Does Neuroglobin Protect Against Stroke? Insights Into the Role of Neurovascular Unit Cells

Ischemic stroke, a leading cause of disability and mortality, initiates a complex damage cascade within the neurovascular unit (NVU), leading to blood-brain barrier (BBB) disruption and neuroinflammation that severely exacerbates secondary injury. Neuroglobin (Ngb), an endogenous protein induced by brain injury, represents a high-potential neuroprotective target. While the precise mechanisms underlying its protective action remain incompletely elucidated, substantial evidence points to its multifaceted ability to mitigate ischemic damage. To fully unlock this potential, a fundamental understanding of how neurons, astrocytes, microglia, and pericytes, coordinate their function in response to stress, and specifically identifying the role Ngb plays within this integrated cellular network, is required. This review examines the post-stroke interplay among these cells, analyzing current knowledge about how Ngb modulates the collective inflammatory response by suppressing pro-inflammatory pathways and fostering a neuroprotective environment. Furthermore, Ngb's upregulation in glial cells and pericytes promotes direct neuronal repair mechanisms, such as neurite outgrowth and axonal regeneration, while supporting neuronal survival and BBB integrity. Importantly, evidence suggests that Ngb's efficacy is most pronounced when its intracellular concentration exceeds the levels achieved through physiological upregulation. In this regard, we integrate broad preclinical evidence with specific insights from nanoparticle-mediated delivery systems that enable effective Ngb transport to NVU cells. These synthesized findings demonstrate beneficial outcomes in stroke models, driven by the modulation of mitochondrial dynamics, cytoskeletal remodeling, and synaptic regeneration pathways. Collectively, the literature indicates that targeted therapeutic Ngb may enhancement strategies effectively complement endogenous levels to orchestrate protective responses across the NVU. Nonetheless, a detailed investigation into the therapeutic utility of Ngb is still required to fully translate encouraging preclinical findings into successful clinical application for improving stroke outcomes.