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Biomedical subjects

E A Cavalheiro

Publications and source records attributed to E A Cavalheiro.

At least 19 recordsLinked to original sources
PubMed2006

Cerebrospinal fluid GABA levels in chronic migraine with and without depression.

Psychiatric comorbidity is one of the key elements in chronic migraine (CM) management. Depression is particularly common in these patients, occurring in up to 85%. Preclinical studies have suggested that gamma-aminobutyric acid (GABA) levels may be decreased in animal models of depression. Also, clinical studies have reported low level in mood disorder patients for both plasma and cerebrospinal fluid (CSF) GABA. We hypothesized that low GABA levels in the brain might be related to the depression associated with CM. We studied 14 chronic migraine patients, with or without depression, compared to age-and sex-matched controls. CSF GABA levels were measured by HPLC. CSF GABA levels showed significant lower levels in depressed patients than those without depression. No difference was found when comparing patients versus controls. A GABA deficiency may be the underlying mechanism of depression in CM. Hence, preventive therapies modulating GABA neurotransmission could be used in CM associated with depression.

Brain↗
PubMed2005

Expression of nestin in the hippocampal formation of rats submitted to the pilocarpine model of epilepsy.

Nestin is an embryonic intermediate filament component protein, transiently expressed by the immediate precursor cells of neurons and glia, during brain development. We studied the nestin distribution in the hippocampal formation of rats submitted to pilocarpine model of epilepsy. Animals were studied during the acute, silent and chronic phases. Rats from control and acute groups presented absence of nestin-immunoreactivity (IR) in the hippocampal cells. In contrast, cells from this region presented strong nestin IR during the silent phase (3 and 7 days after status epilepticus (SE) onset), disappearing 14 days after SE. Nestin IR cells were scattered expressed in all hippocampal formation during the chronic phase. Almost all nestin IR cells exhibited glial fibrillary acidic protein (GFAP), which seems to revert to a more primitive glial form, as part of an adaptive response, transiently re-expressing phenotypic features typical of earlier stages of glial development. The re-expression of this developmental protein in the damaged cerebral tissue suggests that nestin may play an important role in the reconstruction of the glial cytoskeleton and/or remodeling events occurring in the pilocarpine model of epilepsy. Understanding how astrocytes influence network function in the injured hippocampus may, therefore, provide insight into epileptogenic mechanisms.

Animals↗
PubMed2004

Succinate increases neuronal post-synaptic excitatory potentials in vitro and induces convulsive behavior through N-methyl-d-aspartate-mediated mechanisms.

Succinate is a dicarboxylic acid that accumulates due to succinate dehydrogenase inhibition by malonate and methylmalonate exposure. These neurotoxins cause increased excitability and excitotoxic damage, which can be prevented by administering high amounts of succinate. In the present study we investigated whether succinate alters hippocampal field excitatory post-synaptic potentials. Bath application of succinate at intermediate concentrations (0.3-1 mM) increased the slope of field excitatory post-synaptic potentials in hippocampal slices, and at high concentrations (above 1 mM) did not alter or decrease field excitatory post-synaptic potentials slope. Succinate-induced enhancement of field excitatory post-synaptic potentials slope was abolished by the addition of d-2-amino-5-phosphonovaleric acid (50 microM) to the perfusate, supporting the involvement of N-methyl-d-aspartate receptors in the excitatory effect of this organic acid. Accordingly, succinate (0.8-7.5 micromol) i.c.v. administration caused dose-dependent convulsive behavior in mice. The i.c.v. co-administration of MK-801 (7 nmol) fully prevented succinate-induced convulsions, further suggesting the involvement of N-methyl-d-aspartate receptors in the convulsant action of succinate. Our data indicate that accumulation of moderate amounts of succinate may contribute to the excitotoxicity induced by succinate dehydrogenase inhibitors, through the activation of N-methyl-d-aspartate receptors.

Animals↗
PubMed2004

Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons.

Mcl1 is a Bcl2-related antiapoptotic protein originally isolated from human myeloid leukemia cells. Unlike Bcl2, expression has not been reported in CNS neurons. We isolated Mcl1 in a direct screen for candidate modifier genes of neuronal vulnerability by differential display of mRNAs upregulated following prolonged seizures in two mouse strains with contrasting levels of hippocampal cell death. Mcl1 is widely expressed in neurons, and transcription is rapidly induced in both strains. In resistant C57Bl/6J mice, Mcl1 protein levels remain persistently elevated in hippocampal pyramidal neurons after seizures, but fall rapidly in C3H/HeJ hippocampus, coinciding with extensive neuronal apoptosis. DNA damage and caspase-mediated cell death were strikingly increased in Mcl1-deficient mice when compared to +/+ littermates after similar seizures. We identify Mcl1 as a neuronal gene responsive to excitotoxic insult in the brain, and link relative levels of Mcl1 expression to inherited differences in neuronal thresholds for apoptosis.

Animals↗
PubMed2003

Absence-like seizures in adult rats following pilocarpine-induced status epilepticus early in life.

Administration of pilocarpine causes epilepsy in rats if status epilepticus (SE) is induced at an early age. To determine in detail the electrophysiological patterns of the epileptogenic activity in these animals, 46 Wistar rats, 7-17 days old, were subjected to SE induced by pilocarpine and electro-oscillograms from the cortex, hippocampus, amygdala, thalamus and hypothalamus, as well as head, rostrum and vibrissa, eye, ear and forelimb movements, were recorded 120 days later. Six control animals of the same age range did not show any signs of epilepsy. In all the rats subjected to SE, iterative spike-wave complexes (8.1 0.5 Hz in frequency, 18.9 9.1 s in duration) were recorded from the frontal cortex during absence fits. However, similar spike-wave discharges were always found also in the hippocampus and, less frequently, in the amygdala and in thalamic nuclei. Repetitive or single spikes were also detected in these same central structures. Clonic movements and single jerks were recorded from all the rats, either concomitantly with or independently of the spike-wave complexes and spikes. We conclude that rats made epileptic with pilocarpine develop absence seizures also occurring during paradoxical sleep, showing the characteristic spike-wave bursts in neocortical areas and also in the hippocampus. This is in contrast to the well-accepted statement that one of the main characteristics of absence-like fits in the rat is that spike-wave discharges are never recorded from the hippocampal fields.

Animals↗
PubMed2002

Protective effect of systemic treatment with cyclosporine A after global ischemia in rats.

Systemic administration of cyclosporine A (CsA) in single daily doses provides a powerful protection to the ischemic rat brain only to sites where the blood-brain barrier (BBB) is disrupted. This study was aimed at evaluating the effectiveness of prolonged treatment and multiple daily doses of systemic CsA following transient global ischemia in rats without BBB breakdown. Multiple daily doses selectively enhanced cell survival at 7-day recovery in regions displaying delayed neuronal death (DND). The effect was dose dependent, enhanced by prolonging the treatment or further fractionating daily doses, and not accompanied by drug-induced hypothermia. These results suggest that CsA-susceptible immune mediators of DND may be active during the first days following transient global ischemia. Conversely, postischemic hyperthermia may enhance and/or perpetuate similar mechanisms and trigger Alzheimer-like neurodegeneration, as recently reported.

Animals↗
PubMed2002

Deficit in hippocampal long-term potentiation in monosodium glutamate-treated rats.

Rats subjected to monosodium glutamate (MSG) administration during the neonatal period present chronic neuroendocrine dysfunction associated with marked cognitive deficits. Long-term potentiation (LTP) in the hippocampus provides a model suited for the study of mammalian brain plasticity and memory formation. In the present work, we used the LTP protocol to investigate the synaptic plasticity in the hippocampal CA1 area of adult rats subjected to MSG treatment during the first 10 days of life. Synaptic transmission in CA1 area was analyzed using extracellular field recordings in response to Schaffer's collateral fiber stimulation in hippocampal slices. Animals injected with MSG exhibited a dramatic decrement of LTP field excitatory postsynaptic potentials (fEPSPs) compared to control group. Analysis of percent enhancement of fEPSP slope at 2 min after high frequency stimulation (HFS) increased by 189.3 +/- 33.2% in slices from control rats and 129.45 +/- 18.5% (p < 0.01) in slices from MSG-treated rats. Additionally, MSG-treated animals failed to maintain or consolidate LTP as revealed by a significant reduction in fEPSP slope enhancement over time after HFS. The mean fEPSP slope, 60 min after HFS, was 154.28 +/- 21% of the average baseline slope in control slices versus only 124.4 +/- 15% in MSG-treated rats (p < 0.01). At 90 min after HFS, slices from controls reached a potentiation of 44.5 +/- 2.9%, whereas the MSG group displayed an overall response enhancement of 17.65 +/- 2.7% of basal levels (p < 0.01). These findings indicate that MSG-treated rats display a chronic impairment of CA1 synaptic plasticity.

Aging↗
PubMed2002

Glycosaminoglycan levels and proteoglycan expression are altered in the hippocampus of patients with mesial temporal lobe epilepsy.

Extracellular matrix proteoglycans (PGs) and glycosaminoglycans (GAGs) play a crucial role in cell differentiation and synaptogenesis by modulating neurite outgrowth. The chondroitin sulfate (CS)-rich PG, the receptor protein tyrosine phosphatase zeta/beta (RPTP zeta/beta), has been related to neural morphogenesis and axon guidance. Hippocampal sclerosis is the most frequent pathologic finding in patients with intractable mesial temporal lobe epilepsy (MTLE), which is associated with neuron loss, reactive gliosis, and mossy fiber sprouting. In the present study, we investigated the concentration of CS, heparan sulfate (HS) and hyaluronic acid (HA) in the hippocampus and temporal neocortex as well as RPTP zeta/beta expression in the hippocampus of patients with MTLE. Compared to autopsy control tissue, epileptic hippocampi showed a significantly increased concentration of CS (224%; p=0.0109) and HA (146%; p=0.039). HS was instead similar to control values. No differences were found in the concentration of CS, HS, or HA in the temporal neocortex of epileptic patients when compared to control values. In contrast, RPTP zeta/beta immunoreactivity was induced in astrocytes of the inner molecular layer of the dentate gyrus of the sclerotic hippocampus. Because matrix compounds have been associated with tissue injury and repair, the present findings suggest that changes in PGs and GAGs might be related to damage-induced gliosis and neuronal reorganization in the hippocampus of MTLE patients.

Adult↗
PubMed2002

Alterations of the neocortical GABAergic system in the pilocarpine model of temporal lobe epilepsy: neuronal damage and immunocytochemical changes in chronic epileptic rats.

A wealth of previous studies reported pathological alterations in extrahippocampal regions in mesial temporal lobe epilepsy. Previous experimental findings have also demonstrated that the entorhinal cortex and the neocortex are damaged in different animal models of acute limbic seizures. The present study was aimed at verifying possible alterations in neocortical areas, and, in particular, structural changes of GABAergic interneurons in the sensorimotor cortex, in pilocarpine-induced chronic epilepsy in the rat. Series of sections were Nissl stained and processed for immunocytochemistry using antibodies that recognize nonphosphorylated neurofilament (SMI311), glial fibrillary acidic protein (GFAP), the calcium-binding protein parvalbumin (PV) which is expressed by a subset of cortical GABAergic neurons, the GABA transporter (GAT1), and isoform 65 of glutamic acid decarboxylase (GAD65), the GABA synthetic enzyme. Epileptic rats showed decreased cortical thickness, and diffuse gliosis was observed with GFAP antibody. Neurofilament alterations were also detected in sections processed using SMI311 antiserum. In addition, a diffuse decrease of PV, GAD65, and GAT1 immunoreactivity was observed in the sensorimotor cortex. Altered expression of PV, GAD65, and GAT1 pointed out specific neocortical disturbances in GABAergic inhibition, which could play a crucial role in seizure generation and expression. Thus, the present findings indicate that damage of GABAergic interneurons could be strictly associated with neocortical hyperexcitability in temporal lobe epilepsy.

Animals↗
PubMed2002

Postischemic hyperthermia induces Alzheimer-like pathology in the rat brain.

This study addresses the effects of induced hyperthermia on post-ischemic rat brain evaluated histologically and/or immunohistochemically after 7-day, 2-month or 6-month survival. Hyperthermia (38.5 degrees - 40 degrees C) maintained (by heating the cage environment to 34-35 degrees C) for two consecutive periods of 5 and 9 h timed, respectively, from 4- and 21-h recirculation following 10-min global ischemia (two-vessel occlusion + hypotension) induced chronic neuronal death that became apparent in the rat forebrain from 7-day to 2-month survival. Associated immunohistochemical findings after 2 or 6 months of recovery included: (1) complement activation (membrane attack complex formation); (2) generalized overexpression of ubiquitin in surviving forebrain neurons; (3) persistent activation of macrophages; (4) presence of gemistocytic astrocytes in the hippocampus; (5) maturation of amyloid plaques (identified by immunohistochemistry using anti-human beta-A4 primary antibody) in cerebral cortex; and (6) intracellular deposits identified by anti-human hyperphosphorylated tau protein antibodies. This novel non-transgenic, self-sustained model of neurodegeneration triggered by the association of two prevalent insults to the aging human brain (ischemia and hyperthermia) presents morphological features similar to those of Alzheimer's disease. This finding raises the possibility that febrile complications of acute brain injuries may similarly impair human cognitive function in the long run.

Alzheimer Disease↗
PubMed2002

Castration in female rats modifies the development of the pilocarpine model of epilepsy.

Previous studies have shown that the susceptibility to pilocarpine-induced status epilepticus (SE) in female rats changes according to estrous cycle phases. These studies have also shown that following pilocarpine administration changes occur in gonadal, hypophyseal and hypothalamic hormones that could contribute for the sequence of the epileptic events. Accordingly, the present work aimed to investigate the role of sexual hormones withdrawal on the development of the pilocarpine model of epilepsy in female rats. With this purpose, castrated and non-castrated adult female Wistar rats were injected with pilocarpine and some characteristic parameters of the experimental model were observed. The results showed increased mortality after pilocarpine injection in the castrated rats when compared with non-castrated females. The latency period for SE onset and for the first spontaneous seizure was decreased in castrated when compared with non-castrated animals. The mossy fiber sprouting measured by neo-Timm scale during the chronic period, reached grade 3 for castrated epileptic rats while the non-castrated epileptic rats showed grade 2. Our results indicate that castration interferes with the epileptogenesis in the pilocarpine model of epilepsy suggesting that female sexual hormones could have protective effects against pilocarpine-induced SE.

Animals↗
PubMed2002

New insights from the use of pilocarpine and kainate models.

Local or systemic administration of pilocarpine and kainate in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, which can last for several hours. A latent period follows status epilepticus and precedes a chronic phase, which is characterized by the occurrence of spontaneous limbic seizures. These distinct features, in a single animal preparation, of an acute damage induced by status epilepticus, a silent interval between injury and the onset of spontaneous seizures, and a chronic epileptic state have allowed antiepileptic drug (AED) studies with different purposes, (a) in the acute phase, identification of compounds with efficacy against refractory status epilepticus and/or neuroprotection against damage induced by sustained seizures; (b) in the latent period, identification of agents with a potential for preventing epileptogenesis and/or against seizure-induced long-term behavioral deficits and (c) in the chronic phase, testing drugs effective against partial and secondarily generalized seizures. Studies on pilocarpine and kainate models have pointed out that some AEDs or other compounds exert an antiepileptogenic effect. The analogy of the latent phase of pilocarpine and kainate models with the acquisition of amygdala kindling should encourage testing of drugs that have proved to suppress the evolution of amygdala kindling. Drug testing in the chronic phase should not address only the suppression of secondarily generalized motor seizures. Most of current tools used to quantify spontaneous seizure events need to be coupled to electrophysiology and more sophisticated systems for recording and analyzing behavior.

Animals↗
PubMed2002

Evidence that ATP participates in the pathophysiology of pilocarpine-induced temporal lobe epilepsy: fluorimetric, immunohistochemical, and Western blot studies.

PURPOSE: This study was performed to study the role of adenosine triphosphate (ATP) in the brain of pilocarpine-induced chronic epileptic rats. METHODS: ATP-mediated changes in intracellular calcium were studied by the fura-2 method. Immunohistochemistry and Western blotting methods were used to localize and quantify P2X7 receptors in these animals. RESULTS: The fluorimetric study in chronic rats revealed a biphasic response indicating the presence of P2X7 receptors. The Western blotting study showed an increase of 80% of P2X7 expression in chronic rats compared with the control group. P2X7 immunoreactivity resembled mossy fiber sprouting at the dentate gyrus of epileptic animals. CONCLUSIONS: These results suggest that purinergic receptors may participate in the pathophysiology of temporal lobe epilepsy.

Adenosine Triphosphate↗
PubMed2002

Extracellular matrix components are altered in the hippocampus, cortex, and cerebrospinal fluid of patients with mesial temporal lobe epilepsy.

PURPOSE: This work studied the profile of glycosaminoglycans (GAGs) in the hippocampus, cortex, and cerebrospinal fluid of patients with temporal lobe epilepsy (TLE). METHODS: The GAGs were analyzed by agarose gel electrophoresis, enzymatic degradation, and enzyme-linked immunosorbent assay (ELISA). RESULTS: The hippocampus of TLE patients showed increased levels of chondroitin sulfate and hyaluronic acid against normal levels of these GAGs in the neocortex and cerebrospinal fluid (CSF). CONCLUSIONS: These results suggest that these matrix components could be involved in the pathophysiology of TLE.

Cerebral Cortex↗
PubMed2001

The spiny rat Proechimys guyannensis as model of resistance to epilepsy: chemical characterization of hippocampal cell populations and pilocarpine-induced changes.

At variance with pilocarpine-induced epilepsy in the laboratory rat, pilocarpine administration to the tropical rodent Proechimys guyannensis (casiragua) elicited an acute seizure that did not develop in long-lasting status epilepticus and was not followed by spontaneous seizures up to 30 days, when the hippocampus was investigated in treated and control animals. Nissl staining revealed in Proechimys a highly developed hippocampus, with thick hippocampal commissures and continuity of the rostral dentate gyri at the midline. Immunohistochemistry was used to study calbindin, parvalbumin, calretinin, GABA, glutamic acid decarboxylase, and nitric oxide synthase expression. The latter was also investigated with NADPH-diaphorase histochemistry. Cell counts and densitometric evaluation with image analysis were performed. Differences, such as low calbindin immunoreactivity confined to some pyramidal cells, were found in the normal Proechimys hippocampus compared to the laboratory rat. In pilocarpine-treated casiraguas, stereological cell counts in Nissl-stained sections did not reveal significant neuronal loss in hippocampal subfields, where the examined markers exhibited instead striking changes. Calbindin was induced in pyramidal and granule cells and interneuron subsets. The number of parvalbumin- or nitric oxide synthase-containing interneurons and their staining intensity were significantly increased. Glutamic acid decarboxylase(67)-immunoreactive interneurons increased markedly in the hilus and decreased in the CA1 pyramidal layer. The number and staining intensity of calretinin-immunoreactive pyramidal cells and interneurons were significantly reduced. These findings provide the first description of the Proechimys hippocampus and reveal marked long-term variations in protein expression after an epileptic insult, which could reflect adaptive changes in functional hippocampal circuits implicated in resistance to limbic epilepsy.

Animals↗
PubMed2001

Superoxide dismutase, glutathione peroxidase activities and the hydroperoxide concentration are modified in the hippocampus of epileptic rats.

The relationship between free radical and scavenger enzymes has been found in the epileptic phenomena and reactive oxygen species have been implicated in seizure-induced neurodegeneration. Using the epilepsy model obtained by systemic administration of pilocarpine (PILO) in rats, we investigated the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities as well as the hydroperoxide (HPx) concentration in the hippocampus of rats during status epilepticus (SE), silent and chronic periods. The enzyme activities as well as the HPx concentration were measured using spectrophotometric methods and the results compared to values obtained from saline-treated animals. The SOD activity decreased after long-lasting SE period and during the chronic phase. In addition, HPx levels increased in same periods whereas the GPx activity increased only in the hippocampus of animals submitted to 1 h of SE. Animals presenting partial seizures, those submitted to 5 h of SE and animals from the silent period (seizure free) showed normal levels of SOD, GPx and HPx. These results show a direct evidence of lipid peroxidation during seizure activity that could be responsible for neuronal damage in the hippocampus of rats, during the establishment of PILO model of epilepsy.

Animals↗
PubMed2001

Behavioral and electroencephalographic analysis of seizures induced by intrahippocampal injection of granulitoxin, a neurotoxic peptide from the sea anemone Bunodosoma granulifera.

In this study, the behavioral and electroencephalographic (EEG) analysis of seizures induced by the intrahippocampal injection in rats of granulitoxin, a neurotoxic peptide from the sea anemone Bunodosoma granulifera, was determined. The first alterations occurred during microinjection of granulitoxin (8 microg) into the dorsal hippocampus and consisted of seizure activity that began in the hippocampus and spread rapidly to the occipital cortex. This activity lasted 20-30 s, and during this period the rats presented immobility. During the first 40-50 min after its administration, three to four other similar short EEG seizure periods occurred and the rats presented the following behavioral alterations: akinesia, facial automatisms, head tremor, salivation, rearing, jumping, barrel-rolling, wet dog shakes and forelimb clonic movements. Within 40-50 min, the status epilepticus was established and lasted 8-12 h. These results are similar to those observed in the acute phase of the pilocarpine model of temporal lobe epilepsy and suggest that granulitoxin may be a useful tool not only to study the sodium channels, but also to develop a new experimental model of status epilepticus.

Animals↗