Phosphonate analog of 2-oxoglutarate regulates glutamate-glutamine homeostasis and counteracts amyloid beta induced learning and memory deficits in rats

Abstract

Background: Metabolic alteration is a mainstream concept underlying the cognitive decline in neurodegenerative disorders including Alzheimer's disease (AD). Mitochondrial enzyme α-ketoglutarate dehydrogenase complex (α-KGDHC) seems to play a dual-edged sword role in cytotoxic insult. Here, using succinyl phosphonate (SP), a specific α-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 CA₁ area by amyloid-beta (Aβ)_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 Aβ microinjection and behavioral tests were performed one week after the last Aβ 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 Aβ-treated rats. However, administration of SP at the time of Aβ injection precludes the deteriorative effect of Aβ and neuronal injury on both spatial learning and memory performances indicating its preventive action against Aβ pathology at its early stages. Measurement of enzymes activity shows that α-KGDHC activity was reduced in the Aβ treated group, and SP administration restored its activity; also, GDH and GS activities were increased and decreased respectively due to Aβ, and SP reversed the action of Aβ 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.

Keywords: Alzheimer's disease; Amyloid beta; Glutamate-glutamine homeostasis; Spatial learning and memory; α-Ketoglutarate dehydrogenase enzyme complex.