2R,4R-APDC, a Metabotropic Glutamate Receptor Agonist, Reduced Neuronal Apoptosis by Upregulating MicroRNA-128 in a Rat Model After Seizures

• Published in: Neurochemical research Vol. 43; no. 3; pp. 591 - 599
• Main Authors: Feng, Ya-bo, Lin, You-ting, Han, Yu-xiang, Pang, Yue-jiu, Xu, Jing-jing, Xue, Yuan, Yao, Hong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2018; Springer Nature B.V
• Subjects: Animal memory; Animals; Animals, Newborn; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Caspase; Caspase-3; Caspase-9; Cell Biology; Disease Models, Animal; Epilepsy; Excitatory Amino Acid Agonists - pharmacology; Glutamic acid receptors (metabotropic); Hippocampus; Hippocampus - metabolism; Inhibitors; Male; Memory - drug effects; Memory tasks; MicroRNAs; MicroRNAs - metabolism; miRNA; Neurochemistry; Neurology; Neurosciences; Original Paper; Pilocarpine; Proline - analogs & derivatives; Proline - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - agonists; Ribonucleic acid; RNA; Rodents; Seizing; Seizures; Seizures - drug therapy; Seizures - metabolism; Spatial analysis; Spatial memory; Swimming; Up-Regulation - drug effects; 2R,4R-APDC; Neuronal apoptosis; MicroRNA-128; Seizures
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-017-2453-z

This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus. Real-time PCR was used to determine the levels of microRNA-128 (miR-128) in hippocampus. The results of the Morris water maze test showed that the 2R,4R-APDC treatment reduced the escape latencies and swimming lengths of rats after seizures. The TUNEL assay showed that 2R,4R-APDC significantly counteracted seizure-induced cell apoptosis. The western blot confirmed this finding, demonstrating that the levels of cleaved caspase-3 and cleaved caspase-9 were potently decreased by 2R,4R-APDC in rat hippocampus after seizures. In addition, 2R,4R-APDC upregulated miR-128 expression levels in the hippocampus. A miR-128 mimic or inhibitor decreased or increased the percentage of TUNEL-positive cells in rats after seizures and 2R,4R-APDC treatment, respectively. The levels of both cleaved caspase-3 and cleaved caspase-9 were decreased in hippocampus exposed to the miR-128 mimic, whereas they were markedly increased in miR-128 inhibitor-treated hippocampus. In conclusion, 2R,4R-APDC protected hippocampal cells from cell apoptosis after seizures, possibly by upregulating miR-128.