Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms.
Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required.
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Germana Silva
GS
Vasconcelos
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Naiara Coelho
NC
Ximenes
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Caren Nádia Soares
CN
de Sousa
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Tatiana de Queiroz
Tde Q
Oliveira
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Laio Ladislau Lopes
LL
Lima
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
David Freitas
DF
de Lucena
Laboratory of Molecular Psychiatry, INCT for Translational Medicine-CNPq, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Post Graduate Program in Medicine, Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2350, Porto Alegre CEP 90035-903, Brazil.
Clarissa Severino
CS
Gama
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil. Electronic address: daniellesilmacedo@gmail.com.
Danielle
D
Macêdo
Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Post Graduate Program in Pharmacology, Federal University of Ceará, Rua Coronel Nunes de Melo 1127, Fortaleza, CE, Brazil.
Silvânia Maria Mendes
SM
Vasconcelos
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003024:Clozapine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007398:Interpersonal Relations; D007649:Ketamine / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009573:Nitrites / Q000378:metabolism*; D011897:Random Allocation; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008063:Thioctic Acid / Q000627:therapeutic use*
D000975:Antioxidants; D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D009573:Nitrites; D008315:Malondialdehyde; D007649:Ketamine; D008063:Thioctic Acid; D005978:Glutathione; D003024:Clozapine
Alpha-lipoic acid; Clozapine; Ketamine; Nitrite; Oxidative stress; Schizophrenia