Involvement of the Cholinergic Parameters and Glial Cells in Learning Delay Induced by Glutaric Acid: Protection by N-Acetylcysteine.

Abstract

Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight-1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.

• Authors: Fernanda Silva Rodrigues, Viviane Nogueira de Zorzi, Marla Parizzi Funghetto, Fernanda Haupental, Alexandra Seide Cardoso, Sara Marchesan, Andréia M Cardoso, Maria Rosa C Schinger, Alencar Kolinski Machado, Ivana Beatrice Mânica da Cruz, Marta Maria Medeiros Frescura Duarte, Léder L Xavier, Ana Flavia Furian, Mauro Schneider Oliveira, Adair Roberto Soares Santos, Luiz Fernando Freire Royes, Michele Rechia Fighera
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 56 Issue 7 Pg. 4945-4959 (Jul 2019) ISSN: 1559-1182 [Electronic] United States
• PMID: 30421167 (Publication Type: Journal Article)

Chemical References

• Glutarates
• glutaric acid
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology, therapeutic use)
• Animals
• Cholinergic Neurons (drug effects, metabolism)
• Glutarates (toxicity)
• Male
• Maze Learning (drug effects, physiology)
• Memory Disorders (chemically induced, metabolism, prevention & control)
• Neuroglia (drug effects, metabolism)
• Rats
• Rats, Wistar