Spinal Axon Regeneration Induced by Elevation of Cyclic AMP

Qiu, Jin; Cai, Dongming; Dai, Haining; McAtee, Marietta; Hoffman, Paul N.; Bregman, Barbara S.; Filbin, Marie T.

doi:10.1016/s0896-6273(02)00730-4

Cited by 612 publications

(483 citation statements)

References 24 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Pasterkamp

Dai

Terman³

et al. 2006

Molecular and Cellular Neuroscience

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Section: Discussionmentioning

confidence: 99%

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

Pasterkamp

Dai

Terman³

et al. 2006

Molecular and Cellular Neuroscience

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“…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].…”

Section: Intrinsic Capacity To Regeneratementioning

confidence: 99%

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

Hollis

Tuszynski

2011

Neurotherapeutics

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Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

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“…Antibody-mediated blockade of growth-inhibitory molecules (Hata et al 2006;Tan et al 2006), enzymatic degradation of growth-inhibitory glycosaminoglycans (GAGs) (Moon et al 2001;Bradbury et al 2002), and pharmacological elevation of cAMP (Qiu et al 2002;Nikulina et al 2004) all promote axon regeneration after spinal cord injury, as does a peripheral nerve conditioning-lesion (Richardson and Issa,1984;Neumann and Woolf, 1999). Combining some of these treatments has resulted in more favorable axon growth patterns (Lu et al 2004;Steinmetz et al 2005;Tan et al 2006), longer fibers (Chau et al 2004;Yin et al 2006), and in some cases, limited behavioral recovery (Pearse et al 2004;Fouad et al 2005).…”

mentioning

confidence: 99%

Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

Tan

Petruska

Mendell

et al. 2007

Experimental Neurology

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Axon regeneration after experimental spinal cord injury (SCI) can be promoted by combinatorial treatments that increase the intrinsic growth capacity of the damaged neurons and reduce environmental factors that inhibit axon growth. A prior peripheral nerve conditioning lesion is a well established means of increasing the intrinsic growth state of sensory neurons whose axons project within the dorsal columns of the spinal cord. Combining such a prior peripheral nerve conditioning lesion with the infusion of antibodies that neutralize the growth-inhibitory effects of the NG2 chondroitin sulfate proteoglycan promotes sensory axon growth through the glial scar and into the white matter of the dorsal columns. The physiological properties of these regenerated axons, particularly in the chronic SCI phase, have not been established. Here we examined the functional status of regenerated sensory afferents in the dorsal columns after SCI. Six months post-injury, we located and electrically mapped functional sensory axons that had regenerated beyond the injury site. The regenerated axons had reduced conduction velocity, decreased frequency-following ability, and increasing latency to repetitive stimuli. Many of the axons that had regenerated into the dorsal columns rostral to the injury site were chronically demyelinated. These results demonstrate that regenerated sensory axons remain in a chronic pathophysiological state and emphasize the need to restore normal conduction properties to regenerated axons after spinal cord injury.

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Spinal Axon Regeneration Induced by Elevation of Cyclic AMP

Cited by 612 publications

References 24 publications

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

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

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

Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

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