Permitted daily exposure from preclinical studies of Ginkgo biloba L. dry extract

Abstract Resolution 658/2022 of the Brazilian Regulatory Agency requires the determination of the permitted daily exposure (PDE) of pharmaceutical agents. Ginkgo biloba L. is used therapeutically to treat memory deficits and other brain diseases. However, published results indicate that more studies are needed to confirm the safety of Ginkgo biloba. This study aimed to evaluate the dry extract of Ginkgo biloba L. leaves PDE as an ingredient in an oral pharmaceutical product in preclinical studies using mice. Acute oral toxicity and repeated dose experiments were performed based on OECD guidelines, as well as genotoxicity tests. The results indicate that Ginkgo biloba L. has low acute toxicity, no liver toxicity, and does not alter blood glucose levels. No changes in weight gain were observed, but food intake decreased in males during the first week of treatment at the highest dose. Hematological parameters were not altered in males, whereas females presented lower leukocyte and lymphocyte counts and higher neutrophil counts at the highest dose. The lipid profile was not altered in males, whereas total cholesterol was increased in females. The estimated PDE was 0.1 mg/day and, when related to the maximum residual concentration, indicates that the cleaning process used is safe and does not require reassessment.

Vitamin D3 mediates spatial memory improvement through nitric oxide mechanism in demyelinated hippocampus of rat

Abstract Studies have revealed beneficial role of vitamin D3 in neuro-cognitive function. There is also supporting evidence on the involvement of nitric oxide (NO) in the neuro-protective action. However, its over production could contribute to brain disorders. In this study, demyelination was induced by ethidium bromide (EB) injection into the right side of the hippocampus area of male rats. Vitamin D3 was administered to rats for 7 and 28 days prior to behavioral experiments using Morris water maze (MWM). Travelled distance, time spent to reach the platform, and time spent in target zone, were considered for learning and spatial memory evaluation. Nitrite oxide (NO2-) concentration was measured as an indicator for nitric oxide production. The time spent to reach the platform and the travelled distance were decreased significantly by 28 days of vitamin D3 administration (compared to 7 days experiment). Time spent in target quadrant was significantly lowered by administered vitamin on day 28. Therefore, considering a number of studies that have shown the effect of vitamin D3 on cognition, these findings could support their potential effect. Besides, nitric oxide concentration significantly differed in 28 days of vitamin D3 treated group compared with the groups treated with EB or 7 days of vitamin D3.

Evaluation of Glucosamine Effect Against Heart and Brain Damage Induced by Y-radiation or Aluminium Chloride in Female Rats

Abstract Glucosamine is known as anti-inflammatory, antioxidant and as neuroprotective as well as using to treat many of diseases. This work aimed to investigate the remedial effect of glucosamine (20mg/kg b.wt) against the damage induced by a single dose of γ-radiation (8Gy) or aluminium chloride (AlCl3) (100mg/kg b.wt) in the heart and brain tissues of female rats. Serum aspartate aminotransferase (AST), cholesterol, triglycerides (TGs), LDH and creatine kinase (CPK) were measured. Moreover, gene expression of amyloid protein precursor (APP) and seladin-1 were estimated in the brain tissue. Also, acetylcholinesterase activity (AChE) and p-tau protein expression were estimated in brain homogenate. Metallothioneine (MT) was estimated in the heart and brain tissues. Heart and brain histopathological examination was performed. Irradiation significantly decreased serum AST, CPK and LDH, as well as MT levels in heart and brain tissues. Also, gene expression of seladin-1 decreased. On the other hand, irradiation significantly increased serum TGs level and brain AchE activity, tau protein, and β-amyloid percursor (APP). AlCl3 administration (21 days) induced disturbance in most of the estimated parameters, especially AST, TGs, and MT. Glucosamine treatment with irradiation or AlCl3 improved most of the measured parameters. In addition, histopathological examination confirmed the biochemical results. In conclusion: Glucosamine could be used to improve the heart and brain damages induced by γ-radiation exposure or AlCl3.

Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact / Atrofia cerebral en esclerosis múltiple: impacto clínico, cognitivo y terapéutico

ABSTRACT Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients.

RESUMEN La esclerosis múltiple (EM) fue considerada históricamente como una enfermedad inflamatoria de la sustancia blanca. Hoy en día hay mucha evidencia que apoya, además, el compromiso de la sustancia gris y los mecanismos neurodegenerativos, que son al menos parcialmente independientes de la inflamación. La atrofia de la sustancia gris se desarrolla más rápido que la atrofia de la sustancia blanca y predomina en las etapas iniciales de la enfermedad. El mecanismo neurodegenerativo, crea un daño permanente y se correlacionaría con la discapacidad física y cognitiva del paciente. En esta revisión, se describe la evidencia disponible actual con respecto a la atrofia cerebral y su consecuencia en los pacientes con EM.

Beneficial effects of glucan against cisplatin side effects on the nervous system in rats 1

ABSTRACT PURPOSE: To investigate the protective effect of Bg on cisplatin (CP)-induced neurotoxicity in rats. METHODS: Twenty eight rats were randomly distributed into four groups. The first group was kept as a control. In the second group, CP was given at the single dose of 7 mg/kg intraperitoneally. In the third group, βg was orally administered at the dose of 50 mg/kg/day for 14 days. In the fourth group, CP and βg were given together at the same doses. RESULTS: CP treatment caused significant oxidative damage via induction of lipid peroxidation and reductions antioxidant defense system potency in the brain tissue. In addition, histopathological damage increased with CP treatment. On the other hand, βg treatment largely prevented oxidative and histopathological negative effects of CP. CONCLUSIONS: Cisplatin has severe neurotoxic effects in rats and βg supplementation has significant beneficial effects against CP toxicity depending on its antioxidant properties. Thus, it appears that βg might be useful against CP toxicity in patients with cancer in terms of nervous system.

Brain schistosomiasis in mice experimentally infected with Schistosoma mansoni

Introduction Human neuroschistosomiasis has been reported in the literature, but the possibility of modeling neuroschistosomiasis in mice is controversial. Methods In two research laboratories in Brazil that maintain the Schistosoma mansoni life cycle in rodents, two mice developed signs of brain disease (hemiplegia and spinning), and both were autopsied. Results S. mansoni eggs, both with and without granuloma formation, were observed in the brain and meninges of both mice by optical microscopy. Conclusions This is the first description of eggs in the brains of symptomatic mice that were experimentally infected with S. mansoni. An investigation of experimental neuroschistosomiasis is now feasible. .

Effects of Abdominal Meridian Massage with Aroma Oils on Relief of Constipation among Hospitalized Children with Brain related Disabilities

PURPOSE: This study was done to evaluate the effects of 3 times/week and 5 times/week abdominal meridian massage with aroma oils (AMMAO) on the relief of constipation among hospitalized children with disabilities involving the brain lesions (cerebral palsy, epilepsy, and others). METHODS: The participants were 33 hospitalized children with a disability involving the brain (15 were in the 5 times/week of AMMAO group and 18 were in the 3 times/week of AMMAO group). Data were collected from March 21 to May 1, 2011. Chi-square test, t-test, and repeated measures ANOVA with SPSS 18.0 were used to evaluate the effects of AMMAO. RESULTS: While there was no significant difference between the two groups, there was a significant difference within groups between baseline and the end of the intervention period for the following, frequency of suppository use or enemas, amount of stool, and number of bowel movements. CONCLUSION: The results of this study indicate that AMMAO is an effective nursing intervention in relief of constipation for hospitalized children with a disability involving the brain. Therefore it is recommended that AMMAO be used in clinical practice as an effective nursing intervention for relief of constipation to these children.

Oligoclonal bands in the cerebrospinal fluid and increased brain atrophy in early stages of relapsing-remitting multiple sclerosis / Bandas oligoclonales en líquido cefalorraquídeo y incremento de la atrofia cerebral en estadios tempranos de pacientes con esclerosis múltiple forma recaída-remisión

OBJECTIVE: To determine if the presence of oligoclonal bands (OB) at early stages of multiple sclerosis was associated with higher brain atrophy, when compared with patients without OB. METHODS: Relapsing-remitting multiple sclerosis (RRMS) patients with less than two years of disease onset and OB detection in cerebrospinal fluid (CSF) were included. SIENAX was used for total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV). RESULTS: Forty patients were included, 29 had positive IgG-OB. No differences were found between positive and negative patients in gender, expanded disability status scale (EDSS), treatment received, and T2/T1 lesion load. TBV in positive IgG-OB patients was 1.5 mm³ x 10(6) compared with 1.64 mm³ x 10(6) in the negative ones (p=0.02). GMV was 0.51 mm³ x 10(6) in positive IgG-OB compared with 0.62 mm³ x 10(6) in negative ones (p=0.002). No differences in WMV (p=0.09) were seen. CONCLUSIONS: IgG-OB in the CSF was related to neurodegeneration magnetic resonance (MR) markers in early RRMS.

OBJETIVO: Evaluar si la presencia de bandas oligoclonales (BO) en líquido cefalorraquídeo (LCR) de pacientes con esclerosis múltiple recaídaremisión (EMRR) se asociaba con mayor atrofia cerebral al inicio de la enfermedad. MÉTODOS: Pacientes con EMRR con menos que dos años del inicio de la enfermedad y en quiénes se realizó la búsqueda de IgG-BO en LCR fueron incluidos. SIENAX fue usado para la medición del volumen cerebral total (VCT), volumen de substancia gris (VSG) y volumen de sustancia blanca (VSB). RESULTADOS: Cuarenta pacientes fueron incluidos, 29 tenían IgG-BO positivo. No fueron encontradas diferencias entre pacientes positivos y negativos en: género, expanded disability status scale (EDSS), tratamiento recibido y carga lesional en resonancia magnética. El VCT en pacientes IgG-BO positivos fue de 1,5 mm³ x 10(6) versus 1,64 mm³ x 10(6) en BO negativo (p=0,02). El VSG fue 0,51 mm³ x 10(6) BO positivo versus 0,62 mm³ x 10(6) BO negativo (p=0,002). No fueron encontradas diferencias en VSB (p=0,09). CONCLUSIONES: La presencia de IgG-BO en el LCR se asoció con signos de neurodegeneración temprana en este estudio.

Hidatidosis cerebral: aspectos clínicos e imagenológicos. Reporte de 4 casos / Brain hydatidosis: Report of four cases

In only 2% of all cases of hydatidosis, the cysts are located in the brain. We report a 12-year-old male, a 5-year-old girl and a 19-year-old female consulting for intracranial hypertension and a 13-year-old male consulting for a left hemiparesis. Imaging studies found intra-cerebral cysts with characteristics of hydatidosis in all. All lesions were completely removed surgically and the pathological study of the excised piece confirmed the diagnosis of hydatidosis.

Magnetoencephalography in Pediatric Lesional Epilepsy Surgery

This study was performed to assess the usefulness of magnetoencephalography (MEG) as a presurgical evaluation modality in Korean pediatric patients with lesional localization-related epilepsy. The medical records and MEG findings of 13 pediatric patients (6 boys and 7 girls) with localization-related epilepsy, who underwent epilepsy surgery at Seoul National University Children's Hospital, were retrospectively reviewed. The hemispheric concordance rate was 100% (13/13 patients). The lobar or regional concordance rate was 77% (10/13 patients). In most cases, the MEG spike sources were clustered in the proximity of the lesion, either at one side of the margin (nine patients) or around the lesion (one patient); clustered spike sources were distant from the lesion in one patient. Among the patients with clustered spike sources near the lesion, further extensions (three patients) and distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure outcome. It is suggested that MEG is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy.

Encefalopatia hereditária em bovinos no estado do Espírito Santo / Hereditary encephalopaty of cattle in Espírito Santo state, Brazil

Descrevem-se os aspectos epidemiológicos e clínico-necroscópicos de uma doença neurológica hereditária observada em bovinos no município de Ecoporanga, norte do Estado do Espírito Santo. Trata-se de enfermidade do sistema nervoso central verificada exclusivamente em fêmeas, filhas de touro reprodutor de 5 anos de idade da raça Nelore, oriundo do município de Curvelo, Minas Gerais, com vacas mestiças Nelore x Quianini; bezerros machos oriundos deste cruzamento não demonstraram quaisquer sinais relacionados à enfermidade. Os sinais clínicos, presentes ao nascimento ou detectáveis nas primeiras semanas de vida, caracterizam-se por ataxia, perda do equilíbrio, instabilidade, andar em círculos, posicionamento incorreto dos membros no animal em estação ou em marcha (afastamento e/ou desvio de membros da posição normal) e desvio lateral da coluna (eixo principal do corpo em diagonal). De animal para animal, há marcada variação na intensidade das manifestações clínicas. Os bovinos mais afetados morrem devido à incapacidade de se alimentar. O exame macroscópico evidenciou, em grau variável de intensidade, áreas de depressão assimétrica setorial, sobretudo nos lobos frontal e temporal do córtex telencefálico e no córtex cerebelar. Em adição observou-se atrofia de grupos musculares de membros correspondentes às porções defeituosas no sistema nervoso central. O estudo histológico inicial revelou que as áreas deprimidas devem-se à redução setorial de populações neuronais (provavelmente abiotrofia/atrofia) principalmente nos lobos cerebrais frontal e temporal e nas camadas granular e molecular do córtex cerebelar. Estudos morfométrico, imunohistoquímico e ultraestrutural estão sendo realizados e devem trazer mais informações sobre os aspectos microscópicos e patogenéticos. Os achados epidemiológicos indicam que a enfermidade está diretamente ligada ao cromossoma X, com penetrância completa e expressividade variável.

The epidemiological, clinical and pathological aspects of a neurological disease have been described in cattle in the Ecoporanga county, northeastern Espírito Santo, Brazil. This disease of the central nervous system occurred only in daughters of a 5-year-old Nelore bull crossed with Nelore x Quianini cows. The clinical signs, which were detectable immediately or in the first weeks after birth, are characterized by ataxia, instability, circling, abnormal position of the limbs when standing or walking (removal and/or deviation of members from the normal position) and lateral deviation of the vertebral column (main axis of the body in diagonal). The disease is expressed by variable widths in their clinical manifestations. Most affected animals died due to incapacity of milk or food intake. The macroscopic examination shows variable degree of asymmetric sectorial depressed areas of the frontal and temporal telencephalic cortex, and in the cortex of the cerebellum, as well as correspondent muscular (appendicular) atrophy. Histological examination revealed that the depressed areas are due to the sectorial reduction of neuronal populations (probably atrophy/abiotrophy), mainly in the frontal and temporal brain lobes, and in the molecular and granular layers of the cerebellar cortex. Morphometric, immunohistochemical and ultrastructural studies are underway and should provide more information about the microscopical and pathogenetic aspects. Epidemiological data indicate that the illness is directly linked to the chromosome X, with complete penetration and variable expressiveness.

Rhinocerebral zygomycosis in a diabetic patient / Zigomicose rinocerebral em paciente diabética

Rhinocerebral zygomycosis is the most frequent form of fungal infection caused by members of the Zygomycetes class. A fatal case of rhinocerebral zygomycosis caused by Rhizopus (oryzae) arrhizus with histopathological and mycological diagnosis is reported in a diabetic patient.

Zigomicose rinocerebral é a forma mais frequente das infecções fúngicas causadas por membros da classe Zygomicetes. É relatado um caso fatal de zigomicose rinocerebral por Rhizopus (oryzae) arrhizus com diagnóstico histopatológico e micológico, em paciente diabética.

NMO in pediatric patients: brain involvement and clinical expression / NMO en pacientes pediátricos: afectación del cerebro y expresión clínica

OBJECTIVE: To analyze the clinical, neuroimaging characteristics and positivity of the acquaporin water channel (NMO-IgG) in pediatric patients with neuromyelitis optica (NMO). This disorder could have a variable clinical expression. To address such variability, the term NMO spectrum has been suggested. METHOD: We evaluated six pediatric patients, with a median age of 11 years at the time of the study, with the diagnosis of NMO by the Wingerchuck criteria. RESULTS: All the cases exhibited bilateral optic neuritis (ON). Four patients had abnormalities on brain MRI from the onset,although only three of them developed symptoms correlated to those lesions during the course of their disorder. NMO-IgG was positive in 80 percent. CONCLUSION: Optic neuropathy is the most impaired feature in NMO patients. Brain MRI lesions are not compatible with multiple sclerosis and positivity of the NMO-IgG are also present in NMO pediatric patients, confirming the heterogeneity in the expression of this disorder.

OBJETIVO: Analizar las características clínicas y de neuroimagen, y la positividad del canal de agua acuaporin (NMO-IgG) en pacientes pediátricos con neuromielitis óptica (NMO). Este trastorno puede tener una expresión clínica variable. El término espectro de NMO ha sido propuesto para poder incluir la variabilidad. METODO: Evaluamos seis pacientes pediátricos, con una mediana de edad de 11 años al momento del estudio, con el diagnóstico de NMO de acuerdo a los criterios de Wingerchuck. RESULTADOS: Todos los casos exhibían neuritis óptica bilateral (ON). Cuatro pacientes tuvieron anormalidades en la RM cerebral desde el inicio, aunque solo tres de ellos desarrollaron síntomas relacionados con las lesiones durante el curso de la enfermedad. NMO-IgG fue positiva en el 80 por ciento. CONCLUSIÓN: Neuropatía óptica es la característica mayormente observada en los pacientes con NMO. Lesiones cerebrales en la RM cerebral no compatibles con esclerosis multiple y positividad de la NMO-IgG están también presentes en los pacientes pediátricos con NMO; lo cual confirma la heterogeneidad en la expresión clínica de este trastorno.

Morphometric investigation of neurons in the hippocampal CA1, CA3 areas and dentate gyrus in a rat model of sepsis / Investigación morfométrica de neuronas en las áreas hipocampales CA1, CA3 y giro dentado en un modelo de sepsis en rata

Approximately, half of the patients with progressive sepsis develop encephalopathy, but there is scarce knowledge onto question that how the sepsis associated encephalopathy contributes brain dysfunction. Hippocampus is one of the most vulnerable regions during experimental sepsis. In the present study, effects of sepsis on the neuronal density and morphology in CA1, CA3 and DG areas were investigated in a rat model of intraperitoneal sepsis. Twenty-four Wistar rats were divided into three different groups: faecal peritonitis group, sham-operated and un-operated control groups. Pyramidal neuron volume density was significantly higher in CA1 area of the faecal peritonitis group compared to both un-operated (p<0.05) and sham-operated (p<0.05) groups. Pyramidal neuron volume density was also significantly higher in CA3 area of the faecal peritonitis group compared to both un-operated (p<0.05) and sham-operated (p<0.05) groups. Mean nuclear diameter of pyramidal neurons in CA1 area of the faecal peritonitis group was significantly lower (p<0.05) compared to un-operated control group. Dark, shrunken neurons were frequently observed and neuroglial cells appeared to be prevalent in the faecal peritonitis group compared to control groups. These results collectively suggest that intraperitoneal sepsis does not initiate cell death in the early stages of sepsis, although morphological signs of neurodegeneration start to appear.

Aproximadamente, la mitad de los pacientes con sepsis progresiva desarrollan encefalopatía, pero hay escaso conocimiento en cuestión de como la sepsis asociada con encefalopatía contribuye a la disfunción cerebral. El hipocampo es una de las regiones más vulnerables durante la sepsis experimental. En el presente estudio, fueron analizados los efectos de la sepsis sobre la densidad neuronal y la morfología en las áreas CA1, CA3 y giro dentado en un modelo de sepsis intraperitoneal en rata. Veinticuatro ratas Wistar se dividieron en tres grupos diferentes: grupo de peritonitis fecal, operación simulada y control no operado. La densidad del volúmen piramidal fue significativamente mayor en el área CA1 del grupo con peritonitis fecal en comparación con los grupos no operados (p<0,05) y la operación simulada (p<0,05). La densidad de volumen de las neuronas piramidales fue significativamente mayor en el área CA3 del grupo peritonitis fecal en comparación con los no operado (p<0,05) y la operación simulada (p<0,05). El diámetro promedio nuclear de las neuronas piramidales en la zona CA1 del grupo de peritonitis fecal fue significativamente menor (p<0,05) en comparación con el grupo de control no operado. Las neuronas fueron observadas con frecuencia reducidas y las células neurogliales parecen ser frecuentes en el grupo de peritonitis fecal en comparación con grupos de control. Estos resultados en conjunto sugieren que la sepsis intraperitoneal no inicia la muerte celular en las primeras etapas de la sepsis, aunque los signos morfológicos de la neurodegeneración empiezan a aparecer.

Stereotactic biopsy for intracranial lesions: clinical-pathological compatibility in 60 patients / Biopsia estereotáctica para lesões intracranianas: compatibilidade clínico patológica em 60 casos

OBJECTIVE: Image guided stereotactic biopsy (SB) provides cerebral tissue samples for histological analysis from minimal lesions or those that are located in deep regions, being crucial in the elaboration of therapeutic strategies, as well as the prevention of unnecessary neurosurgical interventions. METHOD: Sixty patients with central nervous lesions underwent SB from November 1999 to March 2008. They were followed up to 65 months. Preoperative diagnosis was based on clinical presentation and neuro-radiological features, pathologic diagnosis, clinical outcome. The compatibility of these findings with the pathologic diagnosis was analyzed. RESULTS: Considering diagnosis confirmation when inflammatory hypothesis were made, our accuracy was of 76 percent, with 94 percent of those cases having clinic-pathological correspondence after an average of 65.2 months of follow up. Considering diagnosis confirmation with the preoperative hypothesis of neoplasm, our accuracy was of 69 percent with 90 percent of these cases having clinic-pathological correspondence after an average of 47.3 months of follow-up. Morbidity rate was of 5 percent and mortality was zero. The diagnosis rate was 95 percent. CONCLUSION: Stereotactic biopsy represents a safe and precise method for diagnosis. Anatomic and histopathological analyses have high compatibility with long-term clinical outcome.

OBJETIVO: A biopsia estereotáctica (BE) guiada por imagem propicia amostras de tecido cerebral para análises histológicas, sendo decisiva na estratégia terapêutica e prevenção de intervenções neurocirúrgicas desnecessárias. MÉTODO: 60 pacientes com lesões do sistema nervoso central foram submetidos à biópsia estereotáctica no período de novembro de 1999 a março de 2008. Foram analisados a acurácia do método, a capacidade de confirmar o diagnóstico clínico pré-operatório e o comportamento evolutivo com sua compatibilidade com o diagnóstico patológico. RESULTADOS: As três lesões mais freqüentes foram: neoplasias neuroepiteliais, processos inflamatórios e infecções. Considerando a confirmação diagnóstica quando pensava-se em lesão inflamatória, nossa acurácia foi 76 por cento, com 94 por cento destes casos tendo compatibilidade clínico patológica após média de 65,2 meses de acompanhamento. Considerando a confirmação diagnóstica com a hipótese pré-operatória de lesão neoplásica, nossa acurácia foi 69 por cento, com 90 por cento destes casos tendo compatibilidade clínico-patológica após média de 47,3 meses de acompanhamento. O índice de morbidade foi 5 por cento. A mortalidade foi nula e o índice de diagnóstico foi 95 por cento. CONCLUSÃO: A biopsia estereotáctica é um método seguro e preciso para o diagnóstico. O exame anátomo-patológico possui alta compatibilidade com a evolução clínica dos doentes a longo prazo.