| Objective With the society progress and aging population increase, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkison's diseas, Huntinton's disease, and Amyotrophic lateral sclerosis (ALS) become a worldwide problem that affects billions of people in the globe. Although the pathogenesis of neurodegeneration is not completely known, more and more scholars consider that environmental agents, such as diet, aluminum, and viruses are as important as genetic factors in the etiology of neurodegenerative diseases, and that neuroinflammation and oxidative stress may play a key role in these types of diseases and in normal aging. The cyclooxygenase (COX) pathway generates inflammatory prostaglandins, while the 5-lipoxygenase (5-LOX) pathway generates inflammatory leukotrienes. More and more studies suggest that COX-2 and 5-LOX, as well as their products be involved in neuron damage and neurodegeneration. In this study we try to elucidate the relationship between expression of 5-LOX and COX-2 and neurodegeneration induced by aluminum overload.Methods(1) Neurodegenerative model of mice was established via intracerebroventricular injection of aluminum, once a day for 5 days. Items below were measured: behavioural changes including spontaneous motor counts, passive avoidance test, and spatial learning and memory function test; biochemical changes including MDA contents in cerebral tissue, expression of ChAT, APP, A(, COX-2 and 5-LO protein by immunochemistry, as well as expression of COX-2 and 5-LO mRNA by RT-PCR; and the pathological changes of cerebral tissue.(2) The amount of LDH leakage and MTT absorbance from primary cultured cortical-hippocampus neurons were determined to evaluate the viability of neurons undergoing aluminum overload. The pathomorphology of neurons was also observed. (3) The primary cultured cortical-hippocampus neurons were infected by adenovirus expressing 5-LO mRNA (Ad5-LO) to determine the susceptibility of neurons with 5-LO over expression to aluminum damage.(4) Meloxicam, a selective inhibitor of COX-2, and caffeic acid, a selective inhibitor of 5-LO, were administered both in vivo and in vitro to observe their protective effects on mice and primary cultured cortical-hippocampus neurons against aluminum overload.Results (1) Aluminum overload induced the impairment of learning and memory function, neuron death of hippocampi, increasing of MDA content of cerebral tissue, increasing protein expression of APP, A(, COX-2 and 5-LO, and COX-2 and 5-LO mRNA expression, and decreasing expression of ChAT. Aluminum also resulted in damage of primary cultured cortical-hippocampus neurons.(2) There existed closely relationship between over expression of COX-2 and 5-LO and neuron damage caused by overload of aluminum.(3) Neurons with 5-LO over expression were shown fragile and easy to suffer from aluminum attacking. (4) Meloxicam and caffeic acid obviously prevented mice from the damage of learning and memory function and neuron death, significantly inhibited rising of MDA contents and diminishment of CHAT expression, and blunted the over expression of APP, A(, COX-2 and 5-LO protein expression, as well as COX-2 and 5-LO mRNA expression caused by aluminum overload in dose-dependent manner. The combination use of Meloxicam (low dose) and caffeic acid (low dose) showed more potent effects than either use alone.Conclusions (1) Our experimental results suggest that there are many factors involved in pathogenesis of neuron damage and neurodegeneration induced by aluminum overload in mice, such as oxidative stress, neuroinflammatory, damage to cholinergic neurons and A beta deposit in central nervous system. (2) Our experimental results also indicate that both 5-LOX and COX-2 play a pivitol role in process of neurodegenerative diseases, and a selective inhibitor of COX-2 and 5-LO may have potential value in clinical treatment for some neurodegenerative diseases and other neuron injury-related diseases. |
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