Abstract
Reduced adenosine triphosphate (ATP) levels in ischemic stroke constitute an upstream contributor to neuronal cell death. We have recently created a small chemical, named Kyoto University Substance 121 (KUS121), which can reduce cellular ATP consumption. In this study, we examined whether KUS121 has neuroprotective effects in rodent cerebral ischemia models. We evaluated cell viability and ATP levels in vitro after oxygen glucose deprivation (OGD) in rat cortical primary neuronal cultures incubated with or without KUS121. We found that KUS121 protected neurons from cell death under OGD by preventing ATP depletion. We also used in vivo ischemic stroke models of transient distal middle cerebral artery occlusion in C57BL/6 and B-17 mice. Administration of KUS121 in these models improved functional deficits and reduced brain infarction volume after transient focal cerebral ischemia in both C57BL/6 and B-17 mice. These results indicate that KUS121 could be a novel type of neuroprotective drug for ischemic stroke.
Highlights
Stroke is one of the most common causes of death worldwide[1]
oxygen glucose deprivation (OGD) was performed in rat cortical primary neuronal cultures for 2 h, with a subsequent recovery at 21% O2 and in a glucose-containing media for another 22 h
Simultaneous incubation with 100 or 200 μM Kyoto University Substance 121 (KUS121) significantly improved neuronal viability after OGD; the viability was 18.1 ± 1.9% in vehicle-treated neurons, 43.5 ± 3.1% in neurons treated with 100 μM KUS121, and 42.4 ± 3.7% in those treated with 200 μM KUS121 (p < 0.001; Fig. 1b, Dunnett’s test)
Summary
Stroke is one of the most common causes of death worldwide[1]. In addition to antithrombotic therapy[2], intravenous thrombolysis with alteplase and mechanical thrombectomy have been shown to be very effective from clinical evaluations, albeit in a limited number of patients with ischemic stroke in the acute phase[3,4]. Numerous neuroprotective drugs that modulate key pathogenic factors after cerebral ischemia, including excitotoxicity, oxidative and nitrosative stress, or inflammation, have failed to show significant benefits in the clinical treatment of acute ischemic stroke[6]. In addition to its ATPase activity, VCP is thought to be involved in many cellular functions, including ER-associated and proteasome-mediated protein degradation[8]. KUS121 was shown to inhibit the ATPase activity of VCP in pathological conditions, without apparently inhibiting its other cellular functions[7]. We examined whether KUS121 is effective in in vitro and in vivo cerebral ischemia models. To test KUS121 effects in vivo, we used a mouse model of transient distal middle cerebral artery (MCA) occlusion (MCAO)[14,15]. We performed the ischemic experiment in two mouse strains
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