When stroke strikes, the damage doesn't stop once the blood flow is restored. This episode dives into the dark side of recovery: the Ischemia-Reperfusion (IR) Injury, a devastating "second wave" of damage that causes lasting neurological deficits. We explore a fascinating preclinical study on esketamine, the S-enantiomer of ketamine. Researchers hypothesized that this powerful NMDA receptor antagonist could stop IR injury, which is fueled by excessive excitotoxicity. We reveal how esketamine, when administered immediately after blood flow is restored, actively helps the brain fight back. The findings are compelling: esketamine significantly reduced markers of cell membrane damage (MDA) and, crucially, bolstered the brain’s own antioxidant defense system in the vulnerable hippocampal CA1 region. This dose-dependent effect points toward a new therapeutic window, allowing intervention hours or even days after a clot is removed. Could ketamine be the neuroprotectant that finally helps save the tissue we just rescued? Tune in to understand the science behind this potential breakthrough and the challenge of finding the neuroprotective 'sweet spot' dose. Reference: Erfani, S., Amirhaidari, B., & Khoshnazar, S. M. (2025). Antioxidant Therapeutic Potential of S-Ketamin Against Cerebral Ischemia/Reperfusion Injury in Male Rats. Journal of Isfahan Medical School, 43(821), 749–758. https://doi.org/10.48305/jims.v43.i821.0749