title: Hypothermia-induced neurite outgrowth is mediated by tumor necrosis factor-alpha.
abstract: Systemic or brain-selective hypothermia is a well-established method for neuroprotection after brain trauma. There is increasing evidence that hypothermia exerts beneficial effects on the brain and may also support regenerative responses after brain damage. Here, we have investigated whether hypothermia influences neurite outgrowth in vitro via modulation of the post-injury cytokine milieu. Organotypic brain slices were incubated: deep hypothermia (2 h at 17 degrees C), rewarming (2 h up to 37 degrees C), normothermia (20 h at 37 degrees C). Neurite density and cytokine release (IL 1beta, IL-6, IL-10, and TNF-alpha) were investigated after 24 h. For functional analysis mice deficient in NT-3/NT-4 and TNF-alpha as well as the TNF-alpha inhibitor etanercept were used. Hypothermia led to a significant increase of neurite outgrowth, which was independent of neurotrophin signaling. In contrast to other cytokines investigated, TNF-alpha secretion by organotypic brain slices was significantly increased after deep hypothermia. Moreover, hypothermia-induced neurite extension was abolished after administration of the TNF-alpha inhibitor and in TNF-alpha knockout mice. We demonstrate that TNF-alpha is responsible for inducing neurite outgrowth in the context of deep hypothermia and rewarming. These data suggest that hypothermia not only exerts protective effects in the CNS but may also support neurite outgrowth as a potential mechanism of regeneration.
authors.affiliation: Clinic for Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum, Berlin, Germany. kschmitt@dhzb.de
authors.forename: Katharina R L
authors.initials: KR
authors.lastname: Schmitt
authors.forename: Francesco
authors.initials: F
authors.lastname: Boato
authors.forename: Antje
authors.initials: A
authors.lastname: Diestel
authors.forename: Daniel
authors.initials: D
authors.lastname: Hechler
authors.forename: Andrei
authors.initials: A
authors.lastname: Kruglov
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.forename: Sven
authors.initials: S
authors.lastname: Hendrix
mesh_terms: D000818:Animals; D003080:Cold Temperature; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism; D009924:Organ Culture Techniques; D018124:Receptors, Tumor Necrosis Factor; D017694:Rewarming; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept; C073922:neurotrophin 4