Abstract
To observe the characteristic changes of PGE2-EPs pathway and divergent functions of PGE2 receptor subtypes on neuronal injury. The primary cultured rat hippocampus neuron injury model was established via aluminum maltolate (100 μM). The aluminum-overload neurons were treated with the agonists of EP1 (17-phenyl trinor Prostaglandin E2 ethyl amide), EP2 (Butaprost), EP3 (Sulprostone) and EP4 (CAY10598) and antagonists of EP1 (SC-19220), EP2 (AH6809) and EP4 (L-161982) at different concentrations, respectively. The neuronal viability, lactate dehydrogenase leakage rate and PGE2 content were detected by MTT assay, lactate dehydrogenase assay kit and enzyme-linked immunosorbent assay, respectively. The mRNA and protein expressions of mPGES-1 and EPs were determined by RT-PCR and western blot, respectively. The pathomorphology was identified by hematoxylin-eosin staining. In the model group, neuronal viability significantly decreased, while lactate dehydrogenase leakage rate and PGE2 content increased. The mPGES-1, EP1, EP2 and EP4 mRNA expression, and the mPGES-1, EP1 and EP2 protein expression increased, while EP3 level decreased. EP3 agonist exerted protective function in neuronal viability and lactate dehydrogenase leakage rate, while EP1 agonist, EP2 and EP4 antagonist exerted an opposite effect. In conclusion, aluminum-overload caused an imbalance of PGE2-EP1-4 pathway and activation of EP receptor may provide a viable therapeutic target in neuronal injury.
Highlights
Neurodegenerative diseases (NDDs), including Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), Spinal muscularatrophy (SMA) and related neurological and psychiatric disorders, occur frequently in the elderly
Our previous studies showed that meloxicam significantly improved behavioral and biochemical changes in aluminum overloaded mice, which indicated that selective cyclooxygenase-2 (COX-2) inhibitors have potential values in chronic neuronal damagerelated diseases [4]
Beverages and aluminum additives currently are considered as the main form of aluminum orally ingested by the populations [15]
Summary
Neurodegenerative diseases (NDDs), including Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), Spinal muscularatrophy (SMA) and related neurological and psychiatric disorders, occur frequently in the elderly. AD and cognitive deficit could only be prevented by long-term used of selective COX2 inhibitors, but not cured [5, 6], the risk of complications, such as gastrointestinal ulcers, bleeding, cardiovascular and cerebrovascular diseases increased [7]. To avoid such side effects, some scholars www.impactjournals.com/oncotarget suggested that the downstream intervention of COX-2 (PG synthetase-PGs-PGs receptor signaling pathway) may be superior to upstream interference of COX-2 in the treatment of acute or chronic brain injury [8]
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