Sulforaphane promotes white matter plasticity and improves long-term neurological outcomes after ischemic stroke via the Nrf2 pathway

Post-stroke cognitive impairment (PSCI) is a common condition following ischemic stroke. Neuronal loss and white matter injury are among the most common neuropathological characteristics in patients with PSCI. The present study tested our hypothesis that activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) reduces neuronal loss, white matter injury, and neurobehavioral deficits in a mouse model of PSCI and investigated the underlying protective mechanisms.PSCI was modeled in wildtype (WT) and Nrf2 knockout (KO), male and female mice, by distal middle cerebral artery occlusion (dMCAO), with intraperitoneal injections of the Nrf2 activator sulforaphane (Sfn) or vehicle. Long-term (35 days) sensorimotor and cognitive performances, white matter integrity, oligodendrogenesis by BrdU incorporation, and neurite sprouting using anterograde tract-tracing were evaluated up to 35 days after dMCAO. Neuronal apoptosis was evaluated three days after dMCAO. In vitro, primary neuronal cultures were applied to validate the in vivo findings.Compared to vehicle-injected controls, Sfn treatment improved long-term sensorimotor and cognitive deficits after dMCAO in WT male and female mice. Sfn-treated WT mice also had less myelin loss/axonal injury and showed evidence of Nrf2 activation. Sfn treatment failed to provide the same level of protection in Nrf2 KO mice. Mechanistically, the ability of Sfn to reduce neuronal death after ischemia in vitro and in vivo, augment axonal sprouting and enhance oligodendrogenesis after dMCAO was dependent on Nrf2 activation.Our results support that Nrf2 is critical for Sfn-afforded neuroprotection after ischemic stroke. Thus, targeting Nrf2 may be a promising strategy for the treatment of PSCI.