Glyoxalase 1 Inhibitor Alleviates Autism-like Phenotype in a Prenatal Valproic Acid-Induced Mouse Model

Autism spectrum disorder (ASD) is a severe neurological and developmental disorder that impairs a person's ability to socialize and communicate and affects behavior. The number of patients diagnosed with ASD has risen rapidly. However, the pathophysiology of ASD is poorly understood, and drugs for ASD treatment are strikingly limited. This study aims to evaluate the roles of glyoxalase 1 (GLO1)-methylglyoxal (MG)-γ-aminobutyric acid (GABA) signaling in ASD using a valproic acid (VPA)-induced animal model of autism. The GLO1 levels were analyzed by RT-qPCR and Western blot assay, and MG levels were measured with a Methylglyoxal Assay Kit. The open-field and sniff duration tests were used to assess the interest and anxiety of VPA mice. The three-chamber, marble-burying, and tail-flick tests were applied to determine the sociability, repetitive behavior, and nociceptive threshold of VPA mice. Our results demonstrated that increased GLO1 and decreased MG were observed in VPA mice. Administration of S-p-bromobenzylglutathione cyclopentyl diester (BrBzGCp2), a GLO1 inhibitor, was beneficial for alleviating anxiety, reducing repetitive behavior, and improving the impaired sociability and nociceptive threshold of VPA mice. BrBzGCp2 treatment may be developed as a promising therapeutic strategy for patients with ASD.