Neuronal Ablation of IKK2 Decreases Lesion Size and Improves Functional Outcome after Spinal Cord Injury in Mice.

ABSTRACT: Nuclear factor-kappa B (NF-?B) is a key modulator of inflammation and secondary injury responses in neurodegenerative disease, including spinal cord injury (SCI). Inhibition of astroglial NF-?B reduces inflammation, enhances oligodendrogenesis and improves functional recovery after SCI, however the contribution of neuronal NF-?B to secondary inflammatory responses following SCI has yet to be investigated. We demonstrate that conditional ablation of IKK2 in Synapsin 1-expressing neurons in mice (Syn1creIKK2fl/fl) reduces activation of the classical NF-?B signaling pathway, resulting in impaired motor function and altered memory retention under naïve conditions. Following induction of a moderate SCI phosphorylated NF-?B levels decreased in the spinal cord of Syn1creIKK2fl/fl mice compared to controls, resulting in improvement in functional recovery. Histologically, Syn1creIKK2fl/fl mice exhibited reduced lesion volume but comparable microglial/leukocyte responses after SCI. In parallel, interleukin (IL)-1? expression was significantly decreased within the lesioned spinal cord, whereas IL-5, IL-6, IL-10, tumor necrosis factor (TNF) and chemokine (C-X-C motif) ligand 1 were unchanged compared to control mice. We conclude that conditional ablation of IKK2 in neurons, resulting in reduced neuronal NF-B signaling, and lead to protective effects after SCI and propose the neuronal classical NF-?B pathway as a potential target for the development of new therapeutic, neuroprotective strategies for SCI.

SUBMITTER: Ellman DG 

PROVIDER: S-EPMC6051723 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature