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Brachial plexus injury often involves traumatic root avulsion resulting in permanent paralysis of the innervated muscles. The lack of sufficient regeneration from spinal motoneurons to the peripheral nerve (PN) is considered to be one of the major causes of the unsatisfactory outcome of various surgical interventions for repair of the devastating injury. The present study was undertaken to investigate potential inhibitory signals which influence axonal regeneration after root avulsion injury. The results of the study showed that root avulsion triggered GSK-3β activation in the injured motoneurons and remaining axons in the ventral funiculus. Systemic application of a clinical dose of lithium suppressed activated GSK-3β in the lesioned spinal cord to the normal level and induced extensive axonal regeneration into replanted ventral roots. Our study suggests that GSK-3β activity is involved in negative regulation for axonal elongation and regeneration and lithium, the specific GSK-3β inhibitor, enhances motoneuron regeneration from CNS to PNS. [ABSTRACT FROM AUTHOR]

Wallerian degeneration (WD), composed of the breakdown and phagocytosis of damaged axons and their myelin sheaths distal to the injury, is a major sequela of spinal cord injury (SCI). To understand the microenvironment within WD that may affect repair following SCI, we investigated the fate of major glial types and axons in this region following acute (1 h), subacute (10 days), and chronic (30 days) dorsal funiculotomy at the eighth thoracic (T8) level. This lesion induces a confined WD in two distinct functional pathways, that is, the corticospinal tract (CST) and dorsal ascending tract (DAT) in opposite directions. Here we report that astrocytes, reactive microglia and macrophages were all significantly increased in areas of WD in both the CST and DAT at subacute and chronic stages compared to the sham-operated or acute stage. While the level of GFAP+ astrocytes remained stable after the subacute stage, the number of OX-42+ microglia and ED-1+ macrophages markedly decreased at the chronic stage. Interestingly, a mild but significant increase in ED-1+ macrophages was also found in the intact fiber tracts 3 mm proximal to the injury at the chronic stage, coinciding with axonal dieback observed at that level. Axons distal to the injury experienced a continued and prolonged degeneration in both fiber tracts. Finally, although a significant decrease of Olig2+ oligodendrocyte lineage (OL) cells was found in areas of WD, the presence of these cells at the chronic stage indicates that they are available for endogenous repair. Taken together, our data have provided spatiotemporal evidence for the dynamic pathogenic changes of major cellular components in areas of WD remote to an SCI. Information obtained in this study should be useful for designing experiments aimed at modifying this region to accommodate endogenous or exogenous repair following SCI. [ABSTRACT FROM AUTHOR]

This study was undertaken to elucidate the molecular mechanisms by which lithium regulates the development of spinal cord-derived neural progenitor cells (NPCs) in vitro and after transplanted in vivo. Our results show that lithium at the therapeutic concentration significantly increases the proliferation and neuronal differentiation of NPCs in vitro. Specific ELISAs, western blotting, and quantitative real-time RT-PCR assays demonstrate that lithium treatment significantly elevates the expression and production of brain-derived neurotrophic factor (BDNF) by NPCs in culture. Application of a BDNF neutralizing antibody in culture leads to a marked reduction in the neurogenesis of lithium-treated NPCs to the control level. However, it shows no effects on the proliferation of lithium-treated NPCs. These findings suggest that the BDNF pathway is possibly involved in the supportive role of lithium in inducing NPC neurogenesis but not proliferation. This study also provides evidence that lithium is able to elevate the neuronal generation and BDNF production of NPCs after transplantation into the adult rat ventral horn with motoneuron degeneration because of spinal root avulsion, which highlights the therapeutic potential of lithium in cell replacement strategies for spinal cord injury because of its ability to promote neuronal differentiation and BDNF production of grafted NPCs in the injured spinal cord. [ABSTRACT FROM AUTHOR]