A novel Nrf2 activator, RS9, attenuates secondary brain injury after intracerebral hemorrhage in sub-acute phase

• Published in: Brain research Vol. 1701; pp. 137 - 145
• Main Authors: Sugiyama, Tomoki, Imai, Takahiko, Nakamura, Shinsuke, Yamauchi, Keita, Sawada, Shigenobu, Shimazawa, Masamitsu, Hara, Hideaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.12.2018
• Subjects: Animals; Antioxidants - pharmacology; Brain Edema - metabolism; Brain Injuries - drug therapy; Brain Injuries - metabolism; Cell Death - drug effects; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Disease Models, Animal; Gene Expression Regulation - drug effects; Heme oxygenase-1; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - metabolism; Hemin - metabolism; Intracerebral hemorrhage; Male; Mice; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative stress; Oxidative Stress - drug effects; Protoporphyrins - pharmacology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Superoxide Dismutase - metabolism; Triterpenes - metabolism; Triterpenes - pharmacology; SH-SY5Y; Oxidative stress; BBB; DMSO; Heme oxygenase-1; ALS; CNS; HO-1; PARP; DMEM; Nrf2; FBS; Hb; SBI; DMF; PBS; NQO-1; GST; Intracerebral hemorrhage; BARD; ICH; SOD1; ARE; ROS; Keap1; ANOVAs; ZnPP
• ISSN: 0006-8993; 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2018.08.021

•RS9 decreased brain edema and neurological deficit after ICH.•RS9 up-regulated HO-1 and SOD-1 expression after ICH.•RS9 decreased neuronal cell death after in vitro hemin injury.•RS9 has a protective effect for SBI after ICH. 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.