Rolipram-induced elevation of cAMP or chondroitinase ABC breakdown of inhibitory proteoglycans in the extracellular matrix promotes peripheral nerve regeneration

Abstract

The inhibitory growth environment of myelin and extracellular matrix proteoglycans in the central nervous system may be overcome by elevating neuronal cAMP or degrading inhibitory proteoglycans with chondroitinase ABC (ChABC). In this study, we asked whether similar mechanisms operate in peripheral nerve regeneration where effective Wallerian degeneration removes myelin and extracellular proteoglycans slowly. We repaired transected common peroneal (CP) nerve in rats and either elevated cAMP in the axotomized neurons by subcutaneous rolipram, a specific inhibitor of phosphodiesterase IV, and/or promoted degradation of proteoglycans in the distal nerve stump by local ChABC administration. Rolipram treatment significantly increased the number of motoneurons that regenerated axons across the repair site at one and two weeks, and increased the number of sensory neurons that regenerated axons across the repair site at two weeks. Local application of ChABC had a similar effect to rolipram treatment in promoting motor axon regeneration, the effect being no greater when rolipram and ChABC were administered simultaneously. We conclude that blocking inhibitors of axon regeneration by elevating cAMP or degrading proteoglycans in the distal nerve stump promotes peripheral axon regeneration after surgical repair of a transected nerve. It is likely that elevated cAMP is sufficient to encourage axon outgrowth despite the the inhibitory growth environment such that simultaneous enzymatic proteoglycan degradation does not promote more axon regeneration than either elevated cAMP or proteoglycan degradation alone.

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

“…Findings that rolipram, a type IV inhibitor of the enzyme phosphodiesterase that breaks down cAMP, promoted nerve outgrowth in the CNS inspired our examination of whether local delivery of rolipram might enhance axon regeneration in the PNS [99][100][101]. Indeed, the rolipram infusion of the surgical site via a miniosmotic pump accelerated axon outgrowth across the surgical suture site and into the distal nerve stump in an analogous manner to the effect of the electrical stimulation in accelerating femoral motoneurons to regenerate their axons across the surgical repair site (Fig.…”

Extracellular Matrix Components in Peripheral Nerve Regeneration

“…Even when nerve grafts are used, acellular axons are able to regenerate through the scaffolds of basal lamina (Hall, 1997). In similar models, the inhibitory role of proteoglycans was reduced when enzymes that degrade CSPG were applied into the distal stump or a graft, accelerating regeneration of motor and sensory axons (Krekoski, Neubauer, Zuo, & Muir, 2001;Udina et al, 2010). Antifibronectin antibody reduced neurite outgrowth, but did not influence the capability of axons to grow through the basal lamina (Wang et al, 1992).…”

The Role of Chondroitinase as an Adjuvant to Peripheral Nerve Repair

“…An interesting study by Udina et al [2010] examined the immersion of chABC in combination with rolipram for peripheral nerve repair. After transecting the common peroneal nerves, rats were divided into various treatment groups.…”