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Updated: Sep 29, 2026
Experimental Models to Study the Neuroprotection of Acidic Postconditioning Against Cerebral Ischemia
Published on: July 31, 2017
Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia
Huaxin Sheng1, Jan J Enghild, Russell Bowler
1Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Reactive oxygen species play a role in the response of brain to ischemia. The effects of metalloporphyrin catalytic antioxidants (AEOL 10113 and AEOL 10150) were examined after murine middle cerebral artery occlusion (MCAO). Ninety minutes after reperfusion from 90 min MCAO in the rat, AEOL 10113, AEOL 10150, or vehicle were given intracerebroventricularly. AEOL 10113 and AEOL 10150 similarly reduced infarct size (35%) and neurologic deficit. AEOL 10113 caused behavioral side effects at twice the neuroprotective dose while AEOL 10150 required a 15-fold increase from the neuroprotective dose to cause behavioral changes. AEOL 10150, given 6 h after 90 min MCAO, reduced total infarct size by 43% without temperature effects. Brain AEOL 10150 elimination t(1/2) was 10 h. In the mouse, intravenous AEOL 10150 infusion post-MCAO reduced both infarct size (25%) and neurologic deficit. Brain AEOL 10150 uptake, greater in the ischemic hemisphere, was dose- and time-dependent. AEOL 10150 had direct effects on proteomic events and ameliorated changes caused by ischemia. In primary mixed neuronal/glial cultures exposed to 2 h of O(2)/glucose deprivation, AEOL 10150 reduced lactate dehydrogenase release dose-dependently and selectively preserved aconitase activity in concentrations consistent with neuroprotection in vivo. AEOL 10150 is an effective neuroprotective compound offering a wide therapeutic window with a large margin of safety against adverse behavioral side effects.
Insights
Metalloporphyrin antioxidants AEOL 10113 and AEOL 10150 reduced brain damage and neurological deficits after stroke. AEOL 10150 demonstrated a wider safety margin and sustained neuroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Reactive oxygen species contribute to brain injury following ischemia.
- Metalloporphyrin catalytic antioxidants are being investigated for neuroprotection.
Purpose of the Study:
- To evaluate the neuroprotective effects of AEOL 10113 and AEOL 10150 in rodent models of ischemic stroke.
- To assess the safety and therapeutic window of these compounds.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in rats and mice.
- Intracerebroventricular and intravenous administration of antioxidants.
- Assessment of infarct size, neurological deficit, and behavioral side effects.
- In vitro studies using neuronal/glial cultures exposed to oxygen/glucose deprivation.
Main Results:
- Both AEOL 10113 and AEOL 10150 significantly reduced infarct size and neurological deficits post-MCAO.
- AEOL 10150 showed a wider therapeutic window and fewer behavioral side effects compared to AEOL 10113.
- AEOL 10150 demonstrated sustained neuroprotection up to 6 hours post-ischemia and preserved aconitase activity in vitro.
- Brain uptake of AEOL 10150 was dose- and time-dependent, with higher concentrations in the ischemic hemisphere.
Conclusions:
- AEOL 10150 is a potent neuroprotective agent against ischemic stroke with a favorable safety profile.
- AEOL 10150 offers a wide therapeutic window and potential for delayed administration.
- Further investigation into AEOL 10150's mechanism and clinical application is warranted.
