Mehrabian Zara, Guo Yan, Weinreich Daniel, Bernstein Steven L
Department of Ophthalmology, University of Maryland School of Medicine, Baltimore, MD.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD.
Mol Vis. 2017 Dec 17;23:963-976. eCollection 2017.
Optic nerve (ON) damage following nonarteritic anterior ischemic optic neuropathy (NAION) and its models is associated with neurodegenerative inflammation. Minocycline is a tetracycline derivative antibiotic believed to exert a neuroprotective effect by selective alteration and activation of the neuroinflammatory response. We evaluated minocycline's post-induction ability to modify early and late post-ischemic inflammatory responses and its retinal ganglion cell (RGC)-neuroprotective ability.
We used the rodent NAION (rNAION) model in male Sprague-Dawley rats. Animals received either vehicle or minocycline (33 mg/kg) daily intraperitoneally for 28 days. Early (3 days) ON-cytokine responses were evaluated, and oligodendrocyte death was temporally evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Cellular inflammation was evaluated with immunohistochemistry, and RGC preservation was compared with stereology of Brn3a-positive cells in flat mounted retinas.
Post-rNAION, oligodendrocytes exhibit a delayed pattern of apoptosis extending over a month, with extrinsic monocyte infiltration occurring only in the primary rNAION lesion and progressive distal microglial activation. Post-induction minocycline failed to improve retinal ganglion cell survival compared with the vehicle treated (893.14 vs. 920.72; p>0.9). Cytokine analysis of the rNAION lesion 3 days post-induction revealed that minocycline exert general inflammatory suppression without selective upregulation of cytokines associated with the proposed alternative or neuroprotective M2 inflammatory pathway.
The pattern of cytokine release, extended temporal window of oligodendrocyte death, and progressive microglial activation suggests that selective neuroimmunomodulation, rather than general inflammatory suppression, may be required for effective repair strategies in ischemic optic neuropathies.
非动脉炎性前部缺血性视神经病变（NAION）及其模型后的视神经（ON）损伤与神经退行性炎症相关。米诺环素是一种四环素衍生物抗生素，被认为通过选择性改变和激活神经炎症反应发挥神经保护作用。我们评估了米诺环素诱导后改变缺血后早期和晚期炎症反应的能力及其对视网膜神经节细胞（RGC）的神经保护能力。
我们在雄性Sprague-Dawley大鼠中使用啮齿动物NAION（rNAION）模型。动物每天腹腔注射溶剂或米诺环素（33mg/kg），持续28天。评估早期（3天）视神经细胞因子反应，并使用末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）分析对少突胶质细胞死亡进行时间评估。用免疫组织化学评估细胞炎症，并将RGC的保存情况与平铺视网膜中Brn3a阳性细胞的体视学进行比较。
rNAION后，少突胶质细胞表现出持续一个多月的延迟凋亡模式，外源性单核细胞浸润仅发生在原发性rNAION病变中，远端小胶质细胞逐渐激活。与溶剂处理组相比，诱导后使用米诺环素未能提高视网膜神经节细胞的存活率（893.14对920.72；p>0.9）。诱导后3天对rNAION病变进行细胞因子分析显示，米诺环素发挥了一般的炎症抑制作用，而没有选择性上调与提议的替代性或神经保护性M2炎症途径相关的细胞因子。
细胞因子释放模式、少突胶质细胞死亡的延长时间窗以及小胶质细胞的逐渐激活表明，缺血性视神经病变的有效修复策略可能需要选择性神经免疫调节，而不是一般的炎症抑制。
