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A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase.
Brain Res. 2018 12 15; 1701:137-145.BR

Abstract

The poor prognosis of intracranial hemorrhage (ICH) is attributed to secondary brain injury (SBI), which is caused by oxidative stress. Blood components induce reactive oxygen species (ROS) over-production and cause cytotoxicity. We focused on the antioxidant system and investigated nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a transcription factor that controls several antioxidant enzymes. We examined the effects of a novel Nrf2 activator, RS9, on SBI after ICH. ICH was induced by injecting autologous blood collected from the jugular vein (25 µL) into the striatum of mice. RS9 (0.2 mg/kg, i.p.) was administrated 0, 24, and 48 h after the induction of ICH. Using the ICH model, we measured brain edema, neurological function, neuronal damage and antioxidant proteins expression. We then investigated the mechanisms responsible for the effects of RS9 in vitro using the SH-SY5Y cell line. We used zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, to elucidate the relationship between HO-1 expression and cell death in vitro in a hemin injury model. RS9 decreased brain edema, improved neurological deficits, decreased neuronal damage area and up-regulated HO-1 and superoxide dismutase 1 (SOD) expressions in the ICH mouse model. RS9 also suppressed neuronal cell death and ROS over-production in vitro. These protective effects were cancelled by the ZnPP co-treatment. Our results suggest that the activation of Nrf2 by RS9 exerts neuroprotective effects that are mediated by the attenuation of oxidative stress, and also that RS9 is an effective therapeutic candidate for the treatment for SBI after ICH.

Authors+Show Affiliations

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: nakamuras@gifu-pu.ac.jp.Department of Neurosurgery, Toyohashi Medical Center, Aichi 440-8510, Japan.Department of Neurosurgery, Matsunami General Hospital, 185-1 Dendai, Kasamatsu, Gifu 501-6062, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30142309

Citation

Sugiyama, Tomoki, et al. "A Novel Nrf2 Activator, RS9, Attenuates Secondary Brain Injury After Intracerebral Hemorrhage in Sub-acute Phase." Brain Research, vol. 1701, 2018, pp. 137-145.
Sugiyama T, Imai T, Nakamura S, et al. A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase. Brain Res. 2018;1701:137-145.
Sugiyama, T., Imai, T., Nakamura, S., Yamauchi, K., Sawada, S., Shimazawa, M., & Hara, H. (2018). A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase. Brain Research, 1701, 137-145. https://doi.org/10.1016/j.brainres.2018.08.021
Sugiyama T, et al. A Novel Nrf2 Activator, RS9, Attenuates Secondary Brain Injury After Intracerebral Hemorrhage in Sub-acute Phase. Brain Res. 2018 12 15;1701:137-145. PubMed PMID: 30142309.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase. AU - Sugiyama,Tomoki, AU - Imai,Takahiko, AU - Nakamura,Shinsuke, AU - Yamauchi,Keita, AU - Sawada,Shigenobu, AU - Shimazawa,Masamitsu, AU - Hara,Hideaki, Y1 - 2018/08/22/ PY - 2018/05/17/received PY - 2018/08/07/revised PY - 2018/08/20/accepted PY - 2018/8/25/pubmed PY - 2019/11/5/medline PY - 2018/8/25/entrez KW - Heme oxygenase-1 KW - Intracerebral hemorrhage KW - Nrf2 KW - Oxidative stress SP - 137 EP - 145 JF - Brain research JO - Brain Res. VL - 1701 N2 - The poor prognosis of intracranial hemorrhage (ICH) is attributed to secondary brain injury (SBI), which is caused by oxidative stress. Blood components induce reactive oxygen species (ROS) over-production and cause cytotoxicity. We focused on the antioxidant system and investigated nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a transcription factor that controls several antioxidant enzymes. We examined the effects of a novel Nrf2 activator, RS9, on SBI after ICH. ICH was induced by injecting autologous blood collected from the jugular vein (25 µL) into the striatum of mice. RS9 (0.2 mg/kg, i.p.) was administrated 0, 24, and 48 h after the induction of ICH. Using the ICH model, we measured brain edema, neurological function, neuronal damage and antioxidant proteins expression. We then investigated the mechanisms responsible for the effects of RS9 in vitro using the SH-SY5Y cell line. We used zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, to elucidate the relationship between HO-1 expression and cell death in vitro in a hemin injury model. RS9 decreased brain edema, improved neurological deficits, decreased neuronal damage area and up-regulated HO-1 and superoxide dismutase 1 (SOD) expressions in the ICH mouse model. RS9 also suppressed neuronal cell death and ROS over-production in vitro. These protective effects were cancelled by the ZnPP co-treatment. Our results suggest that the activation of Nrf2 by RS9 exerts neuroprotective effects that are mediated by the attenuation of oxidative stress, and also that RS9 is an effective therapeutic candidate for the treatment for SBI after ICH. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/30142309/A_novel_Nrf2_activator_RS9_attenuates_secondary_brain_injury_after_intracerebral_hemorrhage_in_sub_acute_phase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(18)30443-8 DB - PRIME DP - Unbound Medicine ER -