HMGB1 and ischemia: In contrast, in the penumbra region, microglial activation is closely tied to innate immune receptors, which are mediated by the release of neuromediators, damage-associated molecular patterns (DAMPs), high-mobility group box-1 (HMGB1) protein and reactive oxygen species (ROS), all originating from ischemia-damaged or -stressed neuronal cells (Khoshnam et al., 2017; Jurcau and Simion, 2022).