Abstract
Elevation of intracellular cyclic AMP (cAMP) levels has proven to be one of the most effective means of overcoming inhibition of axonal regeneration by myelin-associated inhibitors such as myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte myelin glycoprotein. Pharmacological manipulation of cAMP through the administration of dibutyryl cAMP or rolipram leads to enhanced axonal growth both in vivo and in vitro, and importantly, upregulation of cAMP within dorsal root ganglion neurons is responsible for the conditioning lesion effect, which indicates that cAMP plays a significant role in the endogenous mechanisms that promote axonal regeneration. The effects of cAMP are transcription-dependent and are mediated through the activation of protein kinase A (PKA) and the transcription factor cyclic AMP response element binding protein (CREB). This leads to the induction of a variety of genes, several of which have been shown to overcome myelin-mediated inhibition in their own right. In this review, we will highlight the pro-regenerative effects of arginase I (ArgI), interleukin (IL)-6, secretory leukocyte protease inhibitor (SLPI), and metallothionein (MT)-I/II, and discuss their potential for therapeutic use in spinal cord injury.
Highlights
our microarray analysis of the conditioning lesion effect has provided us with valuable insight into the spectrum
Another gene that is likely contributing to the conditioning lesion effect is brainderived neurotrophic factor
Like the genes identified in the microarray
Summary
The first cAMP-regulated gene product to be investigated in the context of MAG and myelin-mediated inhibition of neurite outgrowth was ArgI, the rate-limiting enzyme of polyamine synthesis (Cai et al, 2002). Priming neurons with spermidine led to dosedependent increases in neurite outgrowth in the presence of either MAG or myelin, and more importantly, regeneration of retinal ganglion cell axons in the injured optic nerve was significantly increased following a single intravitreal injection of 20 μM spermidine (Deng et al, 2009). This conclusively demonstrated that the products of ArgI activity can directly promote axonal regeneration in vivo. Further elucidation of the mechanisms and downstream pathways involved with IL-6 dependent axonal regeneration could lead us to potential targets that could promote regeneration without exacerbating the hyper-inflammatory response that is elicited after injury to the CNS
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