title: Amelioration of Cerebral Ischemic Injury by a Synthetic Seco-nucleoside LMT497.
abstract: Recently, we reported that the A3 adenosine receptor (A3AR) agonist LJ529 (2-chloro-N(6)-(3-iodobnzyl)-5'-N-methylcarbamoyl-4'-thioadenosine) reduces cerebral ischemic injury via inhibition of recruitment of peripheral inflammatory cells into ischemic brain lesion. A3AR agonists, however, are known to possess anti-platelet activity, which may deter the combination therapy with tissue plasminogen activator for the therapy of cerebral ischemic stroke. Thus, the present study investigates the neuroprotective/anti-ischemic effect of a synthetic seco-nucleoside, LMT497 ((S)-2-((R)-1-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)-2-hydroxyethoxy)-3-hydroxy-N-methylpropanamide) with little anti-platelet activity. LMT497 neither showed A3AR binding activity nor anti-platelet activity. In our present study LMT497 significantly attenuated the injury/death of cortical neurons exposed to oxygen-glucose deprivation (OGD) followed by re-oxygenation (R). LMT497 significantly reduced the ascending cellular level of reactive oxygen species under ischemic conditions by increasing the superoxide dismutase (SOD) levels. LMT497 also inhibited the migration of microglia which mediates inflammatory responses in ischemia. In rats subjected to middle cerebral artery occlusion (MCAO, 1.5 h) followed by reperfusion, LMT497 largely reduced brain infarction volume, and edema, and improved neurological score. Therapeutic efficacy of LMT497 was obtained by twice treatments even at 10 h and 18 h after the onset of ischemia. Collectively, LMT497 could be a therapeutic drug candidate with a wide therapeutic time window for the treatment of cerebral ischemic stroke.
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Sangwoo
authors: S
authors: Ryu
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Joonha
authors: J
authors: Kwon
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Hyeon
authors: H
authors: Park
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: In-Young
authors: IY
authors: Choi
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Sunyoung
authors: S
authors: Hwang
authors: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors: Veeraswamy
authors: V
authors: Gajulapati
authors: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors: Joo Young
authors: JY
authors: Lee
authors: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors: Yongseok
authors: Y
authors: Choi
authors: Dipartimento di Scienze Farmaceutiche and Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia, Università, di Ferrara, 44100 Ferrara, Italy.
authors: Katia
authors: K
authors: Varani
authors: Dipartimento di Scienze Farmaceutiche and Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia, Università, di Ferrara, 44100 Ferrara, Italy.
authors: Pier Andrea
authors: PA
authors: Borea
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Chung
authors: C
authors: Ju
authors: Department of Neuroscience, School of Medicine, Korea University, Seoul 136-705, Korea.
authors: Won-Ki
authors: WK
authors: Kim
keywords: Cl-IB-MECA; LMT497; MCAO; cerebral ischemia; inflammation; oxidative stress