Primary cultures of rat cerebellar granule cells as a model to study neuronal 5-lipoxygenase and FLAP gene expression.
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 patholphysiological 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, and stimulated by stress hormone glucocorticoids (e.g., corticosterone and the synthetic glucocorticoid dexamethasone). Melatonin deficiency and hyperglucocorticoidemia frequently develop 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, aging, or glucocorticoid treatment 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/or aging-increased glucocorticoid secretion and the resultant upregulation of 5-LO expression. Furthermore, we propose that suppressing the 5-LO expression and/or activity will increase the brain's resistance to injury. The results of our ongoing research 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.
Manev
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Department of Psychiatry, University of Illinois at Chicago 60612, USA. HManev@psych.uic.edu
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D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D000831:Animals, Newborn; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats
D058927:5-Lipoxygenase-Activating Proteins; C548594:Alox5ap protein, rat; D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D001094:Arachidonate 5-Lipoxygenase