title: Antimanic-like activity of candesartan in mice: Possible involvement of antioxidant, anti-inflammatory and neurotrophic mechanisms.
abstract: Activation of the brain angiotensin II type 1 receptor (AT1R) triggers pro-oxidant and pro-inflammatory mechanisms which are involved in the neurobiology of bipolar disorder (BD). Candesartan (CDS) is an AT1 receptor antagonist with potential neuroprotective properties. Herein we investigated CDS effects against oxidative, neurotrophic inflammatory and cognitive effects of amphetamine (AMPH)-induced mania. In the reversal protocol adult mice were given AMPH 2 mg/kg i.p. or saline and between days 8 and 14 received CDS 0.1, 0.3 or 1 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention treatment, mice were pretreated with CDS, Li or saline prior to AMPH. Locomotor activity and working memory performance were assessed. Glutathione (GSH), thiobarbituric acid-reactive substance (TBARS) and TNF-α levels were evaluated in the hippocampus (HC) and cerebellar vermis (CV). Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK-3beta) levels were measured in the HC. CDS and Li prevented and reversed the AMPH-induced increases in locomotor activity. Only CDS prevented and reversed AMPH-induced working memory deficits. CDS prevented AMPH-induced alterations in GSH (HC and CV), TBARS (HC and CV), TNF-α (HC and CV) and BDNF (HC) levels. Li prevented alterations in BDNF and phospho-Ser9-GSK3beta. CDS reversed AMPH-induced alterations in GSH (HC and CV), TBARS (HC), TNF-α (CV) and BDNF levels. Li reversed AMPH-induced alterations in TNF-α (HC and CV) and BDNF (HC) levels. CDS is effective in reversing and preventing AMPH-induced behavioral and biochemical alterations, providing a rationale for the design of clinical trials investigating CDS׳s possible therapeutic effects.
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: Júlia Ariana
authors: JA
authors: de Souza Gomes
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: Greicy Coelho
authors: GC
authors: de Souza
authors: IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Vic., Australia; Florey Institute of Neuroscience and Mental Health, Australia; Orygen Youth Health Research Centre, University of Melbourne, Parkville, Vic., Australia.
authors: Michael
authors: M
authors: Berk
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: Lígia Menezes
authors: LM
authors: Cavalcante
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: Francisca Cléa F
authors: FC
authors: de Sousa
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil.
authors: Josiane
authors: J
authors: Budni
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: David Freitas
authors: DF
authors: de Lucena
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil; Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA.
authors: João
authors: J
authors: Quevedo
authors: Translational Psychiatry Research Group, Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
authors: André F
authors: AF
authors: Carvalho
authors: Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil. Electronic address: daniellesilmacedo@gmail.com.
authors: Danielle
authors: D
authors: Macêdo
mesh_terms: D000661:Amphetamine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018692:Antimanic Agents / Q000097:blood / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018020:Lithium Compounds / Q000097:blood / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology; D011897:Random Allocation; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D018692:Antimanic Agents; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018020:Lithium Compounds; D009414:Nerve Growth Factors; D013777:Tetrazoles; D000661:Amphetamine; C081643:candesartan
keywords: Anti-inflammatory; Antioxidant; BDNF; Candesartan; GSK3beta; Mania