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.

α-Lipoic Acid as Adjunctive Treatment for Schizophrenia: An Open-Label Trial.

PURPOSE/BACKGROUND: Accumulating evidence suggests an involvement of oxidative stress in the pathophysiology of schizophrenia. This offers a hypothesis-derived therapeutic approach to hinder oxidative damage and its clinical sequelae. α-Lipoic acid (ALA) is a powerful natural antioxidant indicated to treat diabetic neuropathy. METHODS/PROCEDURES: In this pilot investigation, we administered ALA (100 mg/d) for 4 months, as an adjunct to antipsychotic medication, to 10 patients with schizophrenia. FINDINGS/RESULTS: We found robust improvement in measures of psychopathology (63.9% reduction in Brief Psychiatric Rating Scale scores), neurocognitive parameters, extrapyramidal symptoms, and decreased lipid peroxidation. IMPLICATIONS/CONCLUSIONS: If larger, double-blind, placebo-controlled studies confirm these preliminary findings, ALA could prove useful as adjunctive therapy for schizophrenia.

Gastroprotection of (-)-alpha-bisabolol on acute gastric mucosal lesions in mice: the possible involved pharmacological mechanisms.

(-)-Alpha-Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (-)-Alpha-Bisabolol has generated considerable economic interest, since it possesses a delicate floral odor and has been shown to have anti-septic and anti-inflammatory activity. The aim of this work was to evaluate the gastroprotective action of (-)-alpha-bisabolol on ethanol and indomethacin-induced ulcer models in mice, and further investigate the pharmacological mechanisms involved in this action. The oral administration of (-)-alpha-bisabolol 100 and 200 mg/kg was able to protect the gastric mucosa from ethanol (0.2 mL/animal p.o.) and indomethacin-induced ulcer (20 mg/kg p.o.). Administration of L-NAME (10 mg/kg i.p.), glibenclamide (10 mg/kg i.p.) or indomethacin (10 mg/kg p.o.) was not able to revert the gastroprotection promoted by (-)-alpha-bisabolol 200 mg/kg on the ethanol-induced ulcer. Dosage of gastric reduced glutathione (GSH) levels showed that ethanol and indomethacin reduced the content of non-protein sulfhydryl (NP-SH) groups, while (-)-alpha-bisabolol significantly decreased the reduction of these levels on ulcer-induced mice, but not in mice without ulcer. In conclusion, gastroprotective effect on ethanol and indomethacin-induced ulcer promoted by (-)-alpha-bisabolol may be associated with an increase of gastric sulfydryl groups bioavailability leading to a reduction of gastric oxidative injury induced by ethanol and indomethacin.

Differential effects of cocaine-induced seizures and lethality on M(1)-like muscarinic and dopaminergic D (1)- and D (2)-like binding receptors in mice brain.

This work was designed to study the changes produced by cocaine-induced seizures and lethality on dopaminergic D(1)- and D(2)-like receptors, muscarinic M(1)-like binding sites, as well as acetylcholinesterase activity in mice prefrontal cortex (PFC) and striatum (ST). Binding assays were performed in brain homogenates from the PFC and ST and ligands used were [(3)H]-N-methylscopolamine, [(3)H]-NMS (in the presence of carbachol), [(3)H]-SCH 23390 and [(3)H]-spiroperidol (in presence of mianserin), for muscarinic (M(1)-like), D(1)- and D(2)-like receptors, respectively. Brain acetylcholinesterase (AChE) activity was also determined in these brain areas. Cocaine-induced SE decreased [(3)H]-SCH 23390 binding in both ST and PFC areas. A decrease in [(3)H]-NMS binding and an increase in [(3)H]-spiroperidol binding in PFC was also observed. Cocaine-induced lethality increased [(3)H]-spiroperidol binding in both areas and decreased [(3)H]-NMS binding only in PFC, while no difference was seen in [(3)H]-SCH 23390 binding. Neither SE, nor lethality altered [(3)H]-NMS binding in ST. AChE activity increased after SE in ST while after death the increase occurred in both PFC and ST. In conclusion, cocaine-induced SE and lethality produces differential changes in brain cholinergic and dopaminergic receptors, depending on the brain area studied suggesting an extensive and complex involvement of these with cocaine toxicity in central nervous system.