Abstract WMP47: Nrf2 Deficiency Exacerbates Sensorimotor Deficit and Impairs Long-term Functional Recovery After Ischemic Stroke

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Abstract

Introduction: Ischemic stroke is a devastating form of stroke with extremely high disability that affects more than 690,000 adults each year. Over the past decade, the transcriptional factor Nrf2 has emerged as a master regulator of cellular oxidative stress and inflammation that eventually leads to neuronal death through activation of various cytoprotective and detoxification genes, which are the central features of neurodegeneration, including stroke. Whether Nrf2 improves long-term sensorimotor outcome after ischemic stroke is not known.

Hypothesis: Nrf2 may alleviate sensorimotor deficits and promote long-term recovery after stroke injury.

Methods: Three- to four-month-old male C57BL/6 mice, including Nrf2 knockouts, were subjected to surgery of permanent distal middle cerebral artery occlusion (pMCAO). The functional outcomes were investigated 3 days prior to and 1, 3, 7, 14, 21, and 28 days after pMCAO with a comprehensive behavioral test battery, including open field, modified cylinder, and corner tests.

Results: There was no significant difference in behavior tests between Nrf2 knockout and wildtype mice in basal condition. After pMCAO, although Nrf2 knockout and control mice had similar function deficits in the open field test on day 1, Nrf2 deficiency compared to controls dramatically decelerated recovery in open field locomotor activity at the acute stage of cerebral stroke (1-3 days), but not at later time points. In the modified cylinder test, Nrf2-/- mice displayed remarkably severe sensorimotor deficits by the rate of total contralateral forelimb use and forelimb use in first contact events at the acute stage (0-3 days), especially on day 3, and impaired the recovery by forelimb use in first contact events at all lateral time points over 4 weeks. Such findings were supported by results in the corner test.

Conclusion: These data demonstrate that Nrf2 deficiency exacerbates functional deficits and impairs long-term sensorimotor recovery after pMCAO-induced ischemic stroke damage.

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