Amnesic shellfish Poisoning(ASP), one of the shellfish poisoning syndromes in the United States, is caused by the marine diatom toxin domoic acid (DOM). In adult rats, mice, monkeys and humans DOM poorly penetrates the blood-brain barrier. However DOM has been shown to be very toxic to fetal as well as newborn mice probably because during neurodevelopment the blood brain barrier is incomplete. This fact may explain why neonates show higher sensitivity to neurotoxins like DOM as compared to adult animals. Most studies on the neurotoxicity of DOM have focused on its direct effect on neuronal tissue. Only recently have studies demonstrated that glial tissue, namely astrocytes and microglia (BMphi) are also involved in DOM neurotoxicity to the nervous system. The potential toxic effects of DOM on neurodevelopment are thus less well understood because the effect of DOM on neonatal glia, in particular BMphi is totally unknown (Medline, January 1999). We therefore propose the following working hypothesis: """"""""...exposure to low concentrations of the marine toxin domoic acid may affect the developing brain by activation of neonatal brain microglia and subsequent release of neurotoxic free radicals, cytokines, eicosanoids and matrix metalloproteases in a time- and dose-dependent manner . To test our working hypothesis we have planned 5 different sets of experiments with the purpose of determining if DOM activates rat neonatal BMphi, in a dose- and time-dependent manner. Our 5 specific aims focus our research on 5 neurotoxic mediators the PI and his collaborators have recently shown are released by neonatal BMphi when they become activated, namely the free radicals O2 and NO , the cytokine TNF-alpha, the eicosanoid TXB2 and the matrix metalloproteinase MMP-9.
