title: Rosmarinic acid is anticonvulsant against seizures induced by pentylenetetrazol and pilocarpine in mice.
abstract: Epilepsy is a chronic neurological disease characterized by spontaneous recurrent seizures (SRS). Current anticonvulsant drugs are ineffective in nearly one-third of patients and may cause significant adverse effects. Rosmarinic acid is a naturally occurring substance which displays several biological effects including antioxidant and neuroprotective activity. Since oxidative stress and excitotoxicity play a role in the pathophysiology of seizures, we aimed the present study to test the hypothesis that rosmarinic acid displays anticonvulsant and disease-modifying effects. Female C57BL/6 mice received rosmarinic acid (0, 3, 10, or 30mg/kg; p.o.) 60min before the injection of pentylenetetrazol (PTZ, 60mg/kg; i.p.) or pilocarpine (300mg/kg, i.p.). Myoclonic and generalized tonic-clonic seizure latencies and generalized seizure duration were analyzed by behavioral and electroencephalographic (EEG) methods. The effect of acute administration of rosmarinic acid on mice behavior in the open-field, object recognition, rotarod, and forced swim tests was also evaluated. In an independent set of experiments, we evaluated the effect of rosmarinic acid (3 or 30mg/kg, p.o. for 14days) on the development of SRS and behavioral comorbidities in the pilocarpine post-status epilepticus (SE) model of epilepsy. Rosmarinic acid dose-dependently (peak effect at 30mg/kg) increased the latency to myoclonic jerks and generalized seizures in the PTZ model and increased the latency to myoclonic jerks induced by pilocarpine. Rosmarinic acid (30mg/kg) increased the number of crossings, the time at the center of the open field, and the immobility time in the forced swim test. In the chronic epilepsy model, treatment with rosmarinic acid did not prevent the appearance of SRS or behavioral comorbidities. In summary, rosmarinic acid displayed acute anticonvulsant-like activity against seizures induced by PTZ or pilocarpine in mice, but further studies are needed to determine its epilepsy-modifying potential.
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Jéssica
authors.initials: J
authors.lastname: Grigoletto
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Clarissa Vasconcelos de
authors.initials: CV
authors.lastname: Oliveira
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Ana Claudia Beck
authors.initials: AC
authors.lastname: Grauncke
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Thaíze Lopes de
authors.initials: TL
authors.lastname: Souza
authors.affiliation: Graduate Program in Food and Science Technology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Naieli Schiefelbein
authors.initials: NS
authors.lastname: Souto
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Mayara Lütchemeyer de
authors.initials: ML
authors.lastname: Freitas
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Food and Science Technology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Ana Flávia
authors.initials: AF
authors.lastname: Furian
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil; Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis 88040-900, SC, Brazil.
authors.forename: Adair Roberto Soares
authors.initials: AR
authors.lastname: Santos
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil. Electronic address: ms.oliveira@ufsm.br.
authors.forename: Mauro Schneider
authors.initials: MS
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D053630:Depsides / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole; D010862:Pilocarpine; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D000097123:Rosmarinic Acid
chemical_list: D000927:Anticonvulsants; D002934:Cinnamates; D053630:Depsides; D010433:Pentylenetetrazole; D010862:Pilocarpine; D000097123:Rosmarinic Acid
keywords: Anticonvulsant activity; Anxiolytic activity; Behavior; Comorbidities; Epilepsy; Rosmarinic acid