A novel role of lactosylceramide in inducible nitric oxide synthase gene expression and astrogliosis in spinal cord injury-induced inflammatory disease. Investigation of potential anti-inflammatory interventions in spinal cord injury.

摘要

Astrocytes, the resident CNS immune cells, can be activated by numerous CNS conditions. Activation of these cells results in the expression of pro-inflammatory cytokines and other inflammatory gene products such as inducible nitric oxide synthase (iNOS). The expression of iNOS results in the excessive production of nitric oxide (NO) which is linked with exacerbation of spinal cord injury (SCI) and numerous other neurodegenerative disorders because of its toxicity to neuronal cells from the formation of peroxynitrite and generation of oxidative stress. Another prominent process following any sort of insult to the CNS is astrogliosis, characterized by hypertrophy and proliferation of astroglial cells resulting in the formation of a glial scar which is a major impediment to axonal regeneration and functional recovery following injury.The major requirement of the field of CNS repair in SCI is the development of strategies to block astrogliosis and post-traumatic damage induced by iNOS, pro-inflammatory cytokines expression, and astrogliosis. Previous reports from our laboratory have established a critical role of sphingolipids in potentiation of inflammatory reactions (Pahan et al. 1998 and Giri et al. 2002). The goal of this work was to investigate the involvement of glycosphingolipids (GSL), in SCI-induced inflammatory disease by examining the involvement of GSL in regulation of iNOS gene expression and astrogliosis. Collectively, studies using primary astrocytes have established lactosylceramide (LacCer) as a key signaling modulator in the regulation of cytokine-induced iNOS and glial fibrillary acidic protein (GFAP) gene expression as well as astrocyte hyperproliferation. LacCer production was increased under inflammatory stimuli, which regulated gene expression through the Ras/ERK pathway. Additionally, in a rat model of SCI, treatment with PDMP post-SCI showed significantly improved locomotor function and attenuated post-SCI inflammatory disease. Furthermore, treatment with an additional anti-inflammatory agent, atorvastatin, attenuated post-SCI inflammation and disease-progression, thus, showing significantly improved functional outcome.In conclusion, these studies establish attenuation of acute inflammation to be a promising approach to treat SCI-induced disease processes. Furthermore, it also opens the new therapeutic approach of GSL modulation for amelioration of the pathophysiology of SCI. This work also brings forth the anti-inflammatory efficacy of statins in (yet another) CNS disorder.