Effects of mood stabilizers on DNA damage in an animal model of mania.
OBJECTIVE
Recent studies have suggested that oxidative stress and DNA damage may play a role in the pathophysiology of bipolar disorder (BD). We investigated the effects of the mood stabilizers lithium and valproate on amphetamine-induced DNA damage in an animal model of mania and their correlation with oxidative stress markers.


METHODS
In the first experiment (reversal model), we treated adult male Wistar rats with D-amphetamine (AMPH) or saline for 14 days; between the 8th and 14th days, rats also received lithium, valproate or saline. In the second experiment (prevention model), rats received either lithium, valproate or saline for 14 days; between the 8th and 14th days, we added AMPH or saline. We evaluated DNA damage using single-cell gel electrophoresis (comet assay), and we assessed the mutagenic potential using the micronucleus test. We assessed oxidative stress levels by lipid peroxidation levels (TBARS) and antioxidant enzyme activities (superoxide dismutase and catalase). We assessed DNA damage and oxidative stress markers in blood/plasma and hippocampal samples. We evaluated mutagenesis in fresh lymphocytes.


RESULTS
In both models, we found that AMPH increased peripheral and hippocampal DNA damage. The index of DNA damage correlated positively with lipid peroxidation, whereas lithium and valproate were able to modulate the oxidative balance and prevent recent damage to the DNA. However, lithium and valproate were not able to prevent micronucleus formation.


CONCLUSIONS
Our results support the notion that lithium and valproate exert central and peripheral antioxidant-like properties. In addition, the protection to the integrity of DNA conferred by lithium seems to be limited to transient DNA damage and does not alter micronuclei formation.
Andreazza
Ana Cristina
AC
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Brazil.
Kauer-Sant'Anna
Marcia
M
Frey
Benicio N
BN
Stertz
Laura
L
Zanotto
Caroline
C
Ribeiro
Leticia
L
Giasson
Karine
K
Valvassori
Samira S
SS
Réus
Gislaine Z
GZ
Salvador
Mirian
M
Quevedo
João
J
Gonçalves
Carlos A
CA
Kapczinski
Flavio
F
D000661:Amphetamine; D000818:Animals; D018692:Antimanic Agents / Q000627:therapeutic use / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D001714:Bipolar Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D000697:Central Nervous System Stimulants; D020552:Comet Assay; D004249:DNA Damage; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D018021:Lithium Chloride / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D015162:Micronucleus Tests; D009043:Motor Activity; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000627:therapeutic use / Q000633:toxicity
D018692:Antimanic Agents; D000975:Antioxidants; D000697:Central Nervous System Stimulants; D014635:Valproic Acid; D000661:Amphetamine; D018021:Lithium Chloride