尽管神经胶质细胞系源性神经营养因子(GDNF)在临床前和早期临床研究中显示出缓解帕金森病(PD)的帕金森病征象的功效,后来的试验未达到主要终点,暂停考虑进一步调查。虽然GDNF剂量和给药方法可能导致疗效下降,这些临床研究的一个关键方面是GDNF治疗在PD诊断后约8年开始;这个时间点代表了纹状体中接近100%的黑质纹状体多巴胺标志物耗尽和黑质(SN)中至少50%耗尽后的几年,这表示启动GDNF治疗的时间点晚于一些临床前研究报告。在PD诊断时,黑质纹状体终末损失超过70%,我们利用半帕金森病大鼠来确定GDNF家族受体的表达,GFR-α1和受体酪氨酸激酶,RET,在6-羟基多巴胺(6-OHDA)半切除术后的1周和4周,纹状体和SN之间存在差异。GDNF表达变化最小,GFR-α1在SN纹状体和酪氨酸羟化酶阳性(TH+)细胞中表达逐渐降低,与TH细胞数量减少相关。然而,在黑色星形胶质细胞中,GFR-α1表达增加。到1周时,纹状体中RET表达最大程度地降低,而在SN中,发生了短暂的双边增加,4周后恢复到控制水平。脑源性神经营养因子(BDNF)或其受体的表达,TrkB,在整个病变进展过程中没有变化。一起,这些结果表明纹状体和SN之间的差异GFR-α1和RET表达,和SN中GFR-α1表达的细胞特异性差异,发生在黑质纹状体神经元丢失期间。因此,GDNF受体的靶向损失似乎对于增强GDNF对抗黑质纹状体神经元损失的治疗功效至关重要。重要声明:尽管临床前证据支持GDNF在临床前研究中提供神经保护并改善运动功能,它是否能缓解帕金森病患者的运动障碍存在不确定性。利用建立的6-OHDA半帕金森病大鼠模型,我们确定其同源受体的表达,GFR-α1和RET,在时间表研究中,纹状体和黑质之间的差异影响。在纹状体中,RET的早期和重大损失,但是一个渐进的,GFR-α1的进行性丧失。相比之下,病变黑质中RET短暂增加,但是GFR-α1仅在黑质纹状体神经元中逐渐降低,并与TH细胞丢失相关。我们的结果表明,GFR-α1的直接可用性可能是决定纹状体分娩后GDNF功效的关键因素。
Although glial cell line-derived neurotrophic factor (
GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson\'s disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While
GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating
GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas
GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of
GDNF receptors thus appears critical to enhance
GDNF therapeutic efficacy against nigrostriatal neuron loss. SIGNIFICANCE STATEMENT: Although preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson\'s disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.