Regeneration of Sensory Axons within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation

Abstract

The peripheral branch of primary sensory neurons regenerates after injury, but there is no regeneration when their central branch is severed by spinal cord injury. Here we show that microinjection of a membrane-permeable analog of cAMP in lumbar dorsal root ganglia markedly increases the regeneration of injured central sensory branches. The injured axons regrow into the spinal cord lesion, often traversing the injury site. This result mimics the effect of a conditioning peripheral nerve lesion. We also demonstrate that sensory neurons exposed to cAMP in vivo, when subsequently cultured in vitro, show enhanced growth of neurites and an ability to overcome inhibition by CNS myelin. Thus, stimulating cAMP signaling increases the intrinsic growth capacity of injured sensory axons. This approach may be useful in promoting regeneration after spinal cord injury.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…However, it was only recently that a conditioning lesion was shown to induce regeneration of dorsal column axons in the absence of a peripheral nerve graft 93 . cAMP also seems to have an important role in this phenomenon 76,96 . Twenty-four hours after a peripheral conditioning lesion, cAMP levels in DRGs have more than doubled, but by one week after the lesion, they are back to uninjured control levels.…”

“…columns are lesioned, mimics the effects of a conditioning lesion on both neurons grown in culture and on dorsal column axons in vivo 76,96 (FIG. 4).…”

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…The development of therapies to promote axonal regeneration will require overcoming these disparate inhibitory influences. Recent work suggests that intracellular signaling pathways which dictate axonal responsiveness to inhibitory proteins are tractable targets for overcoming the inhibitory nature of the injured CNS and encouraging functional regeneration (Bertrand et al, 2005;Cai et al, 1999;Dergham et al, 2002;Fournier et al, 2003;Lehmann et al, 1999;Lu et al, 2004;Neumann et al, 2002;Nikulina et al, 2004;Qiu et al, 2002;Sivasankaran et al, 2004). Unfortunately, our current understanding of the signaling pathways that mediate the effects of inhibitory proteins on regenerating and developing axons is still rudimentary.…”

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Priming dorsal root ganglia with neurotrophins in vitro results in elevated cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activation, which similar to conditioning lesion attenuates the neurite outgrowth-inhibitory effects of central myelin [117]. Similarly, conditioning lesions elevate cAMP levels in dorsal root ganglia [118], and conditioning effects can be partly replicated by cAMP injections into dorsal root ganglia (DRG) neurons [118,119].…”