Kainate-induced zinc translocation from presynaptic terminals causes neuronal and astroglial cell death and mRNA loss of BDNF receptors in the hippocampal formation and amygdala

To evaluate the potential role of endogenous zinc in the pathophysiology of epilepsy, we injected kainic acid into the medial septum, which evokes seizure activity and delayed hippocampal degeneration. Different approaches were used. In the hippocampus, we found a movement of zinc from the synaptic compartment to CA1 pyramidal neurons and astrocytes after kainate. The same was true in the amygdala. We found that in those areas showing intense zinc bleaching there was also a loss of reactive astrocytes, which supports the view that release of synaptic zinc induces astrocytic cell death. We have also tested whether the kainate-induced zinc movement from the synaptic compartment to neuronal or glial cells alters the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, trkB. There was a prominent loss of expression of trkB mRNA in areas that coincided precisely with those displaying astrocyte loss and zinc bleaching. In the amygdala, these events were accompanied by a high upregulation of BDNF mRNA. To demonstrate further a role of synaptic zinc in hippocampal pathology, we used two different approaches. We first injected different doses of zinc chloride in the CA1 area. At lower doses (0.1-10 nmol), zinc chloride selectively induced apoptosis in CA1 pyramidal neurons and dentate granular neurons. In a second approach, we found that hippocampal zinc chelation was effective in protecting CA1 pyramidal neurons against kainate-induced cell death.     

Acute and repeated restraint stress influences cellular damage in rat hippocampal slices exposed to oxygen and glucose deprivation

Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress+OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.     

Clinical features of patients with posterior cortex epilepsies and predictors of surgical outcome

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.     

Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A -D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.     

Detailed exploration of face-related processing in congenital prosopagnosia: 2. Functional neuroimaging findings

Specific regions of the human occipito-temporal cortex are consistently activated in functional imaging studies of face processing. To understand the contribution of these regions to face processing, we examined the pattern of fMRI activation in four congenital prosopagnosic (CP) individuals who are markedly impaired at face processing despite normal vision and intelligence, and with no evidence of brain damage. These individuals evinced a normal pattern of fMRI activation in the fusiform gyrus (FFA) and in other ventral occipito-temporal areas, in response to faces, buildings, and other objects, shown both as line drawings in detection and discrimination tasks and under more naturalistic testing conditions when no task was required. CP individuals also showed normal adaptation levels in a block-design adaptation experiment and, like control subjects, exhibited evidence of global face representation in the FFA. The absence of a BOLD-behavioral correlation (profound behavioral deficit, normal face-related activation in the ventral occipito-temporal cortex) challenges existing accounts of face representation, and suggests that activation in these cortical regions per se is not sufficient to ensure intact face processing.     

Increased mitochondrial respiratory chain enzyme activities correlate with minor extent of liver damage in mice suffering from erythropoietic protoporphyria

Mitochondrial dysfunction might play a role in the pathogenesis of liver damage in erythropoietic protoporphyria (EPP). Changes in mitochondrial respiratory chain activities were evaluated in the Fech(m1pas)/Fech(m1pas) mouse model for EPP. Mice from different strains congenic for the same ferrochelatase germline mutation manifest variable degrees of hepatobiliary injury. Protoporphyric animals bred into the C57BL/6J background showed a higher degree of hepatomegaly and liver damage as well as higher protoporphyrin (PP) accumulation than those bred into the SJL/J and BALB/cJ backgrounds. Whereas mitochondrial respiratory chain activities remained unchanged in the liver of protoporphyric mice C57BL/6J, they were increased in protoporphyric mice from both SJL/J and BALB/cJ backgrounds, when compared to wild-type animals. Mitochondrial respiratory chain activities were increased in Hep G2 cell line after accumulation of PP following addition of aminolevulinic acid. As a direct effect of these elevated mitochondrial activities, in both hepatic cells from mutant mouse strains and Hep G2 cells, adenosine 5'-triphosphate (ATP) levels significantly increased as the intracellular PP concentration was reduced. These results indicate that PP modifies intracellular ATP requirements as well as hepatic mitochondrial respiratory chain enzymatic activities and further suggest that an increase of these activities may provide a certain degree of protection against liver damage in protoporphyric mice.     

Lack of inhibition in Parkinson's disease: evidence from a lexical decision task

Persons affected by Parkinson's disease (PD) often show an increased semantic priming effect from target words in lexical decision tasks (hyper-priming) as compared to age-matched controls. In this study, a lexical decision task was used to investigate both semantic priming (Experiment 1) and repetition priming (Experiment 2) from distractor words in PD patients and age-matched controls. With this negative priming procedure, target words in successive trials are never related, and therefore participants always have to switch between unrelated target words. Instead, it is the distractor prime word that is either related or unrelated to the subsequent target, giving the measure of priming. Results showed that PD patients demonstrated a robust effect of positive semantic priming from distractor words. Participants from the control group did not show any semantic priming effect (positive or negative) from distractors. Similarly, PD patients showed positive repetition priming from distractor words, but the control group showed significant repetition negative priming. These results support the view that the hyper-priming effect typically shown by persons with Parkinson's disease is the result of impaired inhibitory processes required to control word activation during reading.