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<p>This review provides a&#xa0;comprehensive examination of the pivotal roles of mitogen-activated protein kinase (MAPK) signaling pathways in the pathophysiology of the blood-brain barrier (BBB). The BBB, which is essential for central nervous system homeostasis, is intricately regulated by MAPK family members—including extracellular signal-regulated kinases (ERK1/2), c‑Jun N‑terminal kinases (JNK), and p38 MAPKs—which modulate endothelial permeability, tight junction integrity, and inflammatory responses. Dysregulation of these pathways significantly compromises BBB integrity by affecting brain endothelial cells, disrupting tight junction organization, altering cytoskeletal dynamics, and increasing matrix metalloproteinase activity. Furthermore, complex crosstalk among pericytes, astrocytes, and microglia—together with oxidative stress—exacerbates BBB dysfunction, promoting inflammation, apoptosis, and autophagy. Experimental evidence from <i>in vitro</i> and <i>in vivo</i> models consistently demonstrates that aberrant MAPK activation increases BBB permeability and drives neuroinflammation, often in association with oxidative stress and degradation of tight junction proteins. Although human studies remain largely correlative, they support these findings by linking dysregulated p38 and JNK signaling to neurological disorders such as Alzheimer’s disease and ischemic stroke. Despite methodological challenges—particularly the limited specificity of MAPK inhibitors and species-related differences—MAPK pathways remain promising therapeutic targets. However, critical barriers such as insufficient brain penetrance and off-targets effects must be addressed. Future research should prioritize precision medicine approaches that consider the spatiotemporal dynamics of MAPK isoform activation and leverage advanced experimental models to develop highly selective, BBB-protective strategies. Such advances will be essential for translating mechanistic insights into effective clinical interventions for neurological diseases.</p>

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MAPK signaling pathways in blood-Brain barrier pathophysiology: a mechanistic and translational review

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Ana Gabriela Bernardo-Cervantes,
  • José Luis Castañeda-Cabral

摘要

This review provides a comprehensive examination of the pivotal roles of mitogen-activated protein kinase (MAPK) signaling pathways in the pathophysiology of the blood-brain barrier (BBB). The BBB, which is essential for central nervous system homeostasis, is intricately regulated by MAPK family members—including extracellular signal-regulated kinases (ERK1/2), c‑Jun N‑terminal kinases (JNK), and p38 MAPKs—which modulate endothelial permeability, tight junction integrity, and inflammatory responses. Dysregulation of these pathways significantly compromises BBB integrity by affecting brain endothelial cells, disrupting tight junction organization, altering cytoskeletal dynamics, and increasing matrix metalloproteinase activity. Furthermore, complex crosstalk among pericytes, astrocytes, and microglia—together with oxidative stress—exacerbates BBB dysfunction, promoting inflammation, apoptosis, and autophagy. Experimental evidence from in vitro and in vivo models consistently demonstrates that aberrant MAPK activation increases BBB permeability and drives neuroinflammation, often in association with oxidative stress and degradation of tight junction proteins. Although human studies remain largely correlative, they support these findings by linking dysregulated p38 and JNK signaling to neurological disorders such as Alzheimer’s disease and ischemic stroke. Despite methodological challenges—particularly the limited specificity of MAPK inhibitors and species-related differences—MAPK pathways remain promising therapeutic targets. However, critical barriers such as insufficient brain penetrance and off-targets effects must be addressed. Future research should prioritize precision medicine approaches that consider the spatiotemporal dynamics of MAPK isoform activation and leverage advanced experimental models to develop highly selective, BBB-protective strategies. Such advances will be essential for translating mechanistic insights into effective clinical interventions for neurological diseases.