Search

Glutamate plays a central role in the fast excitatory synaptic transmission and is a key neurotransmitter involved in several neurophysiological processes. Glutamate levels on the synaptic cleft are related to neural excitability, neuroplasticity, and neuronal damage associated with excitotoxicity. Mice lacking the cellular prion protein (PrP(c)) gene (Prnp) present a decreased astrocytic glutamate uptake in cultures, higher neuronal excitability in vitro and sensitivity to pro-convulsant drugs in vivo, and age-dependent memory impairment. Here, we investigate if PrP(c) might be involved in neuronal uptake and release of glutamate. For this purpose, we compared synaptosomal preparations from the cerebral cortex, entorhinal cortex, hippocampus, cerebellum, and olfactory bulb of 3- or 9-month-old PrP(c) null mice and with respective wild-type controls. Although we observed differences in synaptosomal glutamate release and uptake regarding the age of mice and the brain structure studied, these differences were similar for PrP(c) null mice and their respective wild-type controls. Therefore, despite a possible correlation between neuronal glutamate transporters, excitability, and neuronal damage, our results suggest that PrP(c) expression is not critical for neuronal glutamate transport.

The studies of physiological roles for cellular prion protein (PrP(c)) have focused on possible functions of this protein in the CNS, where it is largely expressed. However, the observation that PrP(c) is expressed also in muscle tissue suggests that the physiological role of PrP(c) might not be limited to the central nervous system. In the present study, we investigated possible functions of PrP(c) in muscle using PrP(c) gene (Prnp) null mice (Prnp(0/0)). For this purpose, we submitted Prnp(0/0) animals to different protocols of exercise, and compared their performance to that of their respective wild-type controls. Prnp(0/0) mice showed an exercise-dependent impairment of locomotor activity. In searching for possible mechanisms associated with the impairment observed, we evaluated mitochondrial respiration (MR) in skeletal or cardiac muscle from these mice during resting or after different intensities of exercise. Baseline MR (states 3 and 4), respiratory control ratio (RCR) and mitochondrial membrane potential (DeltaPsi) were evaluated and were not different in skeletal or cardiac muscle tissue of Prnp(0/0) mice when compared with wild-type animals. We concluded that Prnp(0/0) mice show impairment of swimming capacity, perhaps reflecting impairment of muscular activity under more extreme exercise conditions. In spite of the mitochondrial abnormalities reported in Prnp(0/0) mice, our observation seems not to be related to MR. Our results indicate that further investigations should be conducted in order to improve our knowledge about the function of PrP(c) in muscle physiology and its possible role in several different neuromuscular pathologies.

Purpose: Posterior cortex epilepsies (PCEs) encompass a group of epilepsies originating from the occipital, parietal, or occipital border of the temporal lobe, or from any combination of these regions. When their seizures are refractory to pharmacologic treatment, these patients are usually referred for surgery. The aim of our study was to analyze clinical characteristics of all PCE patients referred for surgery from 1994 to 2003, and to search for predictors of surgical outcome., Methods: We performed a retrospective analysis of clinical and laboratory data from 81 consecutive refractory PCE patients referred for surgery. Surgical and nonsurgical groups of patients were compared, and detailed analyses of all variables of the surgical cases were performed in the search for predictors of seizure outcome., Results: Risk factors for PCEs included gliosis (34.56%), malformations of cortical development (33.33%), tumors (8.64%), brain trauma (3.70%), Sturge-Weber disease (4.93%), vascular malformations (3.70%), family history of epilepsy (3.70%), history of CNS infections (2.46%), and low IQ (2.46%). Of the 81 patients, 44 were submitted to surgery at the time of the completion of this study. Surgical treatment was highly effective in improving seizures (p<0.001) when compared with previous pharmacologic treatment alone. Twenty-eight (65.11%) patients became seizure free after surgery versus none in the nonsurgical group. Regarding outcome predictors, patients with shorter duration of epilepsy and those without neurologic abnormalities on clinical examination had higher chances of favorable evolution., Conclusions: Surgical treatment is effective for the treatment of PCEs and superior to pharmacologic therapy alone. In our series, shorter duration of epilepsy and normal neurologic examination were the only independent variables that predicted better surgical outcome.

Although many studies have investigated the function of cellular prion protein (PrPc), its physiologic role remains elusive. PrPc null mice have been reported to develop normally and to show normal performance in most behavioural tests. In the present study we investigated whether this also holds true after episodes of acute stress. PrPc gene ablated (Prnp0/0) and wild-type mice were subjected to restraint stress, electric foot shock, or swimming and compared with non-stressed animals. Immediately after the stressful situation, the anxiety levels and locomotion of the animals were measured using plus-maze and open-field tests. Among non-stressed animals, there was no significant difference in performance between Prnp0/0 and wild type animals in either test. However, after acute stress provoked by a foot shock or a swimming trial, Prnp0/0 animals showed a significant decrease in anxiety levels when compared with control animals. Moreover, after the swimming test, knockout mice presented decreased locomotion when compared to wild-type mice. Because of this observation, we also assessed both types of mice in a forced swimming test with the objective of better evaluating muscle function and found that Prnp0/0 animals presented reduced forced swimming capacity when compared to controls. As far as we know, this is the first report suggesting that cellular prion protein is involved in modulation of anxiety or muscular activity after acute psychic or physical stress.

Background and Purpose: A large number of patients with epilepsy in the pediatric population have medically intractable epilepsy. In this age group seizures are usually daily or weekly, and response to antiepileptic therapy is poor, especially for those with neurological abnormalities and symptomatic epilepsies. However, several authors have already demonstrated similarly favorable long-term post-surgical seizure control when comparing pediatric and adult populations. In this article we aim to report the experience of the Ribeirão Preto Epilepsy Surgery Program in pediatric epilepsy surgery., Patients and Methods: We analyzed 107 patients with medically intractable epilepsy operated on between July 1994 and December 2002, considering age at surgery, seizure type, pathological findings, and seizure outcome. All data were prospectively collected according to protocols previously approved by the institution ethics committee., Results: We analyzed a total of 115 operations performed in 107 patients. There was no difference in sex distribution. Complex partial seizures occurred in 31.4% of the patients, followed by tonic seizures (25.9%), focal motor seizures (15.4%), and infantile spasms (13.3%). The most common etiologies were cortical developmental abnormalities (25.2%), tumors (16.8%), mesial temporal sclerosis (15.9%), Rasmussen syndrome (6.5%), and tuberous sclerosis (6.5%). Overall post-surgical seizure outcome showed 67.2% of the patients within Engel classes I and II, reaching 75.0% when patients with callosotomies were excluded., Conclusions: Post-surgical seizure control in the pediatric population is similar to that in adult patients, despite the fact that epilepsies in this age group are more frequently of extratemporal origin, suggesting that surgery should be considered in children as soon as intractability is determined.

Cellular prion protein (PrP(c)) gene (Prnp) null mice (Prnp0/0) show higher sensitivity to seizures, enhanced brain oxidative stress, and their neurons exhibit higher excitability "in vitro". Mitochondrial respiration is a useful parameter for the determination of cellular metabolic rate and it is a major source of reactive oxygen species (ROS). In the present study, we investigated the mitochondrial function of different brain areas of Prnp0/0 adult mice and then compared this to normal control animals. Baseline mitochondrial respiration (stages 3 and 4), respiratory control ratio (RCR) and membrane potential were evaluated in the neocortex, entorhinal cortex, hippocampus, and cerebellum. No differences in these parameters were detected between Prnp0/0 and wild-type mice. Thus, we concluded that baseline mitochondrial respiration might not be directly related with the higher oxidative stress previously observed in brains from Prnp0/0 mice.

Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to evaluate the modulation on hippocampal nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on short- and long-term memory. Immediately after training, animals received 5 microl of NGF (0.05, 0.5 or 5.0 ng), bFGF (1.25, 12.5 or 125 ng) or saline per side. At the higher dose, NGF blocked STM. In contrast, NGF at dose of 0.5 and 5.0 ng improved LTM. The bFGF infusion at a dose of 125 ng enhanced LTM. However, bFGF did not alter STM. These findings indicate that hippocampal NGF and bFGF modulate STM and LTM in a different manner.

Psychosis is commonly observed in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). Interictal single photon emission computed tomography (SPECT) was performed to compare regional cerebral blood flow (rCBF) pattern of MTLE-HS patients with psychosis of epilepsy (POE) comorbidity and MTLE-HS patients without any psychiatric disorders (Control group). For this, 21 patients with POE and 23 Control patients were matched by educational level, clinical, demographic, electrophysiological, and MRI data. SPECT scans were acquired using (99m)Tc and interpreted with a semiquantitative method. We analyzed brain regions of interest (ROI) of frontal, temporal, and parietal cortex, in addition to subcortical structures. There were no significant statistical differences of ROI between the POE group and the Control group after Bonferroni adjustment. However, we observed a trend for rCBF increase of right posterior cingulate in the POE Group. This increase would be in accordance with recent findings of cingulate abnormalities in schizophrenia, suggesting that abnormal function in this region might be associated with the psychotic phenomena.

Mutations in the human prion protein gene (PRNP) are responsible for hereditary diseases called transmissible spongiform encephalopathies (TSE) and a polymorphic site at codon 129 determines sensitivity to infectious forms of these maladies. More recently, codon 129 has been related to cognition performance in the elderly, in Alzheimer disease (AD) and in Down syndrome. Furthermore, a rare polymorphism at codon 171 was described in 23% of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS), the most common form of surgically remediable epileptic syndrome. Thus, a method that permits fast and efficient screening of PRNP mutations and polymorphisms in patients, in high risk populations, and in family members is desirable. In the present study, we established the conditions for analysis of the PRNP open reading frame using denaturing high-performance liquid chromatography (DHPLC), whereby unpurified PCR products were subjected to denaturing and reannealing steps leading to heteroduplex formation. We described specific profiles for the PRNP polymorphisms at codons 129 (M/V), 117 (A/A silent), 219 (E/K), 171 (N/S), and the octarepeat deletion using amplified DNA from 562 samples. The chromatograms for TSE-associated mutations at codons 102 (P/L), 183 (T/A), and 210 (V/I) were also determined. Specificity of the DHPLC profile for each PRNP variant allele was confirmed in 100% of the samples by direct and cloned DNA sequencing in addition to endonuclease digestion when applicable. Therefore, the present study shows that DHPLC is a rapid, highly accurate and efficient technique for the detection of PRNP genetic variants.

Background: While it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model., Results: SAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area., Conclusions: Our data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study.

Typical (TPP) and atypical (APP) perfusion patterns (PP) may be seen in ictal SPECT of patients with temporal lobe epilepsy (TLE). APP may pose problem in the lateralization of the epileptogenic zone (EZ). We aimed to investigate predictive variables for the occurrence of TPP and APP. Fifty-one TLE patients were submitted to successful anterior-mesial temporal lobectomy. Univariate (UVA) and multivariate (MVA) analysis were performed upon clinical data, distribution of interictal spikes, and ictal chronology of seizures. From MVA, a final predictive model (FPM) was determined to better predict TPP and APP. Forty patients showed TPP (78.5%) and 11 patients APP (21.5%). Accuracy of ictal SPECT was higher in the unilateral (UIS) than in the bilateral (BIS) interictal spikes group (P = 0.05). FPM showed that patients exhibiting BIS, with shorter proportion of the electrographic seizure occurring after completion of tracer injection, and longer clinical than EEG seizure duration had more APP (P = 0.003). Generalized tonic-clonic seizures did not result in more APP. We concluded that analysis of ictal SPECT in TLE requires the knowledge of TPP and APP, the distribution of interictal spikes on temporal lobes and the ictal chronology of seizures. BIS showed that beyond a more complex epileptogenicity and seizure propagation, they may also lead to APP.

Background: Neurocysticercosis (NCC) is the most common parasitic disease of the human central nervous system and a major health problem for most developing countries. The most common clinical manifestations of NCC are epileptic seizures. Whenever epilepsy and NCC coexist in the same patient, an uncertainty may rise about a causal relationship between them., Observation: We described a female patient with disseminated calcified NCC lesions and intractable epilepsy. Her medical history included cysticercotic meningoencephalitis and status epilepticus caused by active NCC. Fundoscopy showed the ocular presence of parasite; computed tomography of the brain showed evidence of cystic lesions with the scolex and calcified lesions; enzyme-linked immunosorbent assay of the cerebrospinal fluid was positive for cysticercosis. Epileptic seizures started after an 8-year silent period. Magnetic resonance imaging showed left hippocampal sclerosis. Plain x-ray film showed calcifications in muscles and subcutaneous tissue. Video-electroencephalography and ictal and interictal single-photon emission computed tomography disclosed left mesial temporal lobe epilepsy. The patient underwent left temporal lobectomy and has been seizure free since surgery, for a follow-up of 4 years., Conclusion: This case report highlights and supports surgical therapy in patients with epileptic seizures and calcified NCC, even when there are several calcifications, provided that clear localization of epilepsy has been determined by means of a presurgical workup.

Epilepsy is one of the main causes of functional disability, and it is usually associated to psychiatric comorbidity, such as psychosis of epilepsy (POE). POE requires more careful pharmacological treatment, considering the propensity of the antipsychotics (AP) to provoke seizures and the risk of pharmacokinetic interaction with anti-epileptic drugs (AEDs). We discussed the classification and the main types of POE, as well as some characteristics of AP typical and atypical, its potential to decrease the epileptogenic threshold (ET) and possible interactions between AP and AED. Atypical AP, except clozapine, disclosed smaller influence on ET than typical AP. Regarding pharmacokinetic interactions, AEDs are related with a significant increase of the AP metabolism. Therefore, in spite of the risk for AP induced convulsions be dose-dependent, higher doses of AP can be necessary in the treatment of POE.

The authors review the clinical, radiological, electrophysiological, pathological, and molecular aspects of Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy or PLOSL). Nasu-Hakola disease is a unique disease characterized by multiple bone cysts associated with a peculiar form of neurodegeneration that leads to dementia and precocious death usually during the fifth decade of life. The diagnosis can be established on the basis of clinical and radiological findings. Recently, molecular analysis of affected families revealed mutations in the DAP12 (TYROBP) or TREM2 genes, providing an interesting example how mutations in two different subunits of a multi-subunit receptor complex result in an identical human disease phenotype. The association of PLOSL with mutations in the DAP12 or TREM2 genes has led to improved diagnosis of affected individuals. Also, the possible roles of the DAP12/TREM2 signaling pathway in microglia and osteoclasts in humans are just beginning to be elucidated. Some aspects of this peculiar signaling pathway are discussed here.

Adenosine has been shown to be a major regulator in convulsive disorders exerting its anticonvulsant effects on various seizure models. The ectonucleotidase pathway is an important metabolic source of extracellular adenosine. In this study, we evaluated ATP, ADP and AMP hydrolysis in rat serum after a single convulsive injection of pentylenetetrazol (PTZ). The animals were sacrificed at 5 and 30 min, 1, 5, 12, 24 and 48 h after an intraperitoneal injection of PTZ (60 mg/kg). ATP, ADP and AMP hydrolysis by rat blood serum were significantly increased (40-50%) until 24 h after PTZ injection. There were no significant differences in the nucleotide hydrolysis when the in vitro effect of different concentrations of PTZ was analyzed. Changes in nucleotide hydrolysis observed after acute administration of PTZ could not be attributed to phosphodiesterase activity since PTZ-treated rats did not demonstrate significant differences in the hydrolysis of the substrate marker of this enzyme when compared with control rats. These results suggest that the stimulation of the nucleotidase pathway may play an important role in attenuating seizure activity.

1. Cellular prion (PrPc) is a plasma membrane protein involved with copper uptake, protection against oxidative stress, cell adhesion, differentiation, signaling, and survival in the central nervous system. 2. Deletion of PrPc gene (Pmp) in mice enhances sensitivity to seizures in vivo and neuronal excitability in vitro which can be related to: (i) disrupted Ca(+2)-activated K+ currents, with loss of IHAP conductance in hippocampus; (ii) abnormal GABA-A inhibition in the hippocampus; (iii) mossy fiber reorganization in the hippocampus; (iv) changes in ectonucleotidases in both hippocampus and neocortex; and (v) higher levels of neocortical and subcortical oxidative stress. Moreover, postnatal Prnp knockout mice showed a significant reduction of after hyperpolarization potentials in hippocampal CA1 cells. 3. Taken together, these findings suggest that loss of PrPc function contributes to the hyperexcitable and synchronized activities underlying epileptic seizures generated in neocortex and hippocampus. Hence, the role of PrPc on human symptomatic, cryptogenic or idiopathic epileptic syndromes deserves further investigation.

Cellular prion (PrPc) is a plasma membrane glycosyphosphatidylinositol-anchored protein present in neurons but also in other cell types. Protein conservation among species suggests that PrPc may have important physiological roles. Cellular and molecular approaches have established several novel features of the regulation of PrPc expression, cellular trafficking as well as its participation in copper uptake, protection against oxidative stress, cell adhesion, differentiation, signaling and cell survival. It is therefore likely that PrPc plays pleiotropic roles in neuronal and non-neuronal cells, and as such the loss of function of PrPc may be an important component of various diseases.

S100B is an astrocytic calcium-binding protein which has been proposed as a biochemical marker of brain damage or dysfunction in acute and chronic diseases. We investigated whether serum S100B levels could be related to systemic lupus erythematosus (SLE) activity. Patients were grouped as having inactive SLE (ISLE), active SLE without central nervous system (CNS) involvement (ASLE), or active SLE with unequivocal neurologic or psychiatric manifestation (NPSLE). The control group consisted of age- and sex-matched healthy blood donors. S100B levels were determined using a luminescence immunoassay. All SLE groups had higher levels of serum S100B than the control group. Among the SLE groups, significantly higher levels of serum S100B protein were found in the NPSLE group than in the ISLE and ASLE groups, and there was no significant difference in S100B levels between the ISLE and ASLE groups. These preliminary results point to a putative relevance of serum S100B protein levels in SLE patients, specifically concerning CNS involvement present in this disease.