Effects of mood stabilizers on DNA damage in an animal model of mania

Abstract

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.

Conclusion: 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.

Keywords: DNA damage; bipolar disorder; dopamine; lithium; models, animal; oxidative stress.

Fig. 1: Effects of D-amphetamine (AMPH), lithium (Li) and valproate (VPA) on crossing (horizontal) and rearing (vertical) behaviour in the (A) reversal and (B) prevention models. Values are expressed as means and standard deviation. *Statistically different from control group (SAL), as determined by one-way analysis of variance and Tukey test (p < 0.05).

Fig. 2: Frequency of micronucleus in the (A) prevention and (B) reversal models. We carried out the micronucleus analysis in lymphoblastic cells. Values are expressed as means and standard deviation. *Statistically different from control group (SAL), as determined by one-way analysis of variance and Tukey test (p < 0.05). Treatments with D-amphetamine + mood stabilizers did not differ from AMPH + saline in any of the models. AMPH = D-amphetamine; Li = lithium; SAL = saline; VPA = valproate.