Enhancement of axonal regeneration by in vitro conditioning and its inhibition by cyclopentenone prostaglandins

Abstract

Axonal regeneration is enhanced by the prior `conditioning' of peripheral nerve lesions. Here we show that Xenopus dorsal root ganglia (DRG) with attached peripheral nerves (PN-DRG) can be conditioned in vitro, thereafter showing enhanced neurotrophin-induced axonal growth similar to preparations conditioned by axotomy in vivo. Actinomycin D inhibits axonal outgrowth from freshly dissected PN-DRG, but not from conditioned preparations. Synthesis of mRNAs that encode proteins necessary for axonal elongation might therefore occur during the conditioning period, a suggestion that was confirmed by oligonucleotide microarray analysis. Culturing PN-DRG in a compartmentalized system showed that inhibition of protein synthesis (but not RNA synthesis) in the distal nerve impaired the conditioning response, suggesting that changes in gene expression in cultured DRG depend on the synthesis and retrograde transport of protein(s) in peripheral nerves. The culture system was also used to demonstrate retrograde axonal transport of several proteins, including thioredoxin (Trx). Cyclopentenone prostaglandins, which react with Trx, blocked the in vitro conditioning effect, whereas inhibition of other signalling pathways thought to be involved in axonal regeneration did not. This suggests that Trx and/or other targets of these electrophilic prostaglandins regulate axonal regeneration. Consistent with this hypothesis, morpholino-induced suppression of Trx expression in dissociated DRG neurons was associated with reduced neurite outgrowth.

Slowing of axonal regeneration is correlated with increased axonal viscosity during aging

“…This system has been of interest because adult sensory neuron axonal regeneration is enhanced by prior 'conditioning' lesions, which activate and inactivate the expression of groups of proteins linked to embryonic regeneration [7,19-21]. Figure 1 shows an example of the outgrowth of unconditioned neonatal and adult sensory neurons.…”

Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin‐2 Administration

“…This effect could be the consequence of a higher effect in axonal integrity produced by Trx1. In this regard, previous studies have linked Trx1 to a strong protection against axonal damage in a model of retinal nerve damage [74, 75], as well as to the regulation of axonal regeneration [76]. The excess of Trx1 in the system could thus contribute to lower the basal levels of pNF-H by tipping the balance toward axonal regeneration rather than disruption.…”

Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

“…It was reported that 17β-estradiol increased the expression of Trx1 through the cGMP and protein kinase G signaling pathway in neuronal cells (Lee et al, 2003). In addition, Trx1 synthesis may be involved in axonal regeneration, and its inhibition is associated with reduced neurite outgrowth of dorsal root ganglia neurons (Tonge et al, 2008). Both Trx1 and Trx2 may participate in axonal protection.…”