| Summary: | Abstract. This review describes the roles of the low-density lipoprotein receptor–related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood–brain barrier and the blood–nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal–regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.
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