PMID- 31816318 OWN - NLM STAT- MEDLINE DCOM- 20210423 LR - 20210423 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1728 DP - 2020 Feb 1 TI - Chronic mild hyperhomocysteinemia induces anxiety-like symptoms, aversive memory deficits and hippocampus atrophy in adult rats: New insights into physiopathological mechanisms. PG - 146592 LID - S0006-8993(19)30646-8 [pii] LID - 10.1016/j.brainres.2019.146592 [doi] AB - In the last decade, increased homocysteine levels have been implicated as a risk factor for neurodegenerative and psychiatric disorders. We have developed an experimental model of chronic mild hyperhomocysteinemia (HHcy) in order to observe metabolic impairments in the brain of adult rodents. Besides its known effects on brain metabolism, the present study sought to investigate whether chronic mild HHcy could induce learning/memory impairments associated with biochemical and histological damage to the hippocampus. Adult male Wistar rats received daily subcutaneous injections of homocysteine (0.03 mumol/g of body weight) twice a day, from the 30th to the 60th day of life or saline solution (Controls). After injections, anxiety-like and memory tests were performed. Following behavioral analyses, brains were sliced and hippocampal volumes assessed and homogenized for redox state assessment, antioxidant activity, mitochondrial functioning (chain respiratory enzymes and ATP levels) and DNA damage analyses. Behavioral analyses showed that chronic mild HHcy may induce anxiety-like behavior and impair long-term aversive memory (24 h) that was evaluated by inhibitory avoidance task. Mild HHcy decreased locomotor and/or exploratory activities in elevated plus maze test and caused hippocampal atrophy. Decrease in cytochrome c oxidase, DNA damage and redox state changes were also observed in hippocampus of adult rats subjected to mild HHcy. Our findings show that chronic mild HHcy alters biochemical and histological parameters in the hippocampus, leading to behavioral impairments. These findings might be considered in future studies aiming to search for alternative strategies for treating the behavioral impairments in patients with mild elevations in homocysteine levels. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Wyse, A T S AU - Wyse ATS AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-Graduation Program of Biochemistry, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address: wyse@ufrgs.br. FAU - Sanches, E F AU - Sanches EF AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-Graduation Program of Biochemistry, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. FAU - Dos Santos, T M AU - Dos Santos TM AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-Graduation Program of Biochemistry, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. FAU - Siebert, C AU - Siebert C AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-Graduation Program of Biochemistry, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. FAU - Kolling, J AU - Kolling J AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. FAU - Netto, C A AU - Netto CA AD - Biochemistry Department, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Post-Graduation Program of Biochemistry, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191206 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0LVT1QZ0BA (Homocysteine) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 1.9.3.1 (Electron Transport Complex IV) SB - IM MH - Adenosine Triphosphate/metabolism MH - Animals MH - Anxiety/*etiology/pathology MH - Atrophy/etiology/pathology MH - Avoidance Learning MH - Chronic Disease MH - DNA Damage/physiology MH - Electron Transport Complex IV/metabolism MH - Hippocampus/*pathology/physiopathology MH - Homocysteine/blood MH - Hyperhomocysteinemia/chemically induced/*complications MH - Male MH - Memory Disorders/*etiology/physiopathology MH - Open Field Test MH - Oxidative Stress/physiology MH - Rats MH - Rats, Wistar OTO - NOTNLM OT - Behavior OT - DNA damage OT - Hippocampal atrophy OT - Homocysteine OT - Long-term aversive memory OT - Mild hyperhomocisteinemia EDAT- 2019/12/10 06:00 MHDA- 2021/04/24 06:00 CRDT- 2019/12/10 06:00 PHST- 2019/07/05 00:00 [received] PHST- 2019/11/29 00:00 [revised] PHST- 2019/12/04 00:00 [accepted] PHST- 2019/12/10 06:00 [pubmed] PHST- 2021/04/24 06:00 [medline] PHST- 2019/12/10 06:00 [entrez] AID - S0006-8993(19)30646-8 [pii] AID - 10.1016/j.brainres.2019.146592 [doi] PST - ppublish SO - Brain Res. 2020 Feb 1;1728:146592. doi: 10.1016/j.brainres.2019.146592. Epub 2019 Dec 6.