Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative/Nitrative Status and Causes Protein/DNA Damage, as well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective?

Homocysteine is a sulfur-containing amino acid derived from methionine metabolism. When plasma homocysteine levels exceed 10-15 μM, there is a condition known as hyperhomocysteinemia, which occur as a result of an inborn error of methionine metabolism or by non-genetic causes. Mild hyperhomocysteinemia is considered a risk factor for development of neurodegenerative diseases. The objective of the present study was to evaluate whether acetylsalicylic acid has neuroprotective role on the effect of homocysteine on inflammatory, oxidative/nitrative stress, and morphological parameters in cerebral cortex of rats subjected to chronic mild hyperhomocysteinemia. Wistar male rats received homocysteine (0.03 μmol/g of body weight) by subcutaneous injections twice a day and acetylsalicylic acid (25 mg/Kg of body weight) by intraperitoneal injections once a day from the 30th to the 60th postpartum day. Control rats received vehicle solution in the same volume. Results showed that rats subjected to chronic mild hyperhomocysteinemia significantly increased IL-1β, IL-6, and acetylcholinesterase activity and reduced nitrite levels. Homocysteine decreased catalase activity and immunocontent and superoxide dismutase activity, caused protein and DNA damage, and altered neurons ultrastructure. Acetylsalicylic acid totally prevented the effect of homocysteine on acetylcholinesterase activity and catalase activity and immunocontent, as well as the ultrastructural changes, and partially prevented alterations on IL-1β levels, superoxide dismutase activity, sulfhydryl content, and comet assay. Acetylsalicylic acid per se increased DNA damage index. In summary, our findings showed that chronic chemically induced model of mild hyperhomocysteinemia altered some parameters and acetylsalicylic acid administration seemed to be neuroprotective, at least in part, on neurotoxicity of homocysteine.