Andreazza Ana Cristina, Kauer-Sant'Anna Marcia, Frey Benicio N, Stertz Laura, Zanotto Caroline, Ribeiro Leticia, Giasson Karine, Valvassori Samira S, Réus Gislaine Z, Salvador Mirian, Quevedo João, Gonçalves Carlos A, Kapczinski Flavio
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Brazil.
J Psychiatry Neurosci. 2008 Nov;33(6):516-24.
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.
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.
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.
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.
近期研究表明，氧化应激和DNA损伤可能在双相情感障碍（BD）的病理生理学中起作用。我们在躁狂症动物模型中研究了心境稳定剂锂盐和丙戊酸盐对苯丙胺诱导的DNA损伤的影响及其与氧化应激标志物的相关性。
在第一个实验（逆转模型）中，我们用D-苯丙胺（AMPH）或生理盐水治疗成年雄性Wistar大鼠14天；在第8天至14天期间，大鼠还接受锂盐、丙戊酸盐或生理盐水治疗。在第二个实验（预防模型）中，大鼠接受锂盐、丙戊酸盐或生理盐水治疗14天；在第8天至14天期间，我们添加AMPH或生理盐水。我们使用单细胞凝胶电泳（彗星试验）评估DNA损伤，并使用微核试验评估诱变潜力。我们通过脂质过氧化水平（TBARS）和抗氧化酶活性（超氧化物歧化酶和过氧化氢酶）评估氧化应激水平。我们评估血液/血浆和海马样本中的DNA损伤和氧化应激标志物。我们评估新鲜淋巴细胞中的诱变作用。
在两个模型中，我们发现AMPH增加了外周和海马的DNA损伤。DNA损伤指数与脂质过氧化呈正相关，而锂盐和丙戊酸盐能够调节氧化平衡并预防近期的DNA损伤。然而，锂盐和丙戊酸盐不能预防微核形成。
我们的结果支持锂盐和丙戊酸盐具有中枢和外周抗氧化样特性的观点。此外，锂盐对DNA完整性的保护似乎仅限于短暂的DNA损伤，并且不会改变微核形成。
