Effect of fluoxetine on disease progression in a mouse model of ALS.
Effect of fluoxetine on disease progression in a mouse model of ALS.
复制标题
DOI：
10.1152/jn.00425.2013
复制
发表时间：
2014-06
影响因子：
2.5
通讯作者：
Jenna E. Koschnitzky;K. Quinlan;T. Lukas;E. Kajtaz;Emily J Kocevar;W. Mayers;T. Siddique;C. Heckman
中科院分区：
文献类型：
--
作者：
Jenna E. Koschnitzky;K. Quinlan;T. Lukas;E. Kajtaz;Emily J Kocevar;W. Mayers;T. Siddique;C. Heckman
选择性5-羟色胺再摄取抑制剂（SSRIs）和其他抗抑郁药通常用于肌萎缩侧索硬化症（ALS）患者;然而，这些处方对ALS疾病进展的影响尚未进行系统性测试。为了确定SSRI是否影响疾病进展，在以下三个年龄范围之一对突变型超氧化物歧化酶1（SOD 1）小鼠进行了氟西汀（百忧解，5或10 mg/kg）给药：新生儿[产后第5-11天（P）]、成年症状前（P30至末期）和成年症状（P70至末期）。长期成人氟西汀治疗（从P30或P70开始，持续至终末期）对疾病进展无显著影响。相比之下，新生儿氟西汀治疗（P5-11）有两个影响。首先，接受最高剂量（10 mg/kg）的所有动物（突变型SOD 1（G93 A）和对照：非转基因和SOD 1（WT））从P30开始体重持续下降。第二，高剂量SOD 1（G93 A）小鼠比溶剂和低剂量动物更早达到终末期208天（寿命缩短206%），因为运动损伤率增加。氟西汀增加突触5-羟色胺（5-HT）水平，这是已知的增加脊髓运动神经元兴奋性。我们证实，5-羟色胺增加脊髓运动神经元的兴奋性，在这个新生儿的时间段，因此假设，拮抗5-羟色胺受体在同一时间段将改善疾病的结果。然而，赛庚啶（1或5毫克/公斤），5-羟色胺受体拮抗剂，对疾病进展没有影响。这些结果表明，在关键时间窗（从新生儿到青少年状态的转变）期间的短暂抗抑郁治疗对ALS小鼠模型可能是有害的。
Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.