Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.
The present study describes the distribution of glial fibrillary acidic protein (GFAP) and vimentin-immunopositive structures in the brain of the domestic chicken (Gallus domesticus) from hatching to maturity. The telencephalon is penetrated by a vimentin-immunopositive radial fibre system, representing a modified form of radial glia, in day-old chicks. Numerous fibres of this system persist until adulthood, mainly in the lobus parolfactorius, lamina medullaris dorsalis and lamina frontalis superior. GFAP immunoreactivity also appears in the course of development in these fibres. The distribution of GFAP-immunopositive astrocytes in the post-hatch telencephalon is like that found in adult chicken, except for the ectostriatum, in which an adult-like GFAP-immunostaining only develops during week three. This delay may be associated with a relatively slow maturation of this visual centre. In the diencephalon and in the mesencephalic tegmentum of day-old chicks GFAP-immunopositive astrocytes are confined to the border zone of several nuclei. In these areas as well as in the pons most GFAP positive astrocytes only appear gradually during the first two post-hatch weeks, although radial fibres occur only sparsely at hatch. Summarizing these results, a gradual replacement of radial fibres by astrocytes, typical of mammals, cannot be found in chicken. In the nucleus laminaris we observed a characteristic palisade of non-ependymal glia, reactive to GFAP but not to vimentin, which almost completely disappears by adulthood. We suggest that this glial system is instrumental in the development of the dendritic organisation of this nucleus. The optic tectum displays a dense array of GFAP-immunopositive radial glia at hatching, similar in this to the situation found in reptiles. However, in the tectum of reptiles this radial glia persists for the lifetime, whereas in the chick it disappears from the superficial tectal layers. This phenomenon may reflect the fact that there is no replacement of tectal cells or regeneration of retinotectal pathways in the chicken. In the early stage, the large cerebral tracts were found to contain dense accumulations of GFAP-positive cells, with peculiarly long outgrowths accompanying nerve fibres. No vimentin-immunopositivity was found in these glial elements; however vimentin was present in the glia situated at the optic chiasm, the anterior commissure and at other decussations. These structures, as well as the raphe, displayed the most intense vimentin-immunopositivity in the post-hatch chicken. This characteristic glial population may represent glial elements that have been reported to regulate fibre-crossing at the midline.
Niemann-Pick disease (NPD) types A and B are autosomal recessive disorders caused by acid sphingomyelinase (ASM) deficiency due to mutation in the sphingomyelin phosphodiesterase 1 gene (SMPD1). Although a number of SMPD1 mutations were reported, expression studies were performed for only a small number of missense mutations. We evaluated three unrelated patients with clinical manifestations of NPD. Sequence analysis revealed two previously described (S248R and W391G) and two novel (G247D and F572L) missense mutations. To analyze the effects of the novel mutations on ASM function, cDNA was generated by site-directed mutagenesis and expressed in COS-7 cells. In vitro biochemical assays revealed marked deficiency of ASM activity consistent with the disease phenotype in cells homoallelic for each mutation. We show that each mutation dramatically reduced half-life and catalytic activity of ASM with more pronounced decrease by the G247D mutation. These data suggest that impaired protein stability and decreased enzyme activity are responsible for the disease in sphingomyelinase-deficient patients carrying the G247D and F572L mutations.
Abstract. The purpose of the present study was to evaluate the role of the renin-angiotensin system in the secretion of aldosterone during restriction of dietary sodium intake. Rats were kept on control or low-sodium diet for one week. On the 7th morning of diet osmotic minipumps filled with the angiotensin converting enzyme inhibitor (CEI) SQ 20,881, or empty pumps, were implanted subcutaneously (sc). The rats were sacrificed 23 h later. Peripheral blood was analyzed for hormones and electrolytes. Adrenal capsular tissue (z. glomerulosa) was incubated for the determination of the conversion of [3H]corticosterone to [3H]aldosterone. Sodium depletion had no effect on plasma sodium, but it increased potassium concentration. Infusion of CEI had no significant effect on plasma electrolytes. Plasma renin activity was increased both by sodium depletion and CEI. The mean serum aldosterone level was twelve times higher in sodium depleted animals than in controls. Aldosterone level was reduced by about 60 per cent in CEI-infused animals both on control and low-sodium diet. The conversion of corticosterone to aldosterone was significantly stimulated by sodium deprivation. This effect was also inhibited by the CEI SQ 20,881.
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