Osaka-Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan.
PLoS One. 2010 Feb 17;5(2):e9260. doi: 10.1371/journal.pone.0009260.
Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.
METHODOLOGY/PRINCIPAL FINDINGS: A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.
CONCLUSIONS/SIGNIFICANCE: The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.
帕金森病（PD）患者的非运动症状（例如抑郁、焦虑和认知缺陷）先于运动症状出现。尽管这些症状不能通过药物多巴胺替代疗法来治疗，但它们的确切病理机制目前尚不清楚。本研究旨在探讨单侧 6-羟多巴胺（6-OHDA）对黑质致密部（SNc）的损伤是否会影响成年大鼠脑内的细胞增殖。此外，我们还研究了选择性 5-羟色胺再摄取抑制剂（SSRI）氟西汀和选择性去甲肾上腺素再摄取抑制剂马普替林对单侧 6-OHDA 损伤导致的颗粒下区（SGZ）细胞增殖减少的影响。
方法/主要发现：单侧 SNc 注射 6-OHDA 可导致纹状体和 SNc 中酪氨酸羟化酶（TH）免疫反应性几乎完全丧失，以及腹侧被盖区（VTA）中 TH 阳性细胞和纤维减少。另一方面，单独注射载体不会导致 TH 免疫反应性明显改变。单侧 6-OHDA 损伤 SNc 可显著减少 6-OHDA 损伤侧 SGZ 中的细胞增殖，但对侧 SGZ 或侧脑室下区（SVZ）中的细胞增殖没有影响。此外，亚慢性（14 天）给予氟西汀（5mg/kg/天）而非马普替林可显著减轻单侧 6-OHDA 损伤引起的 SGZ 细胞增殖减少。
结论/意义：本研究表明，齿状回颗粒下区的细胞增殖可能部分受到 SNc 和 VTA 的多巴胺控制，亚慢性给予氟西汀可逆转 6-OHDA 引起的 SGZ 细胞增殖减少。因此，氟西汀等 SSRIs 可能是治疗 PD 患者非运动症状和运动症状的潜在药物，这可能与 SGZ 细胞增殖减少有关。
