Successful axon regeneration in the mammalian central nervous system (CNS) is at least partially compromised due to the inhibitors associated with myelin and glial scar. However, the intracellular signaling mechanisms underlying these inhibitory activities are largely unknown. Here we provide biochemical and functional evidence that conventional isoforms of protein kinase C (PKC) are key components in the signaling pathways that mediate the inhibitory activities of myelin components and chondroitin sulfate proteoglycans (CSPGs), the major class of inhibitors in the glial scar. Both the myelin inhibitors and CSPGs induce PKC activation. Blocking PKC activity pharmacologically and genetically attenuates the ability of CNS myelin and CSPGs to activate Rho and inhibit neurite outgrowth. Intrathecal infusion of a PKC inhibitor, Gö6976, into the site of dorsal hemisection promotes regeneration of dorsal column axons across and beyond the lesion site in adult rats. Thus, perturbing PKC activity could represent a therapeutic approach to stimulating axon regeneration after brain and spinal cord injuries.

Axon regeneration in the central nervous system normally fails, in part because of a developmental decline in the intrinsic ability of CNS projection neurons to extend axons. Members of the KLF family of transcription factors regulate regenerative potential in developing CNS neurons. Expression of one family member, KLF7, is down-regulated developmentally, and overexpression of KLF7 in cortical neurons in vitro promotes axonal growth. To circumvent difficulties in achieving high neuronal expression of exogenous KLF7, we created a chimera with the VP16 transactivation domain, which displayed enhanced neuronal expression compared with the native protein while maintaining transcriptional activation and growth promotion in vitro. Overexpression of VP16-KLF7 overcame the developmental loss of regenerative ability in cortical slice cultures. Adult corticospinal tract (CST) neurons failed to upregulate KLF7 in response to axon injury, and overexpression of VP16-KLF7 in vivo promoted both sprouting and regenerative axon growth in the CST of adult mice. These findings identify a unique means of promoting CST axon regeneration in vivo by reengineering a developmentally down-regulated, growth-promoting transcription factor. A xon regeneration generally fails after injury to the CNS, preventing substantial recovery. CNS regeneration is limited in part by the presence of extrinsic inhibitory molecules at the injury site, and also because adult CNS neurons possess an intrinsically low capacity for axon growth compared with embryonic or peripheral nervous system (PNS) neurons (1-3). Intrinsic regenerative capacity appears to be particularly low in the corticospinal tract (CST), an essential motor control pathway and important therapeutic target in humans (4). For instance, CST axons have shown mixed responses when inhibitory signals are neutralized (5, 6), and regenerate minimally or not at all into growth permissive tissue grafts that support some regeneration from propriospinal and brainstem neurons (7-10).The intrinsic molecular mechanisms that limit CNS axon growth remain unclear, but likely reflect a suboptimal pattern of regenerative gene expression (1, 11). In sensory neurons, overexpression of GAP43 and CAP23 or transcription factors, including ATF3, STAT3, or ID2, have produced modest gains in spinal regeneration (12-15). In the visual system, overexpression of p300 modestly increases growth (16), and knockdown of PTEN and SOCS3 results in substantial regeneration (17,18). In the CST, overexpression of the neurotrophin receptor TrkB enables regeneration into subcortical BDNF-secreting tissue grafts, and, notably, knockout of PTEN evokes regeneration in the spinal cord (19,20). The regenerative response evoked by these gene manipulations, including PTEN knockout, remains incomplete in terms of both the distance traveled by regenerating axons and the percent of neurons that respond to treatment.These findings illustrate the critical need to develop additional tools to enhance the intrinsic growth state of CNS neurons.We...

PLA2, increased significantly after SCI, may play a key role in mediating neuronal death and oligodendrocyte demyelination following SCI. Blocking PLA2 action may represent a novel repair strategy to reduce tissue damage and increase function after SCI.

The results in this study present strong evidence that the prognosis for neurologic recovery is adversely affected by both a higher percentage of canal narrowing and a longer duration of canal narrowing after a spinal cord injury. The tolerance for spinal canal narrowing with a contused cord appears diminished, indicating that an injured spinal cord may benefit from early decompression. Additionally, it appears that the longer the spinal cord compression exists after an incomplete spinal cord injury, the worse the prognosis for neurologic recovery.

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