oxadiazoles and Brain-Diseases

Sublethal injury induces tolerance to a subsequent lethal insult, a phenomenon termed preconditioning (PC). PC occurs within hours (early tolerance) or days (delayed tolerance) after the inducing stimulus. In the brain, delayed tolerance has been studied extensively, but very little is known about early tolerance. We investigated whether the proinflammatory agent lipopolysaccharide (LPS), a well-established inducer of delayed tolerance, can also induce early tolerance and, if so, whether nitric oxide (NO) is involved in its mechanisms.. In C57BL/6 mice, LPS was administered and N-methyl-D-aspartate (NMDA) was microinjected into the neocortex 30 minutes to 24 hours later. Lesion volume was assessed 24 hours after NMDA administration in thionine-stained sections.. LPS reduced NMDA lesions when administered 1 hour (-25+/-1%; P<0.05, n=5 per group) or 24 hours (-25+/-4%; P<0.05, n=5 per group) before NMDA application. LPS administration 30 minutes or 2 to 4 hours before NMDA administration was not neuroprotective (P>0.05). The protection at 1 hour was independent of protein synthesis and was blocked by inhibition of neuronal NO synthase or soluble guanylyl cyclase. Furthermore, early protection was not observed in neuronal or endothelial NO synthase-null mice, but it was present in inducible NO synthase-null mice.. The data demonstrate that LPS induces both early and late tolerance. At variance with delayed tolerance, which depends on inducible NO synthase and peroxynitrite, early tolerance is mediated by endothelial and neuronal NO through production of cGMP. The findings suggest that LPS can trigger signaling between endothelial cells and neurons, leading to NO production and cGMP-dependent neuroprotection.

Topics: Animals; Anisomycin; Brain Diseases; Cyclic GMP; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Guanylate Cyclase; Ischemic Preconditioning; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; N-Methylaspartate; Neuroprotective Agents; Neurotoxins; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxadiazoles; Protein Synthesis Inhibitors; Quinoxalines

Two experiments tested the hypothesis that the deficits in conditional discrimination learning produced by ibotenic acid-induced lesions of the ventral pallidum and substantia innominata are produced by loss of the magnocellular cholinergic cells in the nucleus basalis and adjacent regions. Experiment 1 replicated the previously reported deficit in conditional learning produced by ibotenate-induced lesions of the ventral pallidum/substantia innominata, but failed to demonstrate any restoration of learning by a subchronic regimen of the acetylcholinesterase inhibitor physostigmine sufficient to produce significant (30%), but equivalent, degrees of inhibition in the frontal cortex of ventral pallidum/substantia innominata-lesioned or sham-operated rats. Experiment 2 examined the effects of quisqualic acid-induced lesions of the ventral pallidum/substantia innominata. According to most of the measures of learning employed, the quisqualic acid-induced lesion of the ventral pallidum/substantia innominata failed to impair conditional learning, even though the quisqualate-induced lesion produced greater degrees of cholinergic neuron destruction than the ibotenate-induced lesion, as measured in terms of reductions in cortical choline acetyltransferase activity (44% vs 27%). Although consideration of individual data suggested that very high (60%) levels of choline acetyltransferase reduction in Experiment 2 might have detrimental effects of conditional learning, the overall failure of the quisqualate-induced lesions of the ventral pallidum/substantia innominata to impair learning is to be contrasted with the significant behavioural effects of ibotenate-induced lesions. Histological and immunocytochemical analysis showed that the quisqualate-induced lesion, unlike that produced by ibotenate, tended to produce less damage to the overlying dorsal globus pallidus and to parvocellular neurons of the ventral pallidum/substantia innominata, thus implicating these nonspecific effects of ibotenate-induced lesions in their behavioural effects. The present results question previous interpretations of the behavioural effects of ibotenate-induced lesions of the ventral pallidum/substantia innominata in terms of damage inflicted on the cortically-projecting cholinergic cells of the nucleus basalis, and suggest that quisqualic acid, although also nonspecific in its excitotoxic effects, is nevertheless more selective for producing damage to cholinergic neurons in the ventral pall

Topics: Animals; Basal Ganglia; Behavior, Animal; Biomechanical Phenomena; Brain Diseases; Conditioning, Psychological; Discrimination Learning; Globus Pallidus; Ibotenic Acid; Male; Oxadiazoles; Oxazoles; Parasympathetic Nervous System; Quisqualic Acid; Rats; Rats, Inbred Strains; Substantia Innominata; Visual Perception

The neuroprotective effects of the strychnine-insensitive glycine receptor antagonist, HA-966, against N-methyl-D-aspartate (NMDA)- and quisqualate (QA)-mediated brain injury were determined in perinatal rats. Postnatal day (PND) 7 rats received intrastriatal injections of NMDA (25 nmol) or QA (100 nmol) and then were administered intraperitoneal (i.p.) injections of varying doses of HA-966 or vehicle 15 min later. Animals were sacrificed 5 days later and the degree of brain injury was calculated by comparison of the weights of injected and contralateral cerebral hemispheres. HA-966 selectively reduced the degree of NMDA-mediated brain injury in a dose-dependent manner. However, HA-966 did not attenuate QA-mediated brain injury.

Topics: Animals; Animals, Newborn; Aspartic Acid; Brain Diseases; Corpus Striatum; N-Methylaspartate; Oxadiazoles; Pyrrolidinones; Quisqualic Acid; Rats; Rats, Inbred Strains

An intrahippocampal injection of quisqualic acid (QA) was made in chronically implanted freely moving unanesthetized cats and electrographic and clinical observations were made. Fourteen to 40 micrograms of QA injection resulted in a mild limbic seizure within 24 h after QA injection. Some cats demonstrated a pure hippocampal seizure on an electroencephalogram. Electrographic changes and clinical manifestations were less prominent as compared with those of kainic acid. Histopathological examination showed a selective loss of pyramidal cell layer of the CA3 portion in the injected side of the dorsal hippocampus. A mild but constant epileptogenic potency of QA has an advantage for an experimental model of temporal lobe epilepsy in man.

Topics: Animals; Brain Diseases; Cats; Electroencephalography; Hippocampus; Oxadiazoles; Quisqualic Acid; Seizures

Topics: Adjustment Disorders; Adolescent; Adult; Aged; Antidepressive Agents; Brain Diseases; Depression; Depressive Disorder, Major; Female; Humans; Hypothalamus; Male; Mental Disorders; Middle Aged; Neurasthenia; Oxadiazoles; Psychopharmacology; Sydnones; Tablets

Topics: Adolescent; Adult; Antidepressive Agents; Brain Diseases; Enuresis; Female; Humans; Intellectual Disability; Male; Neurotic Disorders; Oxadiazoles; Sydnones

Topics: Adolescent; Adult; Aged; Brain Diseases; Cerebral Angiography; Child; Humans; Middle Aged; Muscles; Oxadiazoles