Prevention of pentylenetetrazole-induced kindling and behavioral comorbidities in mice by levetiracetam combined with the GLP-1 agonist liraglutide: Involvement of brain antioxidant and BDNF upregulating properties.

Kindling is a model for studying epileptogenesis and associated neuropsychiatric conditions. The antiepileptic drug levetiracetam (LEV) presents anti-kindling properties, but some severe neuropsychiatric events, especially depression, have been associated with its use in epileptic patients. The positive modulation of glucagon-like peptide-1 (GLP-1) receptors emerged as a potential target for the treatment of epilepsy and other neurological disorders. Here, we investigated behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling. Male mice received PTZ on alternate days for 21 days. Before PTZ, the animals received LIRA, LEV (alone or in combination with LIRA) or saline. After seizures staging according to Racine's scale, behavioral evaluations were performed to verify anxiety-, depressive-like and cognitive performance. Brain oxidative alterations and BDNF levels were also measured. LEV showed anti-kindling properties, but aggravated depressive-like behavior in PTZ-kindling. In control conditions, LEV induced a pro-depressant effect and impaired avoidance memory retention. LIRA delayed but did not prevent the full kindling development. LIRA prevented the depressive-like behavior induced by PTZ kindling and PTZ + LEV. LEV + LIRA protected against PTZ-induced anxiety-like alterations and impairments in locomotion and cognition. Furthermore, LEV + LIRA reduced nitrite levels and lipid peroxidation in the hippocampus and prefrontal cortex, while it increased reduced glutathione levels in all evaluated brain areas. LIRA or LEV + LIRA increased hippocampal BDNF levels. In conclusion, our results showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects.

Antinociceptive activities of the hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice.

This work studied the antinociceptive effects of the hydroalcoholic extracts (HAEs) from Erythrina velutina (Ev) and Erythrina mulungu (Em) in three experimental models of nociception in mice. The extract was administered intraperitoneally to female mice at the doses of 200 and 400 mg/kg. Inhibitions of abdominal contractions were observed with the doses of 200 (88.6%; 86.8%) and 400 (95.5%; 83.5%) mg/kg of E. velutina and E. mulungu, respectively, as compared to controls. E. velutina and E. mulungu, at both doses, reduced the nociception produced by formalin in the 1st and 2nd phases and this effect was not reversed by the pretreatment with naloxone. In the hot plate test an increase of the reaction time was observed only at 60 (Ev=18.0+/-2.2; Em=20.8+/-2.52) and 90 min (Ev=20.4+/-1.71; Em=23.7+/-2.32) after the treatment with E. velutina and E. mulungu at the dose of 400 mg/kg as compared to controls (T60=11.1+/-0.74; T90=11.9+/-0.86). This effect was not reversed by naloxone. We conclude that E. velutina and E. mulungu presents antinociceptive effects, which are independent of the opioid system.