title: Riluzole attenuates the effects of chemoconvulsants acting on glutamatergic and GABAergic neurotransmission in the planarian Dugesia tigrina.
abstract: Planarians, the non-parasitic flatworms, display dose-dependent, distinct (C-like and corkscrew-like) hyperkinesias upon exposure to 0.001-10 mM aqueous solutions of glutamatergic agonists (L-glutamate and N-methyl-D-aspartate (NMDA)) and 0.001-5 mM concentrations of the glutamate decarboxylase (GAD) inhibitor (semicarbazide). In the planarian seizure-like activity (PSLA) experiments the three chemoconvulsants displayed the following order of potency (EC50): L-glutamate (0.6mM)>NMDA (1.4 mM)>semicarbazide (4.5mM). Planarian hyperkinesias behavior counting experiments also revealed that riluzole (0.001 to 1mM), an anti-convulsive agent, displayed no significant behavioral activity by itself, but attenuated hyperkinesias elicited by the three chemoconvulsants targeting either glutamatergic or GABAergic neurotransmission with the following order of potency (IC50): NMDA (44.7 µM)>semicarbazide (88.3 µM)>L-glutamate (160 µM). Further, (+)-MK-801, a specific NMDA antagonist, alleviated 3mM NMDA (47%) or 3mM L-glutamate (27%) induced planarian hyperkinesias. The results provide pharmacological evidence for the presence of glutamatergic receptor-like and semicarbazide sensitive functional GAD enzyme-like proteins in planaria in addition to demonstrating, for the first time, the anti-convulsive effects of riluzole in an invertebrate model. High performance liquid chromatography coupled with fluorescence detection (HPLC-F) analysis performed on planarian extracts post no drug treatment (control) or treatment with 3mM semicarbazide, combination of 3mM semicarbazide and 0.1 mM riluzole, or 0.1 mM riluzole revealed that 3 mM semicarbazide induced 35% decrease in the GABA levels and a combination of 3mM semicarbazide and 0.1 mM riluzole induced 42% decrease in glutamate levels with respect to the control group.
authors.affiliation: Department of Chemistry and Physics, Saint Cloud State University, Saint Cloud, MN 56301-4498, United States. Electronic address: lramakrishnan@stcloudstate.edu.
authors.forename: Latha
authors.initials: L
authors.lastname: Ramakrishnan
authors.forename: Zachary
authors.initials: Z
authors.lastname: Dalhoff
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Fettig
authors.forename: Michael R
authors.initials: MR
authors.lastname: Eggerichs
authors.forename: Briegette E
authors.initials: BE
authors.lastname: Nelson
authors.forename: Bibita
authors.initials: B
authors.lastname: Shrestha
authors.forename: Amira H
authors.initials: AH
authors.lastname: Elshikh
authors.forename: Pratima
authors.initials: P
authors.lastname: Karki
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006948:Hyperkinesis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016202:N-Methylaspartate / Q000494:pharmacology; D010932:Planarians; D017470:Receptors, Glutamate / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology*; D012663:Semicarbazides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D012663:Semicarbazides; C010059:carbamylhydrazine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D019782:Riluzole
keywords: 2,3-Naphthalene dicarboxaldehyde (PubChem CID:96400); Dizocilpine maleate (PubChem CID: 1207); L-Glutamate (PubChem CID: 33032); N-Methyl-D-aspartate (PubChem CID: 22880); Riluzole hydrochloride (PubChem CID: 6419992); Semicarbazide hydrochloride (PubChem CID:11236); γ-Aminobutyric acid (PubChem CID: 119)