Prior Exposure to Neurotrophins Blocks Inhibition of Axonal Regeneration by MAG and Myelin via a cAMP-Dependent Mechanism

Abstract

MAG is a potent inhibitor of axonal regeneration. Here, inhibition by MAG, and myelin in general, is blocked if neurons are exposed to neurotrophins before encountering the inhibitor; priming cerebellar neurons with BDNF or GDNF, but not NGF, or priming DRG neurons with any of these neurotrophins blocks inhibition by MAG/myelin. Dibutyryl cAMP also overcomes inhibition by MAG/myelin, and cAMP is elevated by neurotrophins. A PKA inhibitor present during priming abrogates the block of inhibition. Finally, if neurons are exposed to MAG/myelin and neurotrophins simultaneously, but with the Gi protein inhibitor, inhibition is blocked. We suggest that priming neurons with particular neurotrophins elevates cAMP and activates PKA, which blocks subsequent inhibition of regeneration and that priming is required because MAG/myelin activates a Gi protein, which blocks increases in cAMP. This is important for encouraging axons to regrow in vivo.

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

“…It was shown that inhibition of G i /G o with PERTUSSIS TOXIN blocked myelin-induced growth cone collapse 67 . We, on the other hand, reported that pertussis toxin had no effect on inhibition by Mag and myelin 68 . This discrepancy in results can perhaps be explained by differences in the acute dynamics of growth cone collapse and the chronic dynamics of the cessation of growth that are required for inhibition (BOX 3).…”

“…Growth cone collapse is probably the first event in inhibition, and many of the treatments that overcome inhibition of axonal growth also block growth cone collapse/repulsion 68,74 . Mechanistically, collapse and turning are the same, all that differs is the amount of growth cone that is exposed to inhibitors.…”

Glycan-dependent binding of galectin-1 to neuropilin-1 promotes axonal regeneration after spinal cord injury

“…[2][3][4][46][47][48][49] During the past years, different therapies have been proposed that lead to axonal outgrowth after SCI such as SM-216289, 36 neurotrophic factors, 50 soluble Nogo receptors, 51 chondroitinase ABC 49 or cellular transplantation. 52 In particular, SM-216289, a small-molecule inhibitor, showed inhibition of Sema3A functions, including growth cone collapse and chemorepulsion of neurite extension.…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…39 The role of MAG as an impediment to axonal regeneration is exemplified by in vitro studies in which its immunodepletion from myelin extracts attenuated inhibitory activity. 37 It has since been shown that elevating cAMP can stimulate adult neurons to extend axons on MAG substrates, 40 an effect related to the growth-enhancing effects of conditioning lesions and neurotrophic factor application (see below). Studies in MAG knockout mice have been equivocal, however, since myelin preparations from these mice are still effective in blocking regeneration, and since severed optic nerve and corticospinal tract (CST) axons regenerate no better in MAG knockouts than in wildtype mice.…”