Guo Cindy X, Mat Nor Mohd N, Danesh-Meyer Helen V, Vessey Kirstan A, Fletcher Erica L, O'Carroll Simon J, Acosta Monica L, Green Colin R
School of Optometry and Vision Science, University of Auckland, Auckland, New Zealand 2New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand 3Department of Ophthalmology, University of Auckland, Auckland, New Zealand.
Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):3961-73. doi: 10.1167/iovs.15-16643.
Drugs that regulate connexin43 (Cx43) gap junction channels can reduce the spread of injury and improve functional outcomes after nervous system trauma. In the eye, Cx43 expression increases in the choroid following light damage. The aim of this study was to investigate whether Cx43 hemichannel block could preserve retinal function postinjury.
Light damage was induced by exposure of adult albino Sprague-Dawley rats to 2700 Lux light for 24 hours. Intravitreal injections of a Cx43 mimetic peptide hemichannel blocker, Peptide5, or sham were administered 2 hours after the onset and at the end of the light damage period. Retinal function was assessed by electroretinogram and inflammatory responses in the choroid and retina were assessed using immunohistochemistry (ionized calcium binding adaptor molecule 1 [Iba-1], leukocyte common antigen [CD45], glial fibrillary acidic protein [GFAP]).
Light-damaged rat eyes had (1) reduced neuronal responses in both the rod and cone pathways and (2) marked inflammatory responses in the choroid and retina. Peptide5 significantly preserved function of photoreceptoral and postphotoreceptoral neurons in these animals. This was evident 24 hours after injury and 2 weeks later, as shown by improved mixed a-wave and mixed b-wave amplitudes, isolated rod PII and PIII amplitudes, and cone PII responses when compared with sham-treated controls. Retinal thinning and inflammation were also significantly reduced in Peptide5-treated eyes when compared with sham-treated controls.
Blocking Cx43 hemichannels after light damage can significantly improve functional outcomes of neurons in both the rod and cone photo-transduction pathways in the light-damaged animal model, likely by reducing choroid inflammation and suppressing the glial-mediated inflammatory response. These data may have relevance for the treatment of conditions such as diabetic retinopathy and age-related macular degeneration.
调节连接蛋白43（Cx43）间隙连接通道的药物可减少损伤扩散并改善神经系统创伤后的功能结局。在眼睛中，光损伤后脉络膜中Cx43表达增加。本研究的目的是调查Cx43半通道阻断是否能在损伤后保留视网膜功能。
将成年白化Sprague-Dawley大鼠暴露于2700勒克斯光照下24小时以诱导光损伤。在光损伤期开始后2小时和结束时，玻璃体内注射Cx43模拟肽半通道阻滞剂Peptide5或进行假注射。通过视网膜电图评估视网膜功能，并使用免疫组织化学（离子钙结合衔接分子1 [Iba-1]、白细胞共同抗原[CD45]、胶质纤维酸性蛋白[GFAP]）评估脉络膜和视网膜中的炎症反应。
光损伤的大鼠眼睛（1）在视杆和视锥通路中的神经元反应均降低，（2）脉络膜和视网膜中有明显的炎症反应。Peptide5显著保留了这些动物中光感受器和光感受器后神经元的功能。损伤后24小时和2周后，与假处理对照组相比，混合a波和混合b波振幅、孤立视杆PII和PIII振幅以及视锥PII反应改善，这一点很明显。与假处理对照组相比，Peptide5处理的眼睛中的视网膜变薄和炎症也显著减轻。
在光损伤后阻断Cx43半通道可显著改善光损伤动物模型中视杆和视锥光转导通路中神经元的功能结局，可能是通过减少脉络膜炎症和抑制胶质细胞介导的炎症反应实现的。这些数据可能与糖尿病性视网膜病变和年龄相关性黄斑变性等疾病的治疗有关。
