Department of Neuroscience and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB Suite 403, MSC 510, Charleston, SC, 29425, USA.
Neuromodulation Division of LivaNova, PLC, 100 Cyberonics Blvd, Houston, TX, 77058, USA.
Brain Stimul. 2020 Sep-Oct;13(5):1323-1332. doi: 10.1016/j.brs.2020.06.078. Epub 2020 Jul 3.
Vagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the solitary nucleus. Degeneration of the LC in Parkinson's disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify disease progression. We previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss.
The goal of this study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model.
Eleven days after DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, noradrenergic lesion, administered systemically)/6-OHDA (6-hydroxydopamine, dopaminergic lesion, administered intrastriatally) rats were implanted with VNS devices, and received either low-frequency VNS, standard-frequency VNS, or high-frequency microburst VNS. After 10 days of treatment and behavioral assessment, rats were euthanized, right prefrontal cortex (PFC) was dissected for norepinephrine assessment, and the left striatum, bilateral substantia nigra (SN), and LC were sectioned for immunohistochemical detection of catecholamine neurons, α-synuclein, astrocytes, and microglia.
At higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC. Additionally, higher VNS frequencies resulted in lower intrasomal α-synuclein accumulation and glial density in the SN.
These data indicate that higher stimulation frequencies provided the greatest attenuation of behavioral and pathological markers in this PD model, indicating therapeutic potential for these VNS paradigms.
迷走神经刺激（VNS）通过孤束核改变蓝斑（LC）中的脑节律。帕金森病（PD）中 LC 的退化是神经退行性过程扩散的早期催化剂，这表明 VNS 刺激 LC 输出具有改变疾病进展的潜力。我们之前在 PD 病变模型中表明，每日两次给予 VNS 可减少神经炎症和运动缺陷，并减轻酪氨酸羟化酶（TH）阳性细胞丢失。
本研究的目的是在 PD 病变模型中描述三种临床相关 VNS 方案的差异作用。
在 DSP-4（N-（2-氯乙基）-N-乙基-2-溴苯甲胺，去甲肾上腺素病变，全身给予）/6-OHDA（6-羟多巴胺，多巴胺病变，纹状体内给予）后 11 天，大鼠植入 VNS 装置，并接受低频 VNS、标准频率 VNS 或高频微爆发 VNS。经过 10 天的治疗和行为评估后，处死大鼠，取出右侧前额叶皮层（PFC）进行去甲肾上腺素评估，并对左侧纹状体、双侧黑质（SN）和 LC 进行切片，用于检测儿茶酚胺神经元、α-突触核蛋白、星形胶质细胞和小胶质细胞的免疫组织化学。
在更高的 VNS 频率下，特别是微爆发 VNS，运动功能得到了更大的改善，SN 和 LC 中的 TH 阳性细胞丢失以及 PFC 中的去甲肾上腺素浓度得到了减弱。此外，更高的 VNS 频率导致 SN 中细胞内α-突触核蛋白积累和胶质密度降低。
这些数据表明，在这种 PD 模型中，更高的刺激频率提供了对行为和病理标志物最大的衰减，表明这些 VNS 方案具有治疗潜力。
