"Glu/GABA-Gln" metabolic loop abnormalities in iminodipropionitrile (IDPN)-induced dyskinetic syndrome

Abstract

Objective: Iminodipropionitrile (IDPN)-induced dyskinetic syndrome is characterized by abnormal repetitive involuntary movements with abnormalities in the neuro-transmission. This study explored the mechanism of glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) metabolic circuit in rat dyskinetic syndrome and the possible regulation mechanism of "tiapride (Tia)."

Methods: Male Wistar rats were assigned to the control group, dyskinetic syndrome group, and Tia group. Dyskinetic syndrome was induced by injecting with 3,3'-iminodipropionitrile for 7 days. Tia group was treated with tiapride, while the control and dyskinetic syndrome groups were gavaged with saline. Eventually the Glu, GABA, and Gln concentrations in striatum were detected using UPLC-3QMS, additionally another amino acid neurotransmitters (aspartate, glycine) were also detected. Expressions of glutamine synthetase (GS), glutamate transporter (EAAT₂), glutamate decarboxylase (GAD65/67), and γ-aminobutyric acid transporter protein (GAD-T) were observed using Western blot and real-time polymerase chain reaction.

Results: The behavior test scores of dyskinetic syndrome group were increased compared with the control group. Tia group decreased the behavior test scores compared with dyskinetic syndrome group. For amino acid neuro-transmission, dyskinetic syndrome group increased Glu level (p < 0.01), decreased GABA level (p < 0.01), increased Glu/GABA ratio (p < 0.01), and decreased Asp level (p < 0.01) compared with control group. Tia group decreased Glu level (p < 0.01), increased GABA level (p < 0.01), decreased Glu/GABA ratio (p < 0.01), and increased Asp level (p < 0.05) compared with dyskinetic syndrome group. For Glu/GABA-Gln circuit, the protein and mRNA expression of GS and EAAT₂ in dyskinetic syndrome group were decreased (p < 0.05). Tia group increased protein and mRNA expression level of GS (p < 0.05) and EAAT₂ (p < 0.01).

Conclusion: The rat dyskinetic syndrome has Glu/GABA-Gln abnormalities. "Tiapride" upregulated the protein expression of GS and EAAT₂, reduce Glu levels, increase γ-GABA levels, and eventually improve amino acid neurotransmitter imbalance.

Keywords: Amino acid neurotransmitters; Glutamic acid/γ-aminobutyric acid–glutamine metabolism loop; The rat dyskinetic syndrome; Tiapride.