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

Abstract

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 openfield and sniff duration tests were used to assess the interest and anxiety of VPA mice. The three-chamber, marble-burying, and tailflick 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.

Role of glyoxalase 1 in methylglyoxal detoxification–the broad player of psychiatric disorders

“…Overexpression of Glo1 in mice on a transgenic bacterial artificial chromosome [ 36 ] and overexpression of Glo1 only in neurons displayed enhanced anxiety-like behavior [ 37 ]. Consistent with these findings, treatment with a GLO1 inhibitor reduced anxiety-like behavior [ 36 , [38] , [39] , [40] ], as summarized in Table 2 . Glo1 knockout (KO) mice have also been reported to exhibit less anxiety-like behavior [ 41 ].…”

“…A recent study on prenatal treatment with valproic acid (VPA) in a mouse model of autism showed enhanced GLO1 expression and reduced MG levels in the brain [ 38 ]. Furthermore, GLO1 inhibitors ameliorated the autism-like phenotype in VPA-treated mice through GABA A stimulation by MG.…”

Reduction of Glyoxalase 1 Expression Links Fetal Methylmercury Exposure to Autism Spectrum Disorder Pathogenesis

“…It is important to note that a recent publication studied the effect of prenatal exposure to valproic acid (VPA) on Glo1 levels in postnatal mice. Here, the researchers found that VPA exposure during gestation results in increased Glo1 levels starting at 8 weeks postnatally which are accompanied by ASD-like behaviors [26]. It is interesting to observe that two different environmental factors can cause different outcomes of Glo1 expression, in relation to ASD progression.…”

Molecular Mechanisms of Aberrant Neuroplasticity in Autism Spectrum Disorders (Review)

“…In 80s of the XX century, autism was considered a relatively rare disease. In recent decades, however, the percentage of ASD diagnosing is growing steadily [ 5 – 9 ]. According to the current epidemiological studies, the rate of revealing these disorders is in the range of 0.5–1% per 150 individuals allowing them to be considered as widespread neurological diseases [ 10 ].…”