ferrous-citrate and Disease-Models--Animal

Indirect evidence, including neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity by nitric oxide synthase (NOS) inhibitors and resistance of transgenic animals deficient in NOS, is controversial. We have reviewed evidence in favor of oxidative stress during the development of MPTP-neurotoxicity and the influence of antioxidants, including nitric oxide (NO) and NO donors, on MPTP-induced dopaminergic neurotoxicity. Systemic administration of MPTP causes dose-dependent generation of hydroxyl radicals (OH) in vivo in the striatum in mice; OH scavengers protect dopaminergic neurons from this insult. On the other hand the role of NO in MPTP-neurotoxicity is controversial. Hitherto, no direct evidence for the involvement of NO in MPTP neurotoxicity has been available. MPTP does not affect inducible-NOS mRNA level or its expression in SN or the striatum. Nitroglycerine, a NO donor, can attenuate MPTP-induced dopamine depletion in the striatum by virtue of its OH scavenging action. Several other NO donors have also been shown to scavenge the OH generated, following Fenton chemistry in vitro, and to protect against in vivo dopaminergic neurotoxicity by small mass iron complex formation. This evidence suggests that NO renders protection against MPTP-induced OH-mediated nigrostriatal lesions, acting as an antioxidant.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Citric Acid; Disease Models, Animal; Dopamine Agents; Ferrous Compounds; Free Radicals; Humans; MPTP Poisoning; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Substantia Nigra

Topics: Alanine Transaminase; Aminolevulinic Acid; Animals; Aspartate Aminotransferases; Citric Acid; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Ferrous Compounds; Gene Expression Regulation; Graft vs Host Disease; Levulinic Acids; Liver; Male; Mice; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sodium Citrate; T-Lymphocytes; Treatment Outcome; Up-Regulation

Topics: Aminolevulinic Acid; Animals; B-Lymphocytes; Blood Urea Nitrogen; Body Weight; CD8-Positive T-Lymphocytes; Citric Acid; Creatine; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; Ferrous Compounds; Fibrosis; Graft vs Host Disease; Heme Oxygenase-1; Levulinic Acids; Lupus Nephritis; Lymphocyte Activation; Membrane Proteins; Mice; Spleen; T-Lymphocytes, Regulatory

Men have worse survival than premenopausal women after intracerebral hemorrhage (ICH). After ICH, overproduction of iron associated with induction of heme oxygenase-1 (HO-1) in brain was observed. Rodent ICH model using ferrous citrate (FC)-infusion into the striatum to simulate iron overload, showed a higher degree of injury severity in males than in females. However, the participation of HO-1 in sex-differences of iron-induced brain injury remains unknown. The present results showed a higher level of HO-1 expression associated with more severe injury in males compared with females after FC-infusion. Estradiol (E2) contributed to lower levels of FC-induced HO-1 expression in females compared with males. Heterozygote ho-1 KO decreased the levels of FC-induced injury severity, histological lesions, behavioral deficits, autophagy and autophagic cell death in the striatum of males but not in females. Moreover, ho-1 deficiency enhanced the neuroprotection by E2 only in males. These results suggested that over induction of HO-1 plays a harmful role in FC-induced brain injury in a male-specific manner. Suppression of HO-1 combined with E2 exhibits a synergistic effect on neuroprotection against FC-induced striatal injury in males. These findings open up the prospect for male-specific neuroprotection targeting HO-1 suppression for patients suffering from striatal iron overload.

Topics: Animals; Apoptosis; Cerebral Hemorrhage; Citric Acid; Corpus Striatum; Disease Models, Animal; Estradiol; Female; Ferrous Compounds; Heme Oxygenase-1; Male; Membrane Proteins; Mice; Mice, Knockout; Severity of Illness Index; Sex Characteristics; Up-Regulation