TY - JOUR
T1 - Up-regulation of astroglial heme oxygenase-1 by a synthetic (S)-verbenone derivative LMT-335 ameliorates oxygen-glucose deprivation-evoked injury in cortical neurons
AU - Ju, Chung
AU - Song, Sumi
AU - Kim, Minkyoung
AU - Choi, Yongseok
AU - Kim, Won Ki
N1 - Funding Information:
This study was supported by a grant (#A100766 to W.-K. Kim) from the Korea Health Technology R&D Project, the Ministry of Health & Welfare and by a grant (#2012K001112 to W.-K. Kim) from Brain Research Center of the 21st Century Frontier Research Program, the Ministry of Science and Technology, Republic of Korea . We are grateful to Dr. Paul L. Prather for his kind and careful reading.
PY - 2013/2/15
Y1 - 2013/2/15
N2 - 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.
AB - 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.
KW - Astroglia
KW - Cerebral ischemia
KW - Heme-oxygenase-1
KW - LMT-335
KW - Oxidative stress
KW - Oxygen-glucose deprivation/re-oxygenation
UR - http://www.scopus.com/inward/record.url?scp=84873736581&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2013.01.033
DO - 10.1016/j.bbrc.2013.01.033
M3 - Article
C2 - 23333396
AN - SCOPUS:84873736581
VL - 431
SP - 484
EP - 489
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -