Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis

Recent evidence shows that neuropeptide expression in the CNS is markedly affected by seizure activity, particularly in the limbic system. Changes in neuropeptides in specific neuronal populations depend on the type and intensity of seizures and on their chronic sequelae (i.e. neurodegeneration and spontaneous convulsions). This paper reviews the effects of seizures on somatostatin-containing neurons, somatostatin mRNA and immunoreactivity, the release of this peptide and its receptor subtypes in the CNS. Differences between kindling and status epilepticus in rats are emphasized and discussed in the light of an inhibitory role of somatostatin on hippocampal excitability. Pharmacological studies show that somatostatin affects electrophysiological properties of neurons, modulates classical neurotransmission and has anticonvulsant properties in experimental models of seizures. This peptidergic system may be an interesting target for pharmacological attempts to control pathological hyperactivity in neurons, thus providing new directions for the development of novel anticonvulsant treatments.     

The oncogene phosphatidylinositol 3'-kinase catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma

The gene of phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) has been implicated as an oncogene in ovarian cancer [L. Shayesteh et al., Nat. Genet., 21: 99-102, 1999]. In this study, we examined the expression of PIK3CA mRNA and its p110alpha protein product in human ovarian carcinoma and investigated its role in regulating angiogenesis via vascular endothelial growth factor (VEGF). PIK3CA mRNA was detected in 66.6% of stage I and 93.9% of advanced stage ovarian cancer specimens and in all 17 ovarian cancer cell lines. PIK3CA mRNA levels were significantly higher in invasive carcinomas compared with benign and low malignant potential neoplasms (P = 0.007), but no significant difference was seen between early and advanced stage carcinomas (P = 0.812). Strong expression of immunoreactive p110alpha was detected in tumor cells and/or stroma endothelium. PIK3CA expression in vivo positively correlated, both at the mRNA and the protein level, with the expression of VEGF as well as with the extent of microvascular development. Furthermore, PIK3CA mRNA overexpression positively correlated with increased proliferation and decreased apoptosis of tumor cells in vivo. In vitro, PIK3CA expression positively correlated with the expression of VEGF in ovarian cancer cells, whereas the phosphatidylinositol 3'-kinase inhibitor Ly294002 reduced both the constitutive and inducible expression of hypoxia-inducible factor-1alpha at the mRNA and protein levels and abrogated VEGF up-regulation by glucose starvation. Furthermore, Ly294002 suppressed cell proliferation and, at higher doses, induced marked apoptosis in ovarian cancer cells. Collectively, these data strongly indicate that PIK3CA supports ovarian cancer growth through multiple and independent pathways affecting cell proliferation, apoptosis and angiogenesis, and plays an important role in ovarian cancer progression.     

Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development

Galanin, a 29- or 30-amino acid neuropeptide, has been implicated in the modulation of seizures. In this study, we constructed a recombinant adeno-associated viral (AAV) vector to constitutively over-express galanin (AAV-GAL). The vector mediated efficient transduction of HEK 293 cells in vitro and robust galanin expression in vivo when injected into the rat dorsal hippocampus. Rats were administered kainic acid intrahippocampally 2.5 months following AAV-GAL or empty vector (AAV-Empty) injection to study the effect of vector-mediated galanin over-expression on seizures. AAV-GAL-injected rats showed a decreased number of seizure episodes and total time spent in seizures compared to AAV-Empty rats, despite similar latencies to development of the first EEG seizure and similar levels of neuronal damage in the CA3 region for both groups. These data show that recombinant AAV mediates strong and stable over-expression of galanin when injected into the rat hippocampus resulting in a significant anticonvulsive effect. The seizure suppression effect of galanin expression in the hippocampus by viral vectors may lead to novel therapeutic strategies for the treatment and management of intractable seizures with focal onset such as temporal lobe epilepsy.     

Kinetics of MK-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a noncompetitive antagonist of the N-methyl-D-aspartate-type of excitatory aminoacid receptors, was measured in plasma and brain tissues after i.p. administration to rats by using a novel high-performance liquid chromatography assay. The drug reached maximal concentrations in plasma and brain within 10 to 30 min of injection (2 mg/kg) with an elimination half-life of 1.9 and 2.05 hr, respectively. Mean ratio of brain area concentration-time curve to plasma area concentration time curve was 12.5, referring to total plasma concentrations. MK-801 distributed almost equally between plasma and red cells (mean blood-to-plasma ratio averaged 1.2 +/- 0.2 when calculated 30 and 180 min from drug administration). Plasma and brain concentrations of MK-801 rose almost linearly from 0.5 to 4 mg/kg 30 min after injection and the brain-to-plasma ratio (12.9 +/- 2.8) was constant in the dose range studied. The distribution of the drug in various brain regions 30 and 180 min after 2 mg/kg i.p. showed no preferential concentration or retention in any of the areas studied. The anticonvulsant effect of MK-801 was evaluated against limbic seizures (measured by EEG) induced by intrahippocampal injection of 120 nmol of quinolinic acid, an agonist of the N-methyl-D-aspartate-type receptors, in freely moving rats. At 0.25 and 0.5 mg/kg, MK-801 significantly lowered by 71 to 77% the number of seizures and by 80% the total time spent in seizures (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Environmental predictors of the occurrence of ground water mosquito immatures in the Paraná Lower Delta, Argentina

Characterizing mosquito larval habitats is essential for understanding the complex interactions between immatures and the biotic and abiotic components of their environment. Using generalized linear mixed models, we studied the environmental predictors of the presence of three ubiquitous mosquito species breeding in ground water habitats in the Paraná Lower Delta, Argentina. During a year-round survey, 34.1% of the 419 ground water habitats inspected were positive for either Culex dolosus s.l. (Lynch Arribálzaga 1891), Aedes crinifer (Theobald 1903), or Culex intrincatus Brèthes 1916. Univariate analysis showed that the former two occurred throughout the year, whereas the latter during the summer and fall. Ae. crinifer and Cx. intrincatus were more frequently collected in secondary forests, whereas Cx. dolosus s.l. was homogeneously distributed among land uses. Best generalized linear mixed models included the sampling period and landscape variables in different combinations for each species. Spatial dependence of the data was evident for Cx. dolosus s.l. and Ae. crinifer. Our results showed that the most widespread species presented different spatio-temporal distribution patterns, related with land use, anthropic intervention, and seasonality, highlighting the complexity of the wetland under study. This methodological approach could aid in the selection of priority areas for vector control and disease risk management.     

The role of cytokines in the pathophysiology of epilepsy

Recent findings in experimental models and in the clinical setting highlight the possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and to the establishment of a chronic epileptic focus. Prototypical inflammatory cytokines such as IL-1 beta, TNF-alpha and IL-6 have been shown to be overexpressed in experimental models of seizures in brain areas of seizure generation and propagation, prominently by glia and to a lesser extent by neurons. Cytokines receptors are also upregulated, and the related intracellular signalling is activated, in both cell populations highlighting autocrine and paracrine actions of cytokines in the brain. Cytokines have been shown to profoundly affect seizures in rodents; in particular, IL-1 beta is endowed of proconvulsant activity in a large variety of seizure models. The recent demonstration of functional interactions between cytokines and classical neurotransmitters such as glutamate and GABA, suggest the possibility that these interactions underlie the cytokine-mediated changes in neuronal excitability, thus promoting seizure phenomena and the associated neuropathology. These findings point out at novel glio-neuronal communications in diseased conditions and highlight potential new targets for therapeutic intervention.