Torasemide Improves the Propionic Acid-Induced Autism in Rats: A Histopathological and Imaging Study

Abstract

Objective: Autism spectrum disorder is a neurodevelopmental disease in which impaired social behaviors, impaired sociality, and restricted and repetitive behaviors are seen. Bumetanide is a loop diuretic that inhibits Na + –K + –2Cl − cotransporter 1 and it is currently used in clinical phase studies in patients with autism spectrum disorder. In present research, it is purposed to demonstrate the beneficial effects of torasemide which is another Na + –K + –2Cl − cotransporter 1 inhibitor on an experimental autism model induced with propionic acid by providing imaging and brain tissue investigations. Methods: Male Wistar rats were used in the present study (n = 30). Propionic acid of 250 mg/kg/day was administrated intraperitoneally in rats to induce autism for 5 days. Three groups were created for present study as follows: group 1, normal control (n = 10); group 2, propionic acid and saline given group (n = 10); group 3, propionic acid + tora-semide-administrated group (n = 10). Results: Torasemide group scored higher on behavioral tests compared to saline group. The brain levels of malondialdehyde, tumor necrosis factor-alpha, interleukin-2, interleukin-17, and Nuclear Factor kappa B (NF-κB), Glial fibrillary acidic protein (GFAP) were remarkably higher in propionic acid + saline group. In histopathology assessments, torasemide group had higher neuronal count of Cornu Ammonis 1, neuronal count of Cornu Ammonis 2 in hippocampus, and Purkinje cells in cerebellum. GFAP immunostaining index (Cornu Ammonis 1) and cerebellum were lower in torasemide group. Magnetic resonance spectroscopy revealed that mean lactate value was higher in propionic acid + saline group compared to torasemide group. Conclusion: Our experimental results showed that torasemide might enhance gamma-aminobutyric acid activity. Torasemide can be considered another promising Na + –K + –2Cl − cotransporter 1 inhibitor in the treatment of autism with a longer half-life and less side effects after further studies.

Neuron-Specific Enolase (NSE) as a Biomarker for Autistic Spectrum Disease (ASD)

“…An electrolyte disturbance was observed in a few patients; we have ignored hyperpotassemia (10 instances) on the grounds of possible hemolyzed blood specimens because of difficult venipunctures in some ASD kids, but the observed lowered sodium may be linked to a functional alteration of the NKCC2, a cotransporter protein of Na + , K + and Cl − encoded by the SLC12A1 gene. This dysfunction is linked to the GABA receptor activity and is improved by administration of lowdose bumetanide -a loop diuretic -which was also shown to ameliorate symptoms of ASD (54); more recently torasemide -another Na + /K + inhibitor, was proposed to be administered in ASD, with less side effects (55).…”

Neuron-Specific Enolase (NSE) as a Biomarker for Autistic Spectrum Disease (ASD)

“…This dysfunction is linked to GABA receptor activity and is improved via the administration of low-dose bumetanide—a loop diuretic—which was also shown to ameliorate symptoms of ASD [ 56 ]. More recently, torasemide, another Na + /K + inhibitor, was proposed to be administered in ASD, with less side effects [ 57 ].…”

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…Recently, a new selective Na-K-Cl cotransporter inhibitor called ARN23746 has been reported to improve sociability in VPA-induced mice, similar to bumetanide ( 276 ). The oral administration of torasemide, a diuretic that also acts as a Na-K-Cl cotransporter inhibitor, has the potential to enhance neuronal viability and reduce astrogliosis in the hippocampus of ASD rat models ( 277 ).…”

“…Bumetanide, a loop diuretic that inhibits the Na-K-Cl cotransporter, has been reported to improve core symptoms of ASD in children over recent years (274). In VPA-treated rats, even a brief maternal bumetanide treatment can prevent hippocampal overgrowth in their offspring (275). In addition, maternal pretreatment with bumetanide effectively restored elevated hippocampal intracellular chloride levels, increased hippocampal excitatory GABA, and enhanced hippocampal gamma oscillations in offspring of VPA-induced rats and Fmr1 mutant mice (259).…”