To ascertain whether signaling due to peripheral inflammation affects motoneuron vulnerability, we examined in adult rats the reaction to axonal injury of facial motoneurons primed by muscle inflammation. In this double-hit paradigm, preconditioning was achieved by injections into the facial muscles of the T cell mitogen phytohemagglutinin, which was found in a previous study (11) to elicit a retrograde response in motoneurons. Facial nerve transection was used as test lesion. Intramuscular injections of saline prior to axotomy were used as control for lectin pretreatment. In rats pretreated with phytohemagglutinin injection, upregulation of the expression of the antiapoptotic bcl-2 gene, examined with in situ hybridization, was significantly higher in facial motoneurons at 2 days postaxotomy compared with saline-injected control cases. After repeated phytohemagglutinin injections followed by nerve transection, induction in facial motoneurons of nitric oxide synthase, revealed by histochemistry and immunohistochemistry, as well as activation of the surrounding microglia, was enhanced at 14 days postaxotomy with respect to the saline-treated control cases. At the same time point, no significant intergroup difference was detected in the intensity of astrocytic activation. At 1 month postaxotomy, stereological cell counts revealed that motoneuron loss was significantly greater in the cases pretreated with phytohemagglutinin than in the saline-treated cases. The data point out that the response of the facial motor nucleus to axonal damage is altered by previous exposure to peripheral inflammation and that such preconditioning stimulus enhances motoneuron vulnerability to nerve injury. © 2002 Elsevier Science (USA).
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