ABSTRACT
BACKGROUND AND PURPOSE: Blockade of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors is a good treatment option for a variety of central nervous system disorders. The present study evaluated the neuroprotective and anticonvulsant effects of EGIS-8332, a non-competitive AMPA receptor antagonist, as a potential drug candidate. EXPERIMENTAL APPROACH: AMPA antagonist effects of EGIS-8332 were measured using patch-clamp techniques. Neuroprotective and anticonvulsant effects of EGIS-8332 were evaluated in various experimental models, relative to those of GYKI 53405. KEY RESULTS: EGIS-8332 inhibited AMPA currents in rat cerebellar Purkinje cells and inhibited the AMPA- and quisqualate-induced excitotoxicity in primary cultures of telencephalon neurons (IC(50)=5.1-9.0 microM), in vitro. Good anticonvulsant actions were obtained in maximal electroshock-, sound- and chemically-induced seizures (range of ED(50)=1.4-14.0 mg kg(-1) i.p.) in mice. Four days after transient global cerebral ischaemia, EGIS-8332 decreased neuronal loss in the hippocampal CA1 area in gerbils and rats. EGIS-8332 dose-dependently reduced cerebral infarct size after permanent middle cerebral artery occlusion in mice and rats (minimum effective dose=3 mg kg(-1) i.p.). Side effects of EGIS-8332 emerged much above its pharmacologically active doses. A tendency for better efficacy of GYKI 53405 than that of EGIS-8332 was observed in anticonvulsant tests that reached statistical significance in few cases, while the contrary was perceived in cerebral ischaemia tests. CONCLUSIONS AND IMPLICATIONS: EGIS-8332 seems suitable for further development for the treatment of epilepsy, ischaemia and stroke based on its efficacy in a variety of experimental disease models, and on its low side effect potential.
Subject(s)
Anticonvulsants/pharmacology , Benzodiazepines/pharmacology , Brain Ischemia/prevention & control , Brain/drug effects , Neuroprotective Agents/pharmacology , Receptors, AMPA/antagonists & inhibitors , Seizures/prevention & control , Animals , Anticonvulsants/adverse effects , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Benzodiazepines/metabolism , Benzodiazepines/therapeutic use , Brain/metabolism , Brain/pathology , Brain Ischemia/metabolism , Brain Ischemia/pathology , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Excitatory Amino Acid Agonists/toxicity , Gerbillinae , Male , Membrane Potentials/drug effects , Mice , Mice, Inbred DBA , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/adverse effects , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/therapeutic use , Patch-Clamp Techniques , Purkinje Cells/drug effects , Purkinje Cells/metabolism , Quisqualic Acid/toxicity , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, AMPA/metabolism , Seizures/etiology , Seizures/metabolism , Telencephalon/drug effects , Telencephalon/metabolism , Time Factors , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolismABSTRACT
Prolonged neurotoxicity of the recreational drug, MDMA (3,4-methylenedioxymethamphetamine) on serotoninergic axon terminals has been suggested. The effect of a single (15 mg/kg) dose of intraperitoneally administered MDMA on serotoninergic fibre density, defined by tryptophan hydroxylase (TpH) and serotonin transporter (5-HTT) immunoreactivity, has been evaluated in the spinal cord and brain areas in Dark Agouti rats, 7 and 180 days after MDMA applications. Immunostaining for amyloid precursor protein (APP) has been performed to examine possible defects of the fast axonal transport, and 5-HTT mRNA expressions were quantified in neurones of medullary raphe nuclei. Seven days after MDMA treatment, a substantial decrease in the density of TpH-immunoreactive fibres was detectable in the frontal cortex, the caudate-putamen, the CA1 region of the hippocampus, and marked decreases were found in the spinal cord. These changes in TpH density showed a high correlation with 5-HTT densities. In contrast, APP-immunoreactive axonal bulbs were not detected in any of the brain regions studied. Seven days after MDMA administrations, significantly elevated 5-HTT mRNA expressions were found in the raphe pallidus and obscurus. Our results suggest that a single dose of MDMA elicits widespread depletion of TpH and 5-HTT immunoreactivity in serotoninergic axons without morphological sign of the blockage of the fast anterograde axonal transport. Our results do not support the notion of MDMA-induced axotomy of serotoninergic neurones. The up-regulation of 5-HTT mRNA expressions 1 week after MDMA injections might indicate the potential recovery of the serotonin system.
Subject(s)
Axonal Transport/drug effects , Central Nervous System/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Nerve Fibers/drug effects , Serotonin Agents/toxicity , Animals , Axonal Transport/physiology , Body Temperature/drug effects , Central Nervous System/metabolism , Central Nervous System/pathology , Gene Expression/drug effects , Gene Expression/physiology , Immunohistochemistry , Male , Nerve Fibers/metabolism , Nerve Fibers/pathology , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Tryptophan Hydroxylase/metabolismABSTRACT
The present paper concerns with the problem of small intestine tumours in children, describing certain particularities. There were three lymphoblastic lymphomas and a cavernous hemangioma. Stress is laid on the rare incidence, the prevalent age, selective localization morpho-clinical forms, diagnostic difficulties, evolutive accidents and therapeutical conditions.
Subject(s)
Hemangioma, Cavernous/pathology , Intestinal Neoplasms/pathology , Intestine, Small/pathology , Lymphoma, Non-Hodgkin/pathology , Child , Child, Preschool , Hemangioma, Cavernous/diagnosis , Humans , Intestinal Neoplasms/diagnosis , Lymphoma, Non-Hodgkin/diagnosis , MaleSubject(s)
Ovarian Neoplasms/diagnosis , Testicular Neoplasms/diagnosis , Adolescent , Child , Child, Preschool , Combined Modality Therapy , Female , Humans , Infant , Male , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Retrospective Studies , Testicular Neoplasms/pathology , Testicular Neoplasms/therapyABSTRACT
Vegetative mycelia and spores of the investigated high- and low-producer strains of Streptomyces griseus bound significant amounts (4%) of streptomycin, which could be removed by increasing ionic strength. The release of antibiotic from the spores was easier when the spores were germinating. This phenomenon is considered to play an ecological role. We suppose that the streptomycin released during the germination process may protect the young hyphae from the different bacteria growing in the microenvironment of the Streptomyces spores.
