Department of Ophthalmology, Medical University of Innsbruck, Innsbruck, Austria.
Acta Ophthalmol. 2011 Nov;89(7):670-5. doi: 10.1111/j.1755-3768.2009.01828.x. Epub 2010 Jan 8.
To evaluate the effect of intravitreal injection of N-methyl-D-aspartate (NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) and the VIP-associated glial protein activity-dependent neuroprotective protein (ADNP) in the rat retina. These elements have well-documented neuroprotective properties and may thus be integrated in endogenous neuroprotective mechanisms in the retina which break down in NMDA excitotoxicity.
A volume of 2 μl of 100 nmol NMDA was intravitreally injected into one eye of rats, the untreated eye served as a control. Time-dependent effects of NMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay and ELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluated by quantitative RT-PCR 20 days after NMDA injection. Topical flunarizine served to find out whether the effect of NMDA is counteracted.
Compared to PACAP-38, VIP levels significantly decreased on days 1, 7, 14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerable than PACAP-38-expressing cells. The expression of VIP and ADNP but not of PACAP-38 was found to be reduced, and application of topical flunarizine counteracted the decrease of VIP. BDNF levels significantly increased after days 1 and 3.
The early upregulation of BDNF seems to act neuroprotectively and leads to a delay of ganglion cell loss. Although there is no direct evidence, the decrease of VIP and ADNP - the consequence of the presence of NMDA receptors on these peptide-expressing cells - might contribute to the breakdown of endogenous neuroprotective mechanisms given that the decrease of the VIP-related ADNP runs in parallel with the decrease of VIP. Activating and maintaining these mechanisms must be the primary aim in the therapy of diseases with retinal neuronal degeneration.
评估 N-甲基-D-天冬氨酸（NMDA）对大鼠视网膜中脑源性神经营养因子（BDNF）、垂体腺苷酸环化酶激活肽-38（PACAP-38）、血管活性肠肽（VIP）和 VIP 相关神经胶质蛋白活性依赖性神经营养蛋白（ADNP）的影响。这些物质具有良好的神经保护作用，因此可能整合在视网膜内源性神经保护机制中，而 NMDA 兴奋性毒性会破坏这些机制。
向大鼠一只眼的玻璃体内注射 2 μl 100nmol NMDA，未处理的眼睛作为对照。通过放射免疫分析和 ELISA 检测 NMDA 对 VIP、PACAP-38 和 BDNF 的时间依赖性影响，并在 NMDA 注射 20 天后通过定量 RT-PCR 评估 NMDA 对 VIP、PACAP-38 和 ADNP 表达的影响。局部氟桂利嗪用于确定 NMDA 的作用是否被拮抗。
与 PACAP-38 相比，NMDA 注射后第 1、7、14、28 和 56 天 VIP 水平显著降低，表明 VIP 能细胞比表达 PACAP-38 的细胞更脆弱。发现 VIP 和 ADNP 的表达减少，但 PACAP-38 的表达没有减少，局部应用氟桂利嗪可拮抗 VIP 的减少。BDNF 水平在第 1 天和第 3 天显著增加。
BDNF 的早期上调似乎具有神经保护作用，并导致节细胞丢失延迟。尽管没有直接证据表明，由于这些肽表达细胞上存在 NMDA 受体，VIP 和 ADNP 的减少可能导致内源性神经保护机制的崩溃，但 VIP 相关的 ADNP 的减少与 VIP 的减少平行，这可能有助于内源性神经保护机制的崩溃。激活和维持这些机制必须是治疗视网膜神经元变性疾病的主要目标。
