Farrand Ariana Q, Helke Kristi L, Aponte-Cofresí Luis, Gooz Monika B, Gregory Rebecca A, Hinson Vanessa K, Boger Heather A
Dept of Neuroscience and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB 403, MSC 510, Charleston, SC, 29425, USA.
Dept of Comparative Medicine, Medical University of South Carolina, 114 Doughty St, STB 648, MSC 777, Charleston, SC, 29425, USA; Dept of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Ave, Children's Hospital 309, MSC 908, Charleston, SC, 29425, USA.
Behav Brain Res. 2019 Nov 5;373:112080. doi: 10.1016/j.bbr.2019.112080. Epub 2019 Jul 10.
Vagus nerve stimulation (VNS) is being explored as a potential therapeutic for Parkinson's disease (PD). VNS is less invasive than other surgical treatments and has beneficial effects on behavior and brain pathology. It has been suggested that VNS exerts these effects by increasing brain-derived neurotrophic factor (BDNF) to enhance pro-survival mechanisms of its receptor, tropomyosin receptor kinase-B (TrkB). We have previously shown that striatal BDNF is increased after VNS in a lesion model of PD. By chronically administering ANA-12, a TrkB-specific antagonist, we aimed to determine TrkB's role in beneficial VNS effects for a PD model. In this study, we administered a noradrenergic neurotoxin, DSP-4, intraperitoneally and one week later administered a bilateral intrastriatal dopaminergic neurotoxin, 6-OHDA. At this time, the left vagus nerve was cuffed for stimulation. Eleven days later, rats received VNS twice per day for ten days, with daily locomotor assessment. Daily ANA-12 injections were given one hour prior to the afternoon stimulation and concurrent locomotor session. Following the final VNS session, rats were euthanized, and left striatum, bilateral substantia nigra and locus coeruleus were sectioned for immunohistochemical detection of neurons, α-synuclein, astrocytes, and microglia. While ANA-12 did not avert behavioral improvements of VNS, and only partially prevented VNS-induced attenuation of neuronal loss in the locus coeruleus, it did stop neuronal and anti-inflammatory effects of VNS in the nigrostriatal system, indicating a role for TrkB in mediating VNS efficacy. However, our data also suggest that BDNF-TrkB is not the sole mechanism of action for VNS in PD.
迷走神经刺激（VNS）正在作为帕金森病（PD）的一种潜在治疗方法进行探索。VNS比其他手术治疗侵入性更小，并且对行为和脑病理具有有益作用。有人提出，VNS通过增加脑源性神经营养因子（BDNF）来增强其受体原肌球蛋白受体激酶B（TrkB）的促存活机制，从而发挥这些作用。我们之前已经表明，在PD损伤模型中，VNS后纹状体BDNF会增加。通过长期给予TrkB特异性拮抗剂ANA-12，我们旨在确定TrkB在PD模型的VNS有益作用中的作用。在本研究中，我们腹腔注射去甲肾上腺素能神经毒素DSP-4，一周后双侧纹状体内注射多巴胺能神经毒素6-OHDA。此时，对左侧迷走神经进行套扎以进行刺激。11天后，大鼠每天接受两次VNS，持续10天，并进行每日运动评估。在下午刺激和同时进行的运动评估前1小时，每天注射ANA-12。在最后一次VNS疗程后，对大鼠实施安乐死，并对左侧纹状体、双侧黑质和蓝斑进行切片，以免疫组织化学法检测神经元、α-突触核蛋白、星形胶质细胞和小胶质细胞。虽然ANA-12并没有避免VNS的行为改善，并且仅部分阻止了VNS诱导的蓝斑神经元损失的减轻，但它确实阻止了VNS在黑质纹状体系统中的神经元和抗炎作用，表明TrkB在介导VNS疗效中发挥作用。然而，我们的数据也表明，BDNF-TrkB不是VNS在PD中的唯一作用机制。
