From anti-inflammation to pro-resolution: a new paradigm for specialized pro-resolving mediators in regulating neuroinflammation and repair after cerebral ischemia-reperfusion

Abstract

Uncontrolled neuroinflammation following cerebral ischemia-reperfusion is a core pathophysiological process driving secondary brain injury and leading to long-term neurological dysfunction. For decades, traditional “anti-inflammatory” strategies targeting the inhibition of key pro-inflammatory pathways have repeatedly failed in clinical translation, compelling a fundamental re-evaluation of the biological nature of inflammation. Inflammation is not a process that passively subsides upon stimulus removal but a dynamic one that requires active “resolution” through endogenous programs to restore tissue homeostasis. Within this precisely regulated program, a family of endogenous lipid mediators derived from polyunsaturated fatty acids-Specialized Pro-resolving Mediators (SPMs)-act as central executors. This review systematically proposes a translational framework for post-stroke inflammation management, shifting from traditional “passive anti-inflammation” to “active pro-resolution.” We first delve into the translational challenges and theoretical limitations of conventional anti-inflammatory therapies. Subsequently, we elaborate on the biosynthetic network of SPMs, their major families (lipoxins, resolvins, protectins, and maresins), and their pleiotropic biological functions, including halting neutrophil infiltration, reprogramming macrophage/microglial functions, enhancing the efficiency of apoptotic cell clearance (efferocytosis), and maintaining blood-brain barrier integrity. The central thesis of this review is that a key mechanism underlying the persistent neuropathological deterioration after cerebral ischemia-reperfusion is the failure of the endogenous inflammation resolution program, termed “resolution dysfunction.” By integrating mounting clinical evidence with extensive preclinical studies, this review provides a systematic argument for this hypothesis. Exogenous administration of SPMs or their stable analogs has demonstrated significant neuroprotective effects in various animal models, effectively reducing infarct volume and improving functional outcomes.