MPMT-OX up-regulates GABAergic transmission and protects against seizure-like behavior in Caenorhabditis elegans

• Published in: Neurotoxicology (Park Forest South) 2019-09, Vol.74, p.272-281
• Main Authors: Câmara, Daniela F., Machado, Marina L., Arantes, Leticia P., Silva, Thayanara C., Silveira, Tássia L., Leal, Julliano G., Dornelles, Luciano, Stefanello, Sílvio T., Soares, Félix A.A.
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazole; Aldicarb; Animals; Anticonvulsants; Behavior, Animal - drug effects; Caenorhabditis elegans; Caenorhabditis elegans Proteins - biosynthesis; Caenorhabditis elegans Proteins - genetics; Cholinergics; Circuits; Electrophysiological Phenomena - drug effects; GABA; GABA Agonists - pharmacology; gamma-Aminobutyric Acid - physiology; Genes; Locomotion - drug effects; Locomotor activity; Mimicry; Nematodes; Nervous system; Neurotransmission; Oxadiazoles - pharmacology; Paralysis; Parasympathetic Nervous System - drug effects; Pentylenetetrazol; Seizure-like behavior; Seizures; Seizures - chemically induced; Seizures - prevention & control; Seizures - psychology; Signal transmission; Synaptic Transmission - drug effects; Synaptic Vesicles - drug effects; Worms; γ-Aminobutyric acid A receptors
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2019.08.001

•The paralysis induced by pentylenetetrazole and aldicarb is attenuated by MPMT-OX treatment.•MPMT-OX increased latency time to the onset of PTZ-induced seizure behavior.•MPMT-OX aid in the recovery of locomotor activity after seizures induction.•The effect of the MPMT-OX is dependent on the presence of unc-25 and unc-47 genes. The signal transmission in the nervous system operates through a sensitive balance between excitatory (E) inputs and inhibitory (I) responses. Imbalances in this system contribute to the development of pathologies such as seizures. In Caenorhabditis elegans, the locomotor circuit operates via the coordinated activity of cholinergic excitatory (E) and GABAergic inhibitory (I) transmission. Changes in E/I inputs can cause uncontrolled electrical discharges, mimicking the physiology of seizures. Molecules derived from 1,3,4-oxadiazole have been found to exhibit diverse biological activities, including anticonvulsant effect. In this work, we study the activity of the compound 2-[(4-methoxyphenylselenyl)methylthio]-5-phenyl-1,3,4-oxadiazole (MPMT-OX) in the GABAergic and cholinergic systems. We demonstrate that MPMT-OX reduced the locomotor activity of C. elegans with a normal balance between the E/I systems and increased the resistance to paralysis in worms exposed to pentylenetetrazol and aldicarb. MPMT-OX increased seizure resistance and assisted in the recovery of locomotor activity in worms with deletions in the genes unc-46, which regulates the transport of GABA into vesicles, and unc-49, which encodes the GABAA receptor. C. elegans with deletions in the unc-25 and unc-47 genes did not respond to treatment. Therefore, we suggest that the compound MPMT-OX upregulates GABAergic signaling in a manner dependent on the unc-25 gene, which is responsible for GABA synthesis, and unc-47, which encodes the vesicular GABA transporter.