title: Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons.
abstract: Excessive generation of free radicals is regarded as a major detrimental factor in cerebral ischemic insults. Neurons are particularly vulnerable to oxidative stress due to their limited anti-oxidant capacity. As an important source of antioxidants in the brain, astroglia are now thought to be attractive targets for pharmacological interventions to reduce neuronal oxidative stress in ischemic stroke. In the present study, we synthesized a novel antioxidant, the (1S)-(-)-verbenone derivative LMT-335, and investigated its anti-ischemic activities. In rat cortical neuronal/glial co-cultures, LMT-335 significantly reduced oxygen-glucose deprivation (OGD)/reoxygenation (R)-induced neuronal injury. Although it did not inhibit N-methyl-d-aspartate-induced excitotoxicity, LMT-335 significantly reduced OGD/R-evoked intracellular oxidative stress. However, the oxygen radical absorbance capacity assay and 1,1-diphenyl-2-picrylhydrazyl assay showed that the free radical scavenging activities of LMT-335 were lower than those of trolox. Instead, LMT-335 significantly increased the astroglial expression of heme oxygenase-1 (HO-1), a well-known anti-oxidant stress protein, as evidenced by immunocytochemistry and immunoblot analyses. Moreover, a selective HO-1 inhibitor, tin protoporphyrin IX (SnPP), significantly blocked the anti-ischemic effect of LMT-335. The present findings indicate that LMT-335 exerts neuroprotective effects against OGD/R by up-regulation of HO-1 in astroglial cells. Our data suggest that astroglial HO-1 represents a potential therapeutic target for the treatment of ischemic stroke.
authors: Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, Republic of Korea.
authors: Chung
authors: C
authors: Ju
authors: Sumi
authors: S
authors: Song
authors: Minkyoung
authors: M
authors: Kim
authors: Yongseok
authors: Y
authors: Choi
authors: Won-Ki
authors: WK
authors: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D000081008:Bicyclic Monoterpenes; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C583048:6,6-dimethyl-4-(4-methylstyryl)bicyclo(3.1.1)hept-3-en-2-one; D001597:Benzylidene Compounds; D000081008:Bicyclic Monoterpenes; D003512:Cyclohexanones; D018696:Neuroprotective Agents; D013729:Terpenes; C052875:verbenone; D051547:Heme Oxygenase-1; D005947:Glucose; D010100:Oxygen