Citric acid is a weak organic acid found in the greatest amounts in citrus fruits. This study examined the effect of citric acid on endotoxin-induced oxidative stress of the brain and liver. Mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 200 lg/kg). Citric acid was given orally at 1, 2, or 4 g/kg at time of endotoxin injection and mice were euthanized 4 h later. LPS induced oxidative stress in the brain and liver tissue, resulting in marked increase in lipid peroxidation (malondialdehyde [MDA]) and nitrite, while significantly decreasing reduced glutathione, glutathione peroxidase (GPx), and paraoxonase 1 (PON1) activity. Tumor necrosis factor-alpha (TNF-a) showed a pronounced increase in brain tissue after endotoxin injection. The administration of citric acid (1-2 g/kg) attenuated LPS-induced elevations in brain MDA, nitrite, TNF-a, GPx, and PON1 activity. In the liver, nitrite was decreased by 1 g/kg citric acid. GPx activity was increased, while PON1 activity was decreased by citric acid. The LPS-induced liver injury, DNA fragmentation, serum transaminase elevations, caspase-3, and inducible nitric oxide synthase expression were attenuated by 1-2 g/kg citric acid. DNA fragmentation, however, increased after 4 g/kg citric acid. Thus in this model of systemic inflammation, citric acid (1-2 g/kg) decreased brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation.

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In malathion intoxicated rats, the neuronal NOS inhibitor 7-NI and to much less extent l-NAME were able to protect the brain and liver tissue integrity along with improvement in oxidative stress parameters. The decrease in DNA damage of peripheral blood lymphocytes by NOS inhibitors also suggests the involvement of nitric oxide in this process.

This study investigated the effect of the serotonin selective reuptake inhibitors (SSRIs) fluoxetine, sertraline, fluvoxamine and the tricyclic antidepressant (TCA) impiramine on oxidative stress in brain and liver induced by lipopolysaccharide administration in mice. Each drug was administered subcutaneously at doses of 10 or 20 mg/kg, for two days prior to intraperitoneal (i.p.) administration of lipopolysaccharide E (LPS: 200 µg/kg). Mice were euthanized 4 h after administration of the lipopolysaccharide. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) concentrations were measured in brain and liver. Results: The administration of lipopolysaccharide increased oxidative stress in brain and liver; it increased brain MDA by 36.1 and liver MDA by 159.8 %. GSH decreased by 34.1 % and 64.8 % and nitric oxide increased by 78.7 % and 103.8 % in brain and liver, respectively. In brain, MDA decreased after the administration of sertraline and by the lower dose of fluoxetine or fluvoxamine, but increased after the higher dose of imipramine. Reduced glutathione increased after sertraline, fluvoxamine and the lower dose of fluoxetine or imipramine. Nitric oxide decreased by sertraline, fluoxetine, fluvoxamine and by the lower dose of imipramine. In the liver, all drugs decreased MDA and increased GSH level. Nitric oxide is decreased by sertraline, fluvoxamine and by the lower dose of fluoxetine or imipramine. It is concluded that, during mild systemic inflammatory illness induced by peripheral bacterial endotoxin injection, the SSRIs fluoxetine, sertraline and fluvoxamine reduced, while the TCA impiramine increased oxidative stress induced in the brain. The SSRIs as well as imipramine reduced oxidative stress due to lipopolysaccharide in liver tissue.

Abstract:We investigated the effect of cerebrolysin, a peptide mixture used for promoting memory and recovery from cerebral stroke, on the development of oxidative stress and nigrostriatal cell injury induced by rotenone administration in rats. Rotenone 1.5 mg/kg was given subcutaneously three times weekly either alone or in combination with cerebrolysin at 21.5, 43, or 86 mg/kg. Rats were euthanized 14 days after starting the rotenone injection. Lipid peroxidation (malondialdehyde), reduced glutathione (GSH), nitric oxide (nitrite) concentrations, paraoxonase 1 (PON1), and acetylcholinesterase (AChE) activities -as well as the monocyte chemoattractant protein-1 (MCP-1) and the antiapoptotic protein Bcl-2 -were measured in the brain. Histopathology, tyrosine hydroxylase, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cleaved caspase-3 immunohistochemistry were also performed. Rotenone caused a significantly elevated oxidative stress and proinflammatory response in the different brain regions. Malondialdehyde and nitric oxide concentrations were significantly increased, while GSH markedly decreased in the cerebral cortex, striatum, hippocampus, and in the rest of the brain. PON1 and AChE activities significantly decreased with respect to the control levels after rotenone application. Striatal Bcl-2 was significantly decreased while MCP-1 increased following rotenone injection. Rotenone caused prominent iNOS, TNF-α, and caspase-3 immunostaining in the striatum and resulted in markedly decreased tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum. Cerebrolysin coadministered with rotenone decreased lipid peroxidation, increased GSH, and inhibited the elevation of nitric oxide induced by rotenone. Cerebrolysin also decreased the rotenone-induced decline in the PON1 and AChE activities and the rotenone-mediated changes in the striatal Bcl-2 and MCP-1 levels. The drug reduced iNOs, TNF-α, and caspase 3 expressions and increased the tyrosine hydroxylase immunoreactivity in the striatum. Cerebrolysin markedly prevented the development of neuronal damage in the cortex and striatum. These data suggest that cerebrolysin may have potential therapeutic effect in Parkinson's disease.