Division of Biomedical Sciences, Riverside School of Medicine, University of California, Riverside, CA, USA.
Department of Bioengineering, Riverside Bourns School of Engineering, University of California, Riverside, CA, USA.
Brain Pathol. 2021 Mar;31(2):312-332. doi: 10.1111/bpa.12930. Epub 2021 Jan 29.
Visual deficits are among the most prevalent symptoms in patients with multiple sclerosis (MS). To understand deficits in the visual pathway during MS and potential treatment effects, we used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The afferent visual pathway was assessed in vivo using optical coherence tomography (OCT), electroretinography (ERG), and visually evoked cortical potentials (VEPs). Inflammation, demyelination, and neurodegeneration were examined by immunohistochemistry ex vivo. In addition, an immunomodulatory, remyelinating agent, the estrogen receptor β ligand chloroindazole (IndCl), was tested for its therapeutic potential in the visual pathway. EAE produced functional deficits in visual system electrophysiology, including suppression of ERG and VEP waveform amplitudes and increased signal latencies. Therapeutic IndCl rescued overall visual system latency by VEP but had little impact on amplitude or ERG findings relative to vehicle. Faster VEP conduction in IndCl-treated mice was associated with enhanced myelin basic protein signal in all visual system structures examined. IndCl preserved retinal ganglion cells (RGCs) and oligodendrocyte density in the prechiasmatic white matter, but similar retinal nerve fiber layer thinning by OCT was noted in vehicle and IndCl-treated mice. Although IndCl differentially attenuated leukocyte and astrocyte staining signal throughout the structures analyzed, axolemmal varicosities were observed in all visual fiber tracts of mice with EAE irrespective of treatment, suggesting impaired axonal energy homeostasis. These data support incomplete functional recovery of VEP amplitude with IndCl, as fiber tracts displayed persistent axon pathology despite remyelination-induced decreases in latencies, evidenced by reduced optic nerve g-ratio in IndCl-treated mice. Although additional studies are required, these findings demonstrate the dynamics of visual pathway dysfunction and disability during EAE, along with the importance of early treatment to mitigate EAE-induced axon damage.
视觉缺陷是多发性硬化症（MS）患者最常见的症状之一。为了了解 MS 期间视觉通路的缺陷和潜在的治疗效果，我们使用实验性自身免疫性脑脊髓炎（EAE），这是 MS 最常用的动物模型。使用光学相干断层扫描（OCT）、视网膜电图（ERG）和视觉诱发电位（VEP）在体内评估传入视觉通路。通过免疫组织化学在体外侧评估炎症、脱髓鞘和神经退行性变。此外，还测试了一种免疫调节、髓鞘再生剂，即雌激素受体β配体氯吲哚（IndCl），以评估其在视觉通路中的治疗潜力。EAE 导致视觉系统电生理学的功能缺陷，包括 ERG 和 VEP 波形幅度的抑制以及信号潜伏期的增加。治疗性 IndCl 通过 VEP 挽救了整个视觉系统的潜伏期，但与载体相比，对幅度或 ERG 发现几乎没有影响。在 IndCl 治疗的小鼠中，更快的 VEP 传导与所有检查的视觉系统结构中的髓鞘碱性蛋白信号增强有关。IndCl 可保留视交叉前白质中的视网膜神经节细胞（RGC）和少突胶质细胞密度，但在载体和 IndCl 治疗的小鼠中观察到类似的视网膜神经纤维层变薄。尽管 IndCl 在整个分析结构中差异地减弱了白细胞和星形胶质细胞染色信号，但在患有 EAE 的小鼠的所有视觉纤维束中都观察到轴突鞘膜的瘤样变，表明轴突能量代谢失衡。这些数据支持 IndCl 对 VEP 幅度的不完全功能恢复，因为尽管潜伏期降低导致髓鞘再生，但纤维束仍显示出持续的轴突病理学，这在 IndCl 治疗的小鼠中表现为视神经 g-比降低。尽管还需要进一步的研究，但这些发现表明了 EAE 期间视觉通路功能障碍和残疾的动态，以及早期治疗以减轻 EAE 诱导的轴突损伤的重要性。
