NORDIHYDROGUAIARETIC ACID PROTECTS HIPPOCAMPAL-NEURONS AGAINST AMYLOID BETA-PEPTIDE TOXICITY, AND ATTENUATES FREE-RADICAL AND CALCIUM ACCUMULATION

Recent findings indicate that amyloid beta-peptide (A beta) can be neu rotoxic by a mechanism involving an increase in the concentration of i ntracellular free Ca2+ ([Ca2+](i)) and the generation of free radicals . In the present study, the lipoxygenase inhibitor/antioxidant nordihy droguaiaretic acid (NDGA) protected cultured rat hippocampal neurons a gainst the toxicity of A beta in a concentration-dependent manner. Mea surements of cellular oxidation (using the oxidation-sensitive dye 2,7 -dichlorofluorescin) and intracellular free Ca2+ levels (using the Ca2 + indicator dye fura-2), showed that NDGA suppressed A beta-induced ac cumulation of reactive oxygen species (ROS) and Ca2+, Ca2+ responses t o glutamate were also suppressed by NDGA. NDGA prevented neuronal inju ry and accumulation of ROS induced by iron, indicating a role for NDGA as an antioxidant in NDGA-mediated neuroprotection. Another lipoxygen ase inhibitor (AA861) also protected against A beta and iron toxicity whereas the the 5-lipoxygenase-activating protein inhibitor L655,238 a nd the cyclooxygenase inhibitor indomethacin were ineffective. These f indings suggest that NDGA can interrupt a neurodegenerative pathway re levant to the pathophysiology of Alzheimer's disease.