Biomedical subjects
Publications and source records attributed to G Casini.
A series of amidinosulfonic acids IIIa-f, analogs of taurine and homotaurine, was synthesized by reacting 2-aminoethane or 3-aminopropane sulfonic acid with lactim ethers Ia-c and then cyclized to sultams IVa-c and Vd-f. The effects of some selected amidinosulfonic acids III on membrane ionic conductances of rat skeletal muscle are described.
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A series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones 5 were prepared and evaluated for their ability to inhibit radioligand binding to BZR, and to prevent sound and pentylenetetrazole (PTZ) induced seizures in mice. The biological and pharmacological results are discussed in the light of some recently proposed pharmacophore models and compared through molecular orbital and molecular modeling studies to those obtained from the close pyrazoloquinoline analogs 6.
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Central visual pathways are similarly organized in all vertebrates, although differences are also evident in the distribution of retinofugal axons in mammals, birds and reptiles. We traced the retinofugal projections in the European lizard Podarcis sicula Rafinesque and compared our observations with previous findings in other reptilian species, as well as in mammals and in birds, in order to contribute to the understanding of similarities and differences in the pattern of organization of visual pathways in these vertebrate classes. Either HRP or 3H-proline injections were placed into one eye. No differences in staining pattern were observed between HRP and 3H-proline experiments. Prominent retinofugal projections were observed to the thalamic nuclei nucleus dorsolateralis, nucleus geniculatus lateralis dorsalis, nucleus geniculatus lateralis ventralis and nucleus geniculatus lateralis ventralis, pars ventralis. In the hypothalamus the suprachiasmatic nucleus, and in the pretectum nuclei geniculatus pretectalis, lentiformis mesencephali and posterodorsalis contained detectable amounts of labeled terminals. Retinal fibers were distributed to layers 14 and 12 of the optic tectum and terminated in layers 13, 11, and 8. Labeled fibers were also present in the basal optic tract, and terminals were located in the nucleus of the basal optic tract. Ipsilateral retinofugal fibers were detected in the optic tract, and terminals were observed in the same thalamic and pretectal nuclei which receive crossed projections. No terminals in the ipsilateral tectal layers could be demonstrated. Compared to the crossed projection, the ipsilateral retinofugal contingent was very small. These results confirm and extend data from previous studies in reptiles and are consistent with the distribution of retinofugal fibers found in other vertebrates. The presence of ipsilateral retinofugal projections represents a common feature of the organization of visual pathways in reptiles, although its importance for binocular interactions remains to be elucidated.
The present and accompanying (Casini, G., and N.C. Brecha, J. Comp. Neurol. 326:302-313, 1992) papers investigate the postnatal development of tyrosine hydroxylase (TH)-immunoreactive (IR) amacrine cells in the rabbit retina. This study is focused on a detailed analysis of the patterns of cellular growth and differentiation of TH-IR amacrine cells, which serve as a model to gain insights into the mechanisms underlying developmental changes associated with the maturation of amacrine cells. Faintly staining TH-IR neurons are present in the proximal inner nuclear layer of newborn retinas. They are characterized by a large nucleus and usually a single primary process lacking varicosities. At postnatal day (PND) 6, TH-IR processes display more complex morphological characteristics, including a few varicosities, and second- and third-order ramifications. Growth cones are often seen. At PNDs 10 and 12 (eye opening), TH-IR cells have general morphological characteristics similar to adult TH-IR amacrines. They display 2-5 primary processes, which start forming a complex network of fibers in lamina 1 of the inner plexiform layer (IPL). TH-IR processes are also present in lamina 3 and rarely in lamina 5 of the IPL. Many fibers ending in growth cones are observed. In addition, very rare, thin TH-IR fibers are present in the outer plexiform layer. At PND 19, TH-IR fibers form a complex, dense network in lamina 1 of the IPL, and loose networks in laminae 3 and 5. Growth cones are not observed at this age. At PND 26, a few "ring-like" structures formed by TH-IR fibers in lamina 1 of the IPL are observed for the first time. In adult retinas, the "ring-like" structures are more numerous than at PND 26. A second, rare type of TH-IR cell ("type B") is encountered in all retinal regions beginning at PND 10. These cells are characterized by weak immunostaining and a small soma size. The present findings show that a significant differentiation of TH-IR neurons occurs during the first 10-12 PNDs. Eye opening is an important period for the maturation of TH-IR amacrines and, more generally, for the maturation of the IPL.
Tyrosine hydroxylase (TH)-immunoreactive (IR) amacrine cells of the rabbit retina mature during the first four postnatal weeks, and their cellular development is described in the preceding paper (Casini, G., and N.C. Brecha, J. Comp. Neurol. 326:283-301, 1992). The present investigation is a quantitative analysis of the postnatal development of the TH-IR amacrine cell population. TH-IR amacrine cells gradually increase in size from birth (soma area of 44.7 +/- 12.4 microns2, mean +/- standard deviation) to adulthood (144.2 +/- 28.0 microns2). Cell density slightly increases from postnatal day (PND) 0 (41.9 +/- 9.5 cells/mm2) to PND 6 (47.2 +/- 7.2 cells/mm2), then markedly decreases from PND 6 to adulthood (17.8 +/- 5.3 cells/mm2) as a consequence of retinal growth. TH-IR cell number almost doubles from PND 0 (about 4,100 cells/retina) to adulthood (about 7,850 cells/retina). The increase in the total number of TH-IR amacrine cells can be explained by the generation of new TH-IR cells in the inner nuclear layer, a delay in the expression of the TH phenotype after neurogenesis by cells committed to be dopaminergic, or the acquisition of this dopaminergic phenotype by uncommitted cells. The development of the TH-IR amacrine cell mosaic was assessed by an evaluation of the distribution of nearest neighbor distances of TH-IR cells. There is a poor correlation between this distribution and a theoretical nonrandom distribution before PND 12. After this age, the nearest neighbor distance distribution shifts towards a nonrandom distribution, and is similar to that of the TH-IR amacrine cell population in the adult retina. The establishment of the TH-IR amacrine cell population mosaic is likely to be achieved through different interacting events, including intrinsic (e.g., genetic) factors, environmental influences, and nonuniform retinal growth. Overall, the population parameters analyzed in the present study approach adult values about the time of eye opening (PND 12) and they reach adult values by PND 26.
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Vasoactive intestinal polypeptide (VIP) immunoreactive (IR) neurons in the rabbit retina constitute a population of wide-field amacrine cells. To better define this cell population, we examined the coexpression of VIP with other putative retinal transmitters or their biosynthetic enzymes, including gamma-aminobutryic acid (GABA), tyrosine hydroxylase (TH), and somatostatin (SRIF). Colchicine-treated retinas were immersion fixed in 4% paraformaldehyde. The retinas were cut either perpendicular or parallel to the vitreal surface and processed by double-label immunofluorescence techniques using antibodies directed to VIP, GABA, TH, and SRIF. The immunoreactive staining patterns obtained with these antibodies were the same as those described in previous studies. GABA-IR neurons were localized to the proximal inner nuclear layer (INL) and ganglion cell layer (GCL) and processes were distributed throughout the inner plexiform layer (IPL). TH- and SRIF-IR neurons were sparsely distributed to the proximal INL and GCL, respectively. TH-IR processes ramified in laminae 1, 3, and 5, and SRIF-IR processes in laminae 1 and 5 of the IPL. Colocalization experiments showed that all VIP-IR neurons contain GABA immunoreactivity. In contrast, colocalization of VIP and TH or SRIF immunoreactivities was never observed. These results demonstrate that VIP-IR wide-field amacrines of the rabbit retina make up a neurochemically and morphologically distinct subpopulation of the GABA-IR amacrine cell population. Furthermore, VIP-IR amacrine cells constitute a distinct group with respect to the TH- and SRIF-IR amacrine cells.
The efferent projections from the Wulst were studied in the little owl, Athene noctua, using anterograde migration of wheat-germ-agglutinin conjugated horseradish peroxidase (WGA-HRP). Wulst projections were distributed to telencephalic, diencephalic and mesencephalic targets in a general pattern similar to that previously described in other avian species. Our results on the organization of the Wulst-optic tectum pathway in the little owl reveal well defined and laminarly arranged terminal projections into the superficial tectal layers, with a distribution suggestive of topographical relationships between neurons of origin in the Wulst and termination fields in the optic tectum. In contrast to lateral-eyed birds, the little owl possesses conspicuous contralateral projections to the optic tectum. Ipsilateral and contralateral efferents are restricted to different tectal regions, i.e. ipsilateral projections to the caudo-dorsal and contralateral projections to the rostro-ventral optic tectum. In addition, the anterior and posterior Wulst differentially contribute to the ipsilateral and contralateral projections to the optic tectum. This differential organization of Wulst efferents, as well as the presence of substantial contralateral projections, might be related to the high degree of binocular overlap typical of frontal-eyed birds. At a functional level, electric potentials recorded in the optic tectum and evoked by visual stimulation showed that information from one eye can reach the ipsilateral optic tectum. After Wulst ablation, the amplitude of these potentials was significantly reduced, indicating that Wulst efferents may influence visually-evoked activity in the optic tectum.
A large homologous series of quaternary ammonium derivatives of perhydropyrrolo[3,4-c]pyridine 5 was synthesized and tested for in vitro antibacterial activity against different Gram-positive and Gram-negative bacteria. Compounds 5 proved to be always more potent than benzalkonium chloride, taken as reference. Antibacterial activity, expressed as log 1/MIC, was found linearly related to lipophilicity up to C13-C14 homologs, where a break in the linear relationship was observed.
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Vasoactive intestinal polypeptide (VIP) possesses neuroactive properties in the nervous system. In this study we characterized VIP immunoreactive neurons in the rabbit retina to provide a basis for a better understanding of the role of this peptide in retinal functions and to further define the morphology of wide-field amacrine cells. VIP immunoreactivity was demonstrated in colchicine-treated retinas. Immunolabeling was observed in amacrine cells located in the proximal inner nuclear layer and, occasionally, in the ganglion cell layer and inner plexiform layer (IPL). Varicose fibers were distributed in laminae 1, 3, and 5 of the IPL. The distribution of VIP immunoreactive cells showed a peak of approximately 50 cells/mm2 in the visual streak and minimum values of approximately 12 cells/mm2 in the peripheral retina. The total number of VIP immunopositive neurons was estimated to be about 11,000. Cell body diameters in the visual streak (8-9 microns) were slightly smaller than those measured in the dorsal or in the ventral retina (9-10 microns). The distribution of nearest neighbor distances (approximately 109 microns in the visual streak and approximately 99 microns in the peripheral retina) showed that VIP immunoreactive neurons were nonrandomly spaced. Labeled neurons emitted one to three thick primary processes, arborizing in secondary processes and collaterals rich in varicosities; these processes often crossed among different IPL laminae. Arborization fields of individual cells overlapped extensively. In the dorsal retina, estimated areas of single arborization fields were larger and processes had lower branching frequency than in the visual streak and in the ventral retina. On the whole, VIP immunoreactive amacrine cells gave rise to a loose meshwork of fibers in the IPL. These characteristics indicate VIP is contained in a class of wide-field amacrine cells and is likely to be involved in widespread regulatory or modulatory functions rather than in the direct transmission of visual information through the retina.
Young homing pigeons were subjected to hippocampal lesion before being placed in their permanent loft to examine what effect such treatment may have on the development of their navigational map, which supports homing from distant unfamiliar locations. When later released from 3 distant unfamiliar locations, the hippocampal-lesioned pigeons were impaired in taking up a homeward bearing. The results identify a deficit in the acquisition of navigational ability after hippocampal ablation in homing pigeons. The results strongly suggest a deficit in navigational map acquisition, but alternative interpretations cannot be excluded. The findings offer the first insight into the central neural structures involved in the acquisition of the pigeon navigational map. Further, the results identify the hippocampus as a structure critical for the regulation of navigational behavior that manifests itself in a natural setting.
Homing behavior was tested in pigeons (Columba livia) after removing a portion of the ventrolateral telencephalon, which receives extensive projections from the olfactory bulb and is comparable with the mammalian pyriform cortex. Ablated pigeons show unaffected cardiac responses to odorous stimuli but altered homing behavior. After the operation, the birds were trained by repeated flock releases along with control birds from a site 40 km from the loft. After being released singly from this familiar site, the ablated birds turned out to be unaffected by the operation. In releases from two unfamiliar sites, ablated birds, unlike control birds, were not homeward oriented and were mostly lost. The ablation of the pyriform cortex has the same effect on homing behavior as olfactory deprivation. It can be concluded that the pyriform cortex plays an important role in the specific mechanisms linking olfactory inputs with the navigational response.
The efferent projections from the visual thalamus to the Wulst were studied in the little owl, Athene noctua. Cells of origin were identified by retrograde labeling after injections of wheat-germ-agglutinin-conjugated horseradish peroxidase into the Wulst. The labeled-cell distribution was correlated with the distribution of anterogradely labeled retinal terminals as revealed by intraocular injections of horseradish peroxidase. The results demonstrated a bilateral thalamofugal visual pathway ascending from the nucleus dorsolateralis anterior thalami (DLA). Projections from the visual thalamus to the Wulst showed a specific and orderly pattern, and retrogradely labeled cells of DLA were distributed equally, in a complementary fashion, on both sides of the brain, with a small region of overlap. Retinal termination fields in DLA largely overlapped relay neurons projecting to either Wulst, although the overlap was not complete. Despite differences in the organization of avian and mammalian visual pathways, which reflect their separate evolutionary origins, similarities between the DLA in the little owl and the lateral geniculate nucleus in mammals suggest that, during evolution similar selective pressures for binocularity led to a similar morphological organization.
Several N,N'-bis-alkyl-perhydropyrrolo[3,4-c]pyridines 4 and the corresponding bis-quaternary derivatives 5 have been prepared through standard methods starting from the bicyclic dilactam 2. Compounds 4 and 5 were evaluated for their inhibitory properties against acetylcholine (ACh), 1,1-dimethylphenyl piperazinium iodide (DMPP), 5-hydroxytryptamine (5-HT) and histamine (H1), and the guinea pig isolated ileum. Pharmacological data indicated that the strongest anticholinergic activity was shown by the dibenzyl amine 4 g, which among the tested molecules presented also a rather potent effect at the ganglia level, resulting about three times more potent than hexamethonium as ganglionic blocking agent. The preliminary SAR coming from the analysis of the pharmacological results are presented and discussed.
Organization of visual pathways was studied in 2-month-old pigeons that underwent unilateral retinal removal on either the day of hatching (ERA, i.e., early retinal ablated) or the 9th day after hatching (LRA, i.e., late retinal ablated). A general size reduction of visual areas contralateral to the removed retina was found in ERA pigeons, which additionally showed an altered differentiation of thalamic visual targets as well as a different cytoarchitectonic arrangement of the superficial layers of the optic tectum. No comparable modifications were found in LRA pigeons. The retinal projections of the remaining eye were studied following intraocular injections of 3H-proline. Both in ERA and LRA pigeons, the distribution of retinofugal afferents to primary visual regions contralateral to the injected eye was similar to that of control pigeons. Anomalous ipsilateral projections from the remaining retina to primary retinorecipient regions were found in ERA pigeons only. Effects of early ablation of one retina on second-order visual connections were also studied. Following injections of wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) into the visual Wulst contralateral to the operated eye, a smaller number of ipsilateral projecting thalamo-Wulst neurons was found as compared with control pigeons. In contrast, the contralateral thalamo-Wulst projections were increased. No changes in thalamo-Wulst projections were found following tracer injections into the opposite Wulst, i.e., ipsilateral to the operated eye. The present study demonstrates a substantial anatomical reorganization of both primary and secondary visual pathways following unilateral retinal removal immediately after hatching, when maturation of the visual system is not yet completed.