JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 24, Number 5, 2008 © Mary Ann Liebert, Inc. DOI: 10.1089/jop.2008.0005 Ferulic Acid, but not Tetramethylpyrazine, Significantly Attenuates Retinal Ischemia/Reperfusion-Induced Alterations by Acting as a Hydroxyl Radical Scavenger Hsiao-Ming Chao, 1–3 De-Ean Lin, 1,4 Ying Chang, 4,5 Weng-Ming Hsu, 6 Shui-Mei Lee, 1,2 Fenq-Lih Lee, 1,2 Chin-Wen Chi, 3,7 Wynn H.T. Pan, 3 Tsung-Yun Liu, 3,7 Wing-Yiu Lui, 8,9 Low-Tone Ho, 7 Cheng-Deng Kuo, 7 Chia-Chin Chan, 1,5 and Fang-Ping Chao 1,7 Abstract Purpose: Ischemia plays an important role in glaucomatous optic neuropathy and retinal vascular occlusive disorders, which renders investigation vital. Methods: Retinal ischemia was induced by raising intraocular pressure to 120 mmHg. Its mechanism and man- agement was evaluated by measuring  OH levels, electroretinogram (ERG) b-wave amplitudes, immunohisto- chemistry, and reverse transcriptase polymerase chain reaction. Results: Ischemia for 45, 60, and 75 min caused significant and time-dependent increased  OH levels, which might contribute to retinal ischemic injures. Specifically, 60 min of ischemia plus reperfusion, causing moder- ate oxidative stress, resulted in retinal changes that were characterized by decreased ERG b-wave amplitudes, loss of choline acetyltransferase immunolabeled amacrine cell bodies/neuronal processes, downregulated Thy- 1 m-RNA levels (indexing retinal ganglion cells; RGCs), and reduced thickness of the Thy-1 immunolabeled RGC and inner plexiform layers. Of clinical importance, this is the first study to show that ischemic detrimen- tal effects are significantly blunted when 0.5 nmol of ferulic acid, one active ingredient of Ligusticum walliichi (Chuanxiong), was applied 24 h before retinal ischemia. Further, but not to a significant level, 0.5 nmole of tetramethylpyazine, another Chuanxiong-active component, showed such an ameliorating trend. Moreover, the 60-min ischemia-induced significant increase in  OH production was significantly attenuated by FA. Conclusions: FA is able to protect against retinal ischemia and possibly glaucoma by, at least in part, acting as a  OH scavenger. 461 Introduction C ENTRAL RETINAL ARTERY AND VEIN OCCLUSION, DIABETES, AND GLAUCOMA are conditions that have been associated with ischemic changes of the retina. Clinically, retinal isch- emia is recognized by an alteration in the b-wave of the elec- troretinogram (ERG), cotton wool spots, hemorrhage, and sometimes pathologic disc “cupping.” Worldwide, there are 65 million people with glaucoma, of whom around 7.5 mil- lion have become blind. 1 Further, glaucoma is the second most common cause of blindness in the world. Even in the developed world, where attempts at early diagnosis are es- tablished, there is little sign that the problem is diminishing. This indicates that glaucoma is an intractable problem that needs to be urgently managed. Glaucoma and retinal isch- emia, such as central retinal artery occlusion (CRAO), share a number of pathologic similarities. 2,3 CRAO, for example, is an ocular emergency that, not uncommonly, ends with a poor visual outcome if treatment is delayed longer than 97 min. 4 Ischemic insult is also known to play an important role 1 Department of Ophthalmology, Veterans General Hospital, Taipei, Taiwan, R.O.C. 2 Department of Ophthalmology, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C. 3 Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C. 4 Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan, R.O.C. 5 Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan, R.O.C. 6 Department of Ophthalmology, School of Medicine, Taipei Medical University, Taiwan, R.O.C. 7 Department of Medical Research and Education, Veterans General Hospital, Taipei, Taiwan, R.O.C. 8 Department of Surgery, Veterans General Hospital, Taipei, Taiwan, R.O.C. 9 Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C.