Juliana Ben

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinsons disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum.

Predictors of meaningful improvement in quality of life after temporal lobe epilepsy surgery: A prospective study

To investigate prospectively the independent predictors of a minimum clinically important change (MCIC) in quality of life (QOL) after anterior temporal lobectomy (ATL) for drug‐resistant mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE‐HS) in Brazilian patients.

Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats

Parkinsons disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

Role of hormonal levels on hospital mortality for male patients with severe traumatic brain injury

Abstract Introduction: Changes in hormone blood levels during the acute phase of traumatic brain injury (TBI) have been described in the literature. The objective was to investigate the association among several hormones plasma levels in the acute phase of severe TBI and the hospital mortality rate of male patients. Methods: The independent association among plasma levels of TSH, LH, FSH, GH, free T4, cortisol, IGF-1 and total testosterone was measured 10 hours and 30 hours after severe TBI and the hospital mortality of 60 consecutive male patients was evaluated. Results: At least one hormonal level abnormality was demonstrated in 3.6–73.1% of patients. The multiple logistic regressions showed a trend for an independent association among hospital mortality and normal or elevated LH levels measured at 10 hours (OR = 3.7, 95% CI = 0.8–16.3, p = 0.08) and 30 hours (OR = 3.9, 95% CI = 0.9–16.7, p = 0.06). Admission with abnormal pupils and a lower Glasgow Coma Score also were independently associated with hospital mortality. Conclusion: The hormonal changes are frequent in the acute phase of severe TBI. The hormones plasma levels, excepting the LH, are not highly consistent with the hospital mortality of male patients.

Moderate traumatic brain injury increases the vulnerability to neurotoxicity induced by systemic administration of 6-hydroxydopamine in mice

Moderate traumatic brain injury (TBI) might increase the vulnerability to neuronal neurodegeneration, but the basis of such selective neuronal susceptibility has remained elusive. In keeping with the disruption of the blood-brain barrier (BBB) caused by TBI, changes in BBB permeability following brain injury could facilitate the access of xenobiotics into the brain. To test this hypothesis, here we evaluated whether TBI would increase the susceptibility of nigrostriatal dopaminergic fibers to the systemic administration of 6-hydroxydopamine (6-OHDA), a classic neurotoxin used to trigger a PD-like phenotype in mice, but that in normal conditions is unable to cross the BBB. Adult Swiss mice were submitted to a moderate TBI using a free weight-drop device and, 5h later, they were injected intraperitoneally with a single dose of 6-OHDA (100mg/kg). Afterwards, during a period of 4weeks, the mice were submitted to a battery of behavioral tests, including the neurological severity score (NSS), the open field and the rotarod. Animals from the TBI plus 6-OHDA group displayed significant motor and neurological impairments that were improved by acute l-DOPA administration (25mg/kg, i.p.). Moreover, the observation of the motor deficits correlates with (i) a significant decrease in the tyrosine hydroxylase levels mainly in the rostral striatum and (ii) a significant increase in the levels of striatal glial fibrillary acidic protein (GFAP) levels. On the whole, the present findings demonstrate that a previous moderate TBI event increases the susceptibility to motor, neurological and neurochemical alterations induced by systemic administration of the dopaminergic neurotoxin 6-OHDA in mice.

Effects of Hypericum perforatum on turning behavior in an animal model of Parkinson's disease

A Doenca de Parkinson e uma doenca neurodegenerativa relacionada a idade, caracterizada pela morte lenta e progressiva de neuronios dopaminergicos da substância negra pars compacta. O Hypericum perforatum (H. perforatum) e um fitoterapico utilizado como antidepressivo, apresentando propriedades antioxidantes, anti-inflamatorias e nootropicas. Neste trabalho, avaliaram-se os efeitos do tratamento com H. perforatum no comportamento rotatorio de ratos no modelo da doenca de Parkinson induzido pela administracao unilateral de 6-OHDA no feixe prosencefalico medial. Ratos Wistar machos foram tratados com H. perforatum (100, 200 ou 400 mg/kg, v.o.) por 35 dias (do 28o dia antes ate o 7o dia apos a lesao). As rotacoes ipsilaterais e contralaterais a lesao foram registradas no 7o, 14o e 21o dias apos a cirurgia. As tres doses de H. perforatum utilizadas reduziram o numero de rotacoes contralaterais, indicando um possivel efeito neuroprotetor da planta. Porem, o H. perforatum nao impediu a reducao na expressao da enzima tirosina hidroxilase no estriado lesionado, quantificada por Western blot. Propomos que o H. perforatum possa bloquear o aumento da expressao dos receptores dopaminergicos no estriado lesionado com 6-OHDA. Entretanto, estudos adicionais sao necessarios para identificar o mecanismo exato pelo qual o H. perforatum reduziu o numero de rotacoes contralaterais. Os resultados do presente estudo sugerem o H. perforatum como um potencial agente terapeutico para a doenca de Parkinson.

Decline in word-finding: The objective cognitive finding most relevant to patients after mesial temporal lobe epilepsy surgery

PURPOSE The purpose of this study was to investigate the following: i) the objective impairment in neuropsychological tests that were associated with the subjective perception of cognitive function decline in Brazilian patients who underwent mesial temporal lobe epilepsy (MTLE) surgery and ii) the predictive variables for those impaired objective neuropsychological tests. METHODS Forty-eight adults with MTLE (27 right HS and 23 male) were divided according to their perception of changes (Decline or No-decline) of cognitive function domain of the QOLIE-31 questionnaire applied before and 1year after the ATL. The mean (SD) of changes in the raw score difference of the neuropsychological tests before and after the ATL was compared between Decline and No-decline groups. Receiver Operating Characteristic curves, sensitivity, specificity, and predictive values were used to assess the optimum cutoff points of neuropsychological test score changes to predict patient-reported subjective cognitive decline. KEY FINDINGS Six (12.5%) patients reported a perception of cognitive function decline after ATL. Among the 25 cognitive tests analyzed, only changes in the Boston Naming Test (BNT) were associated with subjective cognitive decline reported by patients. A reduction of ≥8 points in the raw score of BNT after surgery had 91% of sensitivity and 45% specificity for predicting subjective perception of cognitive function decline by the patient. Left side surgery and age older than 40years were more associated with an important BNT reduction with overall accuracy of 91.7%, 95% predictive ability for no impairment, and 75% for impairment of cognitive function. SIGNIFICANCE Impairment in word-finding seems to be the objective cognitive finding most relevant to Brazilian patients after mesial temporal lobe epilepsy surgery. Similar to American patients, the side of surgery and age are good predictors for no decline in the BNT, but shows a lower accuracy to predict its decline. If replicated in other populations, the results may have wider implications for the surgical management of patients with drug-resistant MTLE.

Brain MAPKs levels are differentially associated with seizures threshold and severity progression in pentylenetetrazole-kindled mice.

1,4,51 Programa de Pos-Graduac ~ao em Neuroci ^encias, Centro de Ci encias Biol^ ogicas, Universidade Federal de Santa Catarina, Florianopolis, Brazil2 Departamento de Bioquimica, Centro de Ci^encias Biol ogicas, Universidade Federal de Santa Catarina, Florianopolis, Brazil3 Departamento de Farmacologia, Centro de Ci^encias Biol ogicas, Universidade Federal de Santa Catarina, Florianopolis, Brazil4 Departamento de Clinica Medica, Centro de Ci^encias da Sa ude, Hospital Universitario (HU), Universidade Federal de Santa Catarina, Florianopolis,Brazil5 Centro de Neuroci^encias Aplicadas (CeNAp), Hospital Universit ario (HU), Florianopolis, Brazil6 Disciplina de Neurologia Experimental, Escola Paulista de Medicina/Universidade Federal de S~ao Paulo (EPM/UNIFESP), S ~ao Paulo, BrazilCorrespondenceR. Walz, M.D., Ph.D., Departamento de ClinicaMedica, Hospital Universitario, 3 andar, UFSC,Campus Universitario, Trindade Florianopolis,Brazil.Tel.: +55-48-3721-9149;Fax: +55-48-3721-9014;E-mail: rogerwalz@hotmail.comReceived 2 May 2013; revision 28 May 2013;accepted 29 May 2013doi: 10.1111/cns.12147

Neuropsychological functioning and brain energetics of drug resistant mesial temporal lobe epilepsy patients

Interictal hypometabolism is commonly measured by 18-fluoro-deoxyglucose Positron Emission Tomography (FDG-PET) in the temporal lobe of patients with mesial temporal lobe epilepsy (MTLE-HS). Left temporal lobe interictal FDG-PET hypometabolism has been associated with verbal memory impairment, while right temporal lobe FDG-PET hypometabolism is associated with nonverbal memory impairment. The biochemical mechanisms involved in these findings remain unknown. In comparison to healthy controls (n=21), surgically treated patients with MTLE-HS (n=32, left side=17) had significant lower scores in the Rey Auditory Verbal Learning Test (RAVLT retention and delayed), Logical Memory II (LMII), Boston Naming test (BNT), Letter Fluency and Category Fluency. We investigated whether enzymatic activities of the mitochondrial enzymes Complex I (C I), Complex II (C II), Complex IV (C IV) and Succinate Dehydrogenase (SDH) from the resected samples of the middle temporal neocortex (mTCx), amygdala (AMY) and hippocampus (HIP) were associated with performance in the RAVLT, LMII, BNT and fluency tests of our patients. After controlling for the side of hippocampus sclerosis, years of education, disease duration, antiepileptic treatment and seizure outcome after surgery, no independent associations were observed between the cognitive test scores and the analyzed mitochondrial enzymatic activities (p>0.37). Results indicate that memory and language impairment observed in MTLE-HS patients are not strongly associated with the levels of mitochondrial CI, CII, SDH and C IV enzymatic activities in the temporal lobe structures ipsilateral to the HS lesion.

Mitochondrial respiratory chain complex enzyme activities of limbic structures and psychiatric diagnosis in temporal lobe epilepsy patients: Preliminary results

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS) is the most common type of surgically remediable epilepsy.1 Psychiatric psychopathology may be overrepresented in epilepsy2 and Axis I psychiatric diagnosis has been reported in 40% of Brazilian drugresistant MTLEHS patients.3 Depression and anxiety disorders are frequent psychiatric comorbidities and may contribute to the reduction of quality of life MTLEHS patients before4,5 and after epilepsy surgery.6 Mitochondria are organelles that play a role in cellular metabolism by ATP production through oxidative phosphorylation, a process carried out by respiratory chain complexes.7 Hypometabolism has been demonstrated in the epileptogenic areas of MTLEHS patients by 18fluorodeoxyglucose positron emission computed tomography (FDGPET)8 and depression diagnosis in patients with temporal lobe epilepsy was associated with orbitofrontal hypometabolism ipsilateral to the epileptogenic zone.9 There are no studies investigating whether psychiatric disorders are correlated with mitochondrial enzymatic activities in human neocortical and limbic structures. The epilepsy surgery offers an opportunity to obtain human samples of amygdala and hippocampus under wellcontrolled conditions,6,7,10 structures known to be involved with psychiatric disorders.