PMID- 36064157 OWN - NLM STAT- MEDLINE DCOM- 20220929 LR - 20221006 IS - 1873-6815 (Electronic) IS - 0531-5565 (Linking) VI - 168 DP - 2022 Oct 15 TI - Phosphonate analog of 2-oxoglutarate regulates glutamate-glutamine homeostasis and counteracts amyloid beta induced learning and memory deficits in rats. PG - 111944 LID - S0531-5565(22)00252-2 [pii] LID - 10.1016/j.exger.2022.111944 [doi] AB - BACKGROUND: Metabolic alteration is a mainstream concept underlying the cognitive decline in neurodegenerative disorders including Alzheimer's disease (AD). Mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC) seems to play a dual-edged sword role in cytotoxic insult. Here, using succinyl phosphonate (SP), a specific alpha-KGDHC inhibitor, we aimed to examine its potential action on AD progression. METHODS: Male Wistar rats were assigned to two separate experiments. First, they were bilaterally microinjected into the dorsal CA(1) area by amyloid-beta (Abeta)(25-35) for four consecutive days. Seven days after the last injection, they were trained to acquire Morris Water Maze (MWM) task for three successive days when they were treated with SP after each training session. In the second experiment, SP was administered 30 min after the first Abeta microinjection and behavioral tests were performed one week after the last Abeta administration. The activity of glutamate dehydrogenase (GDH), and glutamine synthetase (GS), as key enzymes involved in glutamate-glutamine homeostasis and histological assays were evaluated in the hippocampi. RESULTS: Our behavioral results indicated that post-training SP treatment enhanced task acquisition but did not change memory performance in Abeta-treated rats. However, administration of SP at the time of Abeta injection precludes the deteriorative effect of Abeta and neuronal injury on both spatial learning and memory performances indicating its preventive action against Abeta pathology at its early stages. Measurement of enzymes activity shows that alpha-KGDHC activity was reduced in the Abeta treated group, and SP administration restored its activity; also, GDH and GS activities were increased and decreased respectively due to Abeta, and SP reversed the action of Abeta on these enzymes. CONCLUSIONS: This study proposes that SP possibly a promising therapeutic approach to improve memory impairment in AD, especially in the early phases of this disease. CI - Copyright (c) 2022. Published by Elsevier Inc. FAU - Sayehmiri, Fatemeh AU - Sayehmiri F AD - School of Medicine, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Khodagholi, Fariba AU - Khodagholi F AD - Neurobilogy Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: khodagholi@sbmu.ac.ir. FAU - Pourbadie, Hamid Gholami AU - Pourbadie HG AD - Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran. FAU - Naderi, Nima AU - Naderi N AD - Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Aliakbarzadeh, Faezeh AU - Aliakbarzadeh F AD - Department of Environmental Health Engineering, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Hashemi, Reza AU - Hashemi R AD - School of Medicine, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Naderi, Soudabeh AU - Naderi S AD - School of Medicine, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Motamedi, Fereshteh AU - Motamedi F AD - Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: motamedi@ams.ac.ir. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220903 PL - England TA - Exp Gerontol JT - Experimental gerontology JID - 0047061 RN - 0 (Amyloid beta-Peptides) RN - 0 (Glutamates) RN - 0 (Ketoglutaric Acids) RN - 0 (Organophosphonates) RN - 0 (Peptide Fragments) RN - 0RH81L854J (Glutamine) RN - EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex) RN - EC 1.4.1.2 (Glutamate Dehydrogenase) RN - EC 6.3.1.2 (Glutamate-Ammonia Ligase) SB - IM MH - *Alzheimer Disease/metabolism MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Disease Models, Animal MH - Glutamate Dehydrogenase/metabolism/pharmacology/therapeutic use MH - Glutamate-Ammonia Ligase/metabolism/pharmacology MH - Glutamates/pharmacology MH - Glutamine/metabolism/pharmacology MH - Hippocampus/metabolism MH - Homeostasis MH - Ketoglutarate Dehydrogenase Complex/metabolism/pharmacology MH - Ketoglutaric Acids/metabolism/pharmacology/therapeutic use MH - Male MH - Maze Learning MH - Memory Disorders/drug therapy/metabolism/prevention & control MH - *Organophosphonates/metabolism/pharmacology/therapeutic use MH - Peptide Fragments/metabolism/pharmacology MH - Rats MH - Rats, Wistar OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid beta OT - Glutamate-glutamine homeostasis OT - Spatial learning and memory OT - alpha-Ketoglutarate dehydrogenase enzyme complex COIS- Declaration of competing interest None. EDAT- 2022/09/06 06:00 MHDA- 2022/09/30 06:00 CRDT- 2022/09/05 19:28 PHST- 2022/05/17 00:00 [received] PHST- 2022/07/28 00:00 [revised] PHST- 2022/08/24 00:00 [accepted] PHST- 2022/09/06 06:00 [pubmed] PHST- 2022/09/30 06:00 [medline] PHST- 2022/09/05 19:28 [entrez] AID - S0531-5565(22)00252-2 [pii] AID - 10.1016/j.exger.2022.111944 [doi] PST - ppublish SO - Exp Gerontol. 2022 Oct 15;168:111944. doi: 10.1016/j.exger.2022.111944. Epub 2022 Sep 3.