Aromatic hydrocarbon 1,2‐diacetylbenzene cross‐links neurofilament and other proteins

Abstract

Here we explored the mechanisms of secretory phospholipase A2 (sPLA2) and glutamate (glu) in neuronal signalling and cell damage. Rats or primary neuronal cultures were treated with MK-801 and injected with/exposed to sPLA2 or glu. MK-801 partially inhibited sPLA2-and glu-induced neuronal death as well as [3H]arachidonic acid release. The involvement of cytosolic PLA2 (cPLA2) and plateletactivating factor (PAF) in sPLA2 or glu signalling was explored by treating cells with the selective cPLA2 inhibitor, AACOCF3, PAF-acetyl hydrolase (PAF-AH) or the presynaptic PAFreceptor antagonist, BN52021. AACOCF3 blocked sPLA2-and glu-induced neuronal death by 26 and 77%, respectively. PAF-AH ameliorated sPLA2 as well as glu neurotoxicity by 31 and 47%, whereas BN52021 inhibited sPLA2 induced neurotoxicity by 11% but did not significantly protect against gluinduced neurotoxicity. Expression in neurons of early response genes in response to sPLA2 or glu was further examined. An up-regulation of COX-2, c-fos, and c-jun, but not COX-1, was observed at earlier time points after rat striatal injection of glu as compared to sPLA2 injection. Moreover we treated neuronal cells with COX-2 inhibitors and found that neuronal cell death after sPLA2 and glu exposure was inhibited by 35 and 33%, respectively. Thus sPLA2 activates a neuronal signalling cascade that includes activation of cPLA2, AA-release, production of PAF and induction of COX-2. Hence sPLA2 and glu signalling are overlapping, but not identical. Cytosolic PLA2 may primarily drive glutamatergic neurotransmission, whereas PAF plays a more crucial role in sPLA2 neuronal signalling. CP11-02Aluminum triggers NFjB signalling, inflammatory and apoptotic gene expression in human neural cells W. J. Lukiw and N. G. Bazan Neuroscience Center & Deptartment of Ophthalmology, Louisiana State, University Health Sciences Center, New Orleans, LA, USA Aluminum, the most abundant neurotoxic metal in the biosphere, has been implicated in the etiology of neurodegenerative disorders including Alzheimers disease (AD). To further understand aluminum's influence on brain gene expression we examined 2360 RNA message levels in normal human neural progenitor (NHNP) cells using DNA microarrays. Of the 53 gene expression levels that were altered by a factor of >3-fold (p < 0.05) over control, 44 were down-regulated. This group included transcripts encoding 17 transcription factors (TFs) or TF kinases, 12 membrane receptors, genes encoding 10 growth factors, neurotransmitters, DNA ligase, DNA repair enzymes and antiapoptotic factors such as bcl-2. The only TFs found to be consistently induced by aluminum on these panels were members of the pro-inflammatory (PI) NFjB gene family. As verified independently by RT-PCR, eight of the nine genes found to be induced by aluminum encoded PI or proapoptotic signalling elements, including NFjB p52/p65, IL-1 precursor, COX-2 and DAXX, a FAS binding protein known to induce apoptosis and repress transcription. These PI gene promoters contain multiple NFjB binding si...