-reperfusion. Herein, we investigate the possible involvement of the plasminogen/plasmin system and endogenous MMPs inhibitor underlying the melatonin-mediated MMP-9 inhibition. Mice were subjected to 1-hr ischemia and 48-hr reperfusion of the right middle cerebral artery. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhagic transformation were measured. Extracellular matrix damage was determined by Western immunoblot analysis for laminin protein. The activity and expression of MMP-2 and MMP-9 were determined by gelatin zymography, in situ zymography, and Western immunoblot analysis. In addition, the activities of tissue and urokinase plasminogen activators (tPA and uPA) were evaluated by plasminogen-dependent casein zymography. Endogenous plasminogen activator inhibitor (PAI) and tissue inhibitors of MMP (TIMP-1) were investigated using enzyme-linked immunosorbent assay (ELISA) and Western immunoblot analysis, respectively. Cerebral ischemia-reperfusion induced increased MMP-9 activity and expression at 12-48 hr after reperfusion onset. Relative to controls, melatonin-treated animals had significantly decreased MMP-9 activity and expression (P<0.05), in addition to reduced brain infarction and hemorrhagic transformation as well as improved laminin protein preservation. This melatonin-mediated MMP-9 inhibition was accompanied by reduced uPA activity (P<0.05), as well as increased TIMP-1 expression and PAI activity (P<0.05, respectively). These results demonstrate the melatonin's pluripotent mechanisms for attenuating postischemic MMP-9 activation and neurovascular damage, and further support it as an add-on to thrombolytic therapy for ischemic stroke patients.
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Fibrinolisina/metabolismo , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Melatonina/farmacología , Plasminógeno/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Ataque Isquémico Transitorio/enzimología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/enzimología , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVES: We evaluated electrophysiological benefits of reperfusion following ischemic stroke. METHODS: Rats received either transient proximal occlusion of the right middle cerebral artery for 30 (Group I, n=8) or 90 minutes (Group II, n=8) or permanent thermocoagulation of the distal right middle cerebral artery (Group III, n=6). Neurobehavioral outcome and somatosensory evoked potentials (SSEPs) were examined before and at 7 days after the onset of brain ischemia. Brain infarction was assessed after the rats were euthanized. RESULTS: Before ischemia, stable SSEPs were consistently recorded. At 7 days post-insult, Group III (permanent occlusion) had the greatest reduction in the SSEPs recorded ipsilaterally and contralaterally. Groups I and II (transient ischemic groups) also had depressant SSEPs recorded from the ipsilateral ischemic and the contralateral intact brain (electrophysiological diaschisis). However, prolonged ischemia resulted in greater brain infarction and increased neurological deficits in addition to greater reductions in the ipsilateral and the contralateral SSEPs. CONCLUSION: Early reperfusion facilitates the electrophysiological recovery in both ipsilateral lesional and the contralateral intact brain, which may be closely relevant to post-injury brain rewiring. We also demonstrated that contralateral electrophysiological diaschisis could be greatly reversed by early reperfusion and is independent of the lesion size of striatum.
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Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Potenciales Evocados Somatosensoriales/fisiología , Recuperación de la Función/fisiología , Reperfusión/métodos , Animales , Circulación Cerebrovascular/fisiología , Fenómenos Electrofisiológicos/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoAsunto(s)
Enfermedades Cerebelosas , Aneurisma Intracraneal/complicaciones , Hemorragias Intracraneales , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/etiología , Enfermedades Cerebelosas/cirugía , Craneotomía/métodos , Humanos , Hemorragias Intracraneales/complicaciones , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/cirugía , Masculino , Persona de Mediana Edad , Neurocirugia/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: The early postoperative period is a critical time for patients after receiving a decompressive craniotomy. Prompt detection and early management of postoperative recurrent/residual hemorrhagic complications may dramatically improve clinical outcomes. METHODS: The present cohort retrospective study involved 135 patients who received decompressive craniotomy and intensive care unit (ICU) supervision as life-saving measures. The purpose of the study was to evaluate the effects of propofol sedation on the clinical outcome during the ICU stay. The patients' demographic data, hemodynamic variables, the dose of propofol used during the first 48 hours after surgery, residual/recurrent blood clot volume after surgery, and neurologic and clinical outcomes were reviewed. The propofol dosages used for sedation were further divided into three categories: < 0.66, 0.66-3.33 and > 3.33 mg/kg/hr, based on the doses infused during the first 12 hours after surgery. RESULTS: Our results indicated that the patients of the propofol-sedated group had a significantly smaller amount of residual/recurrent blood clot (p < 0.05) than did those of the non-sedated group. The 30-day mortality rate was significantly lower in the propofol-sedated group (p < 0.05) than in the non-sedated group. Among the propofol-sedated patients, those who received a dose of 0.66-3.33 mg/kg/hr in the first 12 hours after surgery achieved significantly improved clinical and neurologic outcomes than those who received either more than 3.33 mg/kg/hr or less than 0.66 mg/kg/hr of propofol. CONCLUSION: Our results support the use of propofol sedation during the early postoperative period after craniotomy in hemorrhagic stroke patients, because it improved both neurologic and clinical outcomes. However, early postoperative use of propofol sedation at larger dosages warrants special attention.
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Hemorragia Cerebral/cirugía , Hipnóticos y Sedantes/farmacología , Propofol/farmacología , Accidente Cerebrovascular/cirugía , Adulto , Anciano , Plaquetas/efectos de los fármacos , Plaquetas/fisiología , Hemorragia Cerebral/fisiopatología , Estudios de Cohortes , Craneotomía , Femenino , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estudios Retrospectivos , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Synapto-dendritic dysfunction and rearrangement takes place over time at the peri-infarct brain after stroke, and the event plays an important role in post-stroke functional recovery. Here, we evaluated whether melatonin would modulate the synapto-dendritic plasticity after stroke. Adult male Sprague-Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Local cerebral blood perfusion, somatosensory electrophysiological recordings and neurobehavioral tests were serially measured. Animals were sacrificed at 7 days after tMCAO. The brain was processed for Nissl-stained histology, Golgi-Cox-impregnated sections, or Western blotting for presynaptic proteins, synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin (a calcium-binding protein found on presynaptic vesicle membranes). Relative to controls, melatonin-treated animals had significantly reduced infarction volumes (P < 0.05) and improved neurobehavioral outcomes, as accessed by sensorimotor and rota-rod motor performance tests (P < 0.05, respectively). Melatonin also significantly improved the SNAP-25, but not synaptophysin, protein expression in the ischemic brain (P < 0.05). Moreover, melatonin significantly improved the dendritic spine density and the somatosensory electrophysiological field potentials both in the ischemic brain and the contralateral homotopic intact brain (P < 0.05, respectively). Together, melatonin not only effectively attenuated the loss of presynaptic protein, SANP-25, and dendritic spine density in the ischemic territory, but also improved the reductions in the dendritic spine density in the contralateral intact brain. This synapto-dendritic plasticity may partly account for the melatonin-mediated improvements in functional and electrophysiological circuitry after stroke.
Asunto(s)
Espinas Dendríticas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Ataque Isquémico Transitorio , Melatonina/farmacología , Proteína 25 Asociada a Sinaptosomas/metabolismo , Animales , Western Blotting , Peso Corporal/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
We investigated the protective effects of magnolol, an active antioxidant and free radical scavenger extracted from Magnolia officinalis, in a hind limb ischemic-reperfusion animal model. Adult male Sprague-Dawley rats were subjected to hind limb ischemic insult for 2 hours and were intravenously treated with magnolol at 0.01 mg/kg (n=8), 0.3 mg/kg (n=8) mg/kg or 1 mg/kg (n=8) mg/kg, or vehicle (n=8). At 24 h post-insult, the levels of nitrite/nitrate (NOX), malondialdehyde (MDA) and myeloperoxidase (MPO), as well as the degree of muscle damage, were assessed. Relative to controls, animals treated with magnolol (0.3 and 1 mg/kg) had attenuated muscular inflammation, edema and damage. Magnolol (0.3-1 mg/kg) also effectively reduced postischemic rises in the MDA, NOx and MPO levels (p<0.05, respectively). Magnolol administrated at 0.01 mg/kg, however, failed to protect against the ischemic-perfusion limb injury. In addition, magnolol (0.01-1 mg/kg) did not affect local muscular blood reperfusion or other physiological parameters, including hematocrit, glucose, arterial blood gases and mean arterial blood pressure. Thus, intravenous administration with magnolol at 0.3-1 mg/kg protects against ischemic limb damage in rats. This cytoprotection may be attributed to its antioxidant, anti-nitrosative and anti-inflammatory actions.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Miembro Posterior/irrigación sanguínea , Lignanos/uso terapéutico , Magnolia/química , Fitoterapia , Daño por Reperfusión/prevención & control , Animales , Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/farmacología , Temperatura Corporal/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Miembro Posterior/enzimología , Miembro Posterior/patología , Lignanos/farmacología , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/sangre , Peroxidasa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Daño por Reperfusión/enzimología , Daño por Reperfusión/patologíaRESUMEN
Occipital condyle fracture (OCF) is an uncommon but potentially fatal disease entity. It is most commonly identified in patients suffering from severe craniocerebral trauma. The advent of computed tomography has made early detection possible. Traditional treatment using a hard neck collar is sufficient to produce solid fusion in most OCF patients. Delayed diagnosis, however, may result in neurologic deterioration due to potential displacement of fractured condylar fragments. Here we report a case of isolated, stable OCF in a patient with a minor head injury. A high level of clinical awareness of this rare disease entity is imperative for the management of traumatized patients, especially for those who have minor head injuries but persistent neck pain.