AGING-ASSOCIATED UP-REGULATION OF NEURONAL 5-LIPOXYGENASE EXPRESSION - PUTATIVE ROLE IN NEURONAL VULNERABILITY

Aging is associated with neurodegenerative processes, 5-Lipoxygenase ( 5-LO), which is also expressed in neurons, is the key enzyme in the sy nthesis of leukotrienes, inflammatory eicosanoids that are capable of promoting neurodegeneration, We hypothesized that neuronal 5-LO expres sion can be up-regulated in aging and that this may increase the brain 's vulnerability to neurodegeneration. We observed differences in the distribution of 5-LO-like immunoreactivity in various brain areas of a dult young (2-month-old) vs, old (24-month-old) male rats, Greater 5-L O-like immunoreactivity was found in old vs, young rats, in particular in the dendrites of pyramidal neurons in limbic structures, including the hippocampus, and in layer V pyramidal cells of the frontoparietal cortex and their apical dendrites, The aging-increased expression of neuronal 5-LO protein appears to be due to increased 5-LO gene express ion, Using a quantitative reverse transcription/polymerase chain react ion assay and 5-LO-specific oligonucleotide primers and their mutated internal standards, we observed about a 2.5-fold greater hippocampal 5 -LO mRNA content in old rats, 5-LO-like immunoreactivity was also obse rved in small, nonpyramidal cells, which were positive for glutamic ac id decarboxylase or glial fibrillary acid protein, This type of 5-LO i mmunostaining did not increase in the old rats, Hippocampal excitotoxi c injury induced by systemic injection of kainate was greater in old r ats, Neuroprotection was observed with the 5-LO inhibitor, caffeic aci d, Together, these results suggest that aging increases both neuronal 5-LO expression and neuronal vulnerability to 5-LO inhibitor-sensitive excitotoxicity, and indicate that the 5-LO system might play a signif icant role in the pathobiology of aging-associated neurodegenerative d iseases.