Neuroscience Letters 395 (2006) 103–107 The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice Seong-Ho Koh a,1 , Sang Mok Lee a,1 , Hyun Young Kim a , Kyu-Yong Lee a , Young Joo Lee a , Hee-Tae Kim a , Juhan Kim a , Myung-Ho Kim a , Myung Sil Hwang b , Chiwon Song b , Ki-Wha Yang b , Kwang Woo Lee c , Seung Hyun Kim a,∗ , Ok-Hee Kim b a Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea b Department of Toxicological Research, National Institute of Toxicological Research, KFDA, Seoul, Republic of Korea c Department of Neurology, Neuroscience Center, Seoul National University, Seoul, Republic of Korea Received 31 August 2005; received in revised form 10 October 2005; accepted 25 October 2005 Abstract Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinson’s and Alzheimer’s diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic lateral sclerosis (ALS). This study was undertaken to evaluate the effect of EGCG on ALS model mice with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene. We treated each group of 11 ALS model mice with EGCG (1.5, 2.9, and 5.8 g/g body weight), dissolved in 0.5 ml of 0.9% sterile NaCl, and one group of 11 with 0.5 ml of 0.9% sterile NaCl (control group) intraorally every day after 60 days of age (presymptomatic treatment). The treatment of more than 2.9 g EGCG/g body weight significantly prolonged the symptom onset and life span, preserved more survival signals, and attenuated death signals. These data suggest that EGCG could be a potential therapeutic candidate for ALS as a disease-modifying agent. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: ALS; EGCG; Transgenic mouse; Neuronal cell death Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by selective degeneration of motor neurons. Recent studies using ALS models or the spinal cord of ALS patients have emphasized the role of oxidative stress, excitotoxicity, calcium mediated toxicity, genetic defects, autoimmunity and accumulation of abnormal proteins as its pathogenic mechanisms [3,5,7,12,14,24]. In the case of oxida- tive stress, antioxidant therapy has been tried to prevent neu- ronal cell death and/or delay the progression of ALS [2,5,17, 25]. Epigallocatechin gallate (EGCG), one of the major con- stituents of green tea, has been known to have anti-apoptotic, anti-cancer, anti-mutagenic, and anti-neurodegenerative effects. Our previous study showed that EGCG prevented oxida- ∗ Corresponding author. Tel.: +82 2 2290 8371; fax: +82 2 2296 8370. E-mail address: kimsh1@hanyang.ac.kr (S.H. Kim). 1 Both authors contributed equally as the first authors. tive stress-induced apoptosis of motor neurons transfected with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene, by up-regulating survival signals, including phosphatidylinositol 3-kinase (PI3-K), phospho-Akt (pAkt), and phospho-glycogen synthase kinase-3 (pGSK-3) and by down-regulating of death signals, such as mitochondrial dam- age, activated caspase-3, and cleaved poly(ADP-ribose) poly- merase (PARP) [17]. Recently, we demonstrated that increased activity of GSK-3 was one of the important pathogenic mech- anisms of an in vitro model of familial ALS [19], and EGCG had an inhibitory effect on GSK-3 activity [17]. Considering these neuroprotective effects of EGCG in the in vitro model of ALS, we can hypothesize that treatment with EGCG may delay symptom onset and prolong survival time of an animal model of familial ALS. In this present study, we examined whether treatment with EGCG could delay the outbreak and/or progression of ALS and what would be its effect on the PI3-K/Akt and GSK-3 pathway as well as on the caspase-3 pathway in transgenic mice carry- 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.10.056