Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells.
Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells.
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DOI：
10.1001/archopht.120.6.797
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发表时间：
2002-06
影响因子：
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通讯作者：
Hua Gao;X. Qiao;L. Cantor;D. WuDunn
中科院分区：
文献类型：
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作者：
Hua Gao;X. Qiao;L. Cantor;D. WuDunn
酒石酸溴莫尼定是一种α（2）-肾上腺素能激动剂，被广泛用作降低眼内压的抗青光眼药物。最近的研究表明，溴莫尼定可能对视神经挤压损伤后的视网膜神经节细胞（RGC）具有神经保护作用。脑源性神经营养因子（BDNF），一种存在于RGC中的有效神经保护因子，促进RGC在培养和视神经损伤后的存活。我们检验了溴莫尼定神经保护的可能机制是通过上调RGCs中内源性BDNF表达的假设。方法将酒石酸溴莫尼定眼内注射液（0.85-34 μ M）一次性注入SD大鼠眼内。每只动物的对侧眼注射平衡盐溶液（BSS）并用作对照眼。为了确定BDNF信使RNA的表达，摘除动物眼睛并进行原位杂交，或者分离视网膜并进行北方印迹分析，使用大鼠BDNF放射性标记的核糖核酸探针。结果在注射生理盐水的对照眼中，BDNF存在于少数RGCs中。溴莫尼定注射后两天，与对照组相比，BDNF阳性RGCs的数量从55%增加到166%，这取决于溴莫尼定浓度。此外，与对照眼相比，溴莫尼定注射眼的单个RGCs中BDNF信号强度升高50%。北方杂交显示溴莫尼定组BDNF表达较对照组增加28%（P <0.003）。在溴莫尼定或BSS对照组之间没有观察到BDNF受体、trk B表达的显著差异。结论：玻璃体内单剂量低浓度溴莫尼定足以显著增加RGCs内源性BDNF表达。这些结果表明，溴莫尼定的神经保护作用可能是通过上调RGCs中的BDNF介导的。BDNF在溴莫尼定神经保护作用中的作用有待进一步研究。临床相关性溴莫尼定可能（潜在）在临床上用作视神经病变（包括青光眼）以及缺血性和创伤性视神经病变的神经保护剂。
OBJECTIVES Brimonidine tartrate ophth, an alpha(2)-adrenergic agonist, is widely used as an antiglaucoma agent for lowering intraocular pressure. Recent studies suggest that brimonidine may be neuroprotective for retinal ganglion cells (RGCs) following optic nerve crush injury. Brain-derived neurotrophic factor (BDNF), a potent neuroprotective factor present in the RGCs, promotes RGC survival in culture and following optic nerve injury. We tested the hypothesis that a possible mechanism of brimonidine neuroprotection is through up-regulation of endogenous BDNF expression in the RGCs. METHODS A single dosage of brimonidine tartrate ophth solution (0.85-34 microM) was injected intravitreally into Sprague-Dawley rat eyes. The fellow eyes of each animal were injected with balanced salt solution (BSS) and used as control eyes. To determine BDNF messenger RNA expression, animal eyes were enucleated and processed for in situ hybridization, or retinas were isolated and processed for Northern blot analysis using rat BDNF radiolabeled riboprobes. RESULTS In the control eyes injected with saline, BDNF was present in a minority of the RGCs. Two days after brimonidine injection, the number of BDNF-positive RGCs was increased from 55% to 166%, depending on brimonidine concentrations, when compared with those in the controls. In addition, the BDNF signal intensities in individual RGCs were elevated 50% in brimonidine-injected eyes compared with control eyes. Northern blot revealed a 28% increase of BDNF expression in the brimonidine group compared with the controls (P <.003). No significant difference was observed in BDNF receptor, trk B, expression between brimonidine, or BSS control groups. CONCLUSIONS A single dose of a low concentration of intravitreal brimonidine is sufficient to significantly increase endogenous BDNF expression in RGCs. These results suggest that brimonidine neuroprotection may be mediated through up-regulation of BDNF in the RGCs. The BDNF should be further investigated regarding its role in the neuroprotective effects reported with brimonidine. CLINICAL RELEVANCE Brimonidine may be (potentially) used clinically as a neuroprotective agent in optic neuropathy, including glaucoma, and ischemic and traumatic optic neuropathy.