Non-steroidal anti-inflammatory agents, tolmetin and sulindac, attenuate oxidative stress in rat brain homogenate and reduce quinolinic acid-induced neurodegeneration in rat hippocampal neurons.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease in the elderly. Anti-inflammatory agents have been shown to be beneficial in preventing neurodegenerative disorders such as AD. In this study we investigated the possible antioxidant and neuroprotective properties of two non-steroidal anti-inflammatory drugs (NSAIDS), tolmetin and sulindac, using quinolinic acid (QA)-induced neurotoxicity as a model. We used the thiobarbituric acid assay to measure the extent of lipid peroxidation and the nitroblue tetrazolium assay to measure the superoxide anion generated in rat brain homogenate. QA (1 mM) induced lipid peroxidation in rat brain homogenate was significantly curtailed by co-treatment of the homogenate with tolmetin and/or sulindac. Tolmetin and sulindac both reduced the generation of superoxide anions by the known neurotoxin, potassium cyanide (KCN). Intrahippocampal injections of QA induced neurotoxicity in rat hippocampus. N-Methyl-D-Aspartate (NMDA) receptor counts were conducted do give an indication of the amount protection offered by the NSAIDS. QA drastically reduced the number of NMDA binding sites by approximately 37%. This sharp decrease was considerably attenuated by the pre-treatment of the rats with tolmetin and sulindac (5 mg/kg/bd for five days). This study shows the antioxidant and neuroprotective properties of tolmetin and sulindac and hereby postulates that these drugs have important implications in the prevention or treatment of neurodegenerative diseases such as AD.
Dairam
Amichand
A
Faculty of Pharmacy, Rhodes University, P.O. Box 94, Grahamstown 6140, South Africa.
Chetty
Prakash
P
Daya
Santy
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013816:Thermodynamics; D014046:Tolmetin / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; D013467:Sulindac; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D014046:Tolmetin; D017378:Quinolinic Acid