cyclic-gmp and Brain-Diseases

Topics: Acetylcholine; Adolescent; Adult; Age Factors; Aged; Animals; Biogenic Amines; Brain; Brain Diseases; Catecholamines; Child; Cyclic AMP; Cyclic GMP; Dopamine beta-Hydroxylase; Female; gamma-Aminobutyric Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Rabbits; Rats; Serotonin

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

The central metabolism of dopamine, serotonin, cyclic AMP and cyclic GMP was studied by use of the probenecid test in three patients with bismuth encephalopathy and in one patient with mercury encephalopathy. The accumulation of HVA and of cGMP in the cerebrospinal fluid was depressed during the acute phase of bismuth encephalopathy with severe hyposomnia, while it was increased in a patient with regression of clinical symptoms and normal in a patient with more advanced recovery. The patient with chronic mercury poisoning showing a severe cerebellar ataxia and rigidity had an almost complete suppression of HVA accumulation and an increase of cGMP accumulation. No pronounced differences of 5-HIAA and cAMP behavior were found. It is concluded that the central metabolism of dopamine and of cGMP is severely affected in bismuth and mercury encephalopathies.

Topics: Adult; Biogenic Amines; Bismuth; Brain Diseases; Cyclic AMP; Cyclic GMP; Dopamine; Female; Humans; Male; Mercury Poisoning; Middle Aged; Poisoning; Probenecid; Serotonin