Aging is associated with chronic neurodegenerative diseases and increased brain vulnerability that may lead to a worse outcome from brain insults in elderly than in young subjects. Inflammation is one of the pathophysiological mechanisms of both chronic and acute neurodegeneration. Leukotrienes are inflammatory lipid mediators whose formation from arachidonic acid is initiated by 5-lipoxygenase (5-LO). 5-LO is also expressed in neurons and can be activated by brain injuries, whereas 5-LO inhibitors can provide neuroprotection. The expression of the 5-LO gene appears to be inhibited by the pineal hormone, melatonin, which also is a potent neuroprotective agent. Melatonin deficiency normally develops with aging. We found that old or pinealectomized, i.e., melatonin-deficient, rats are more susceptible to kainate-triggered excitotoxic limbic brain injury than the corresponding young or sham-pinealectomized controls, and that pinealectomy or aging result in an enhanced expression of 5-LO in limbic structures. We hypothesize that an aging brain is at a higher risk of neurodegeneration via aging-suppressed melatonin secretion and the resultant upregulation of 5-LO expression, and that suppressing the 5-LO expression and/or activity will increase the brain's resistance to injury. These hypotheses will be tested in the following AIMS: (1) Characterize in aging rats (i.e., at 2, 6, 12, and 24 months of age): the neuronal expression of mRNAs and proteins of 5-LO and its activating protein FLAP; the effect of kainate on leukotriene formation and neuronal damage in the hippocampus and the entorhinal cortex; blood and brain melatonin levels (2) Characterize in limbic structures of young and old rats the effects of the nuclear melatonin receptor agonist CGP-52608 or melatonin on 5-L0 expression and kainate-induced leukotriene formation and neuronal damage; (3) Investigate the action of different classes of 5-LO inhibitors on kainate-induced leukotriene formation and neuronal damage; and (4) Investigate whether kainate is less neurotoxic in 5-LO-deficient (i.e., knockout) mice, and whether aging equally affects the vulnerability to kainate of 5-LO-deficient and age-matched wild mice. Techniques to be used include: quantitative reverse transcription/polymerase chain reaction for 5-LO and FLAP mRNAs, 5-LO and FLAP immunocytochemistry/immonobloting, enzyme- or radio- immunoassays, gas chromatography/mass spectrometry, TUNEL/Nissl stainings, and computer-assisted quantitative morphometry. The results are expected to elucidate the role of 5-LO in aging and neurodegeneration and to indicate neuroprotective therapies that would target the 5-LO pathway.
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