Retrograde signaling in axonal regeneration

Neuronal regeneration in the peripheral nervous system requires mobilization of intrinsic neurite outgrowth mechanisms. This process depends on retrograde signaling between lesion site and soma to provide accurate and timely information on the nature and extent of axonal damage, and to elicit an appropriate cell body response. An early phase of electrophysiological signaling is followed by an ensemble of motor-driven signals, some of which are dependent on local protein translation in the axon and formation of an importins-coordinated retrograde complex. In addition to eliciting the cell body response, computational analyses suggest that this biphasic mechanism may provide information on the distance of the leson site from the neuronal cell body. Encouraging recent data suggest that it may be possible to apply this emerging understanding of retrograde signaling mechanisms to activate intrinsic regeneration mechanisms also in growth-refractory central neurons.     

Matrix metalloproteinases and proteoglycans in axonal regeneration

After an injury to the adult mammalian central nervous system (CNS), a variety of growth-inhibitory molecules are upregulated. A glial scar forms at the site of injury and is composed of numerous molecular substances, including chondroitin sulfate proteoglycans (CSPGs). These proteoglycans inhibit axonal growth in vitro and in vivo. Matrix metalloproteinases (MMPs) can degrade the core protein of some CSPGs as well as other growth-inhibitory molecules such as Nogo and tenascin-C. MMPs have been shown to facilitate axonal regeneration in the adult mammalian peripheral nervous system (PNS). This review will focus on the various roles of proteoglycans and MMPs within the injured nervous system. First, we will present a general background on the injured central nervous system and explore the roles that proteoglycans play in the injured PNS and CNS. Second, we will discuss the various functions of MMPs within the injured PNS and CNS. Special attention will be paid to the possibility of how MMPs might modify the growth-inhibitory extracellular environment of the injured adult mammalian spinal cord and facilitate axonal regeneration in the CNS.     

Time course of axonal regeneration in acute motor axonal neuropathy

Patients with acute motor axonal neuropathy (AMAN) generally recover well. We reviewed clinical and electrophysiologic recovery in 13 patients for up to 5 years. Twelve patients showed rapid recovery over 12 months, whereas in the remaining one the recovery was slow and incomplete at 5 years. In AMAN, axonal degeneration appears to develop predominantly in the motor nerve terminals, and only occasionally more proximally in the nerve roots. Nerve terminal degeneration-regeneration presumably provides a mechanism for good recovery.     

Prior collateral sprouting enhances axonal regeneration

Regeneration is accelerated in axons which have undergone collateral sprouting prior to crushing.     

Central axonal regeneration and autoimmunity in adult birds

After traumatic lesion adult cock spinal cord displays lively axonal regenerative activity. After 22 days, morphological regeneration regresses; functional regeneration is never observed. Before and after spinal lesion in the cocks, IgG decoration of myelin sheaths is never observed. The sera of both injured and intact animals tested both by immunohistochemical methods on intact spinal cord sections and by immunoelectrophoresis on a protein extract of homologous spinal cord are always negative. The authors suggest that the absence in Birds of any autoimmune response against c.n.s. antigens after surgical exposition, as observed in Mammals, is possibly related to the capacity of the central axons to regenerate in Birds, as observed by the Authors in Amphibia and Reptilia (Triturus and Lacerta).     

Microfluidic systems for axonal growth and regeneration research

<正>Damage to the adult mammalian central nervous system(CNS)often results in persistent neurological deficits with limited recovery of functions.The past decade has seen increasing research efforts in neural regeneration research with the ultimate goal of achieving functional recovery.Many studies have focused on prevention of further neural damage and restoration of functional connections that are com-     

Calcium channel inhibition-mediated axonal stabilization improves axonal regeneration after optic nerve crush

正Axonal projections are specialized neuronal compartments and the longest parts of neurons.Axonal degeneration is a common pathological feature in many neurodegenerative disorders,such as Parkinson’s disease,amyotrophic lateral sclerosis,glaucoma,as well as in traumatic lesions of the central nervous system(CNS),such as spinal cord injury.In many neurological disorders,the axon is     

Batrachotoxin induced axonal necrosis followed by regeneration

Batrachotoxin (BTX), when applied to peripheral nerve in concentrations sufficient to block impulse transmission and axonal transport, causes axonal necrosis. Quantitation of this phenomenon reveals reduction of both myelinated and unmyelinated fibers 7 days post-BTX injection. Evidence for regeneration correlates with the previously reported recovery of postsynaptic events.     

cAMP, tubulin, axonal transport, and regeneration

Mounting a regenerative response after injury is a multistep process for PNS neurons. The reason for failure of mammalian CNS neurons to regenerate successfully may involve more than one of those steps. Han et al. [Exp. Neurol. 189 (2004) 293] and others show that increasing cAMP levels in neuronal cell bodies elicits a partial regenerative response, altering expression of tubulin isotypes but not expression of other growth-associated genes or rate of axonal transport. This approach allows identification of specific steps in the regenerative response and the roles played by these steps.     

Interaction between serotonergic and noradrenergic axons during axonal regeneration

The present experiments focused on the morphological interaction between serotonergic (5-HT) and noradrenergic (NA) axons during regeneration following partial axonal denervation in the cerebral cortex in adult rats. The denervation paradigm used employed two neurotoxins, one for 5-HT and one for NA axons, infused together at one cortical site while a single neurotoxin to either 5-HT or NA was infused at the symmetrical cortical site in the other hemisphere. This treatment enabled us to assess the role of 5-HT or NA axons in the regeneration of the other monoaminergic axon. 5-HT axon regeneration became apparent as early as 28 days after the toxin injection, whereas the regeneration of NA axons was not evident even at 60 days after the toxin injection. Since NA axons revealed marked regeneration in the cortical site with denervation of 5-HT axons, intact 5-HT axons may be inhibitory on the regeneration of NA axons. In contrast, since the regeneration of 5-HT axons was suppressed in the absence of NA axons, NA axons appear to exert a facilitatory effect on 5-HT axon regeneration. These results suggest that the role of 5-HT axons in the regeneration of NA axons is opposite to that of NA axons in the regeneration of 5-HT axons. In addition, the regeneration of 5-HT axons occurred much faster than that of NA axons in response to axonal damage. The differential roles of 5-HT and NA axons in axonal regeneration may play a role in a variety of physiological functions related to these monoamines and possibly in the pathophysiology of clinical depression.     

Retina-derived growth-promoting extract supports axonal regeneration in vivo

The ability of a growth-promoting extract derived from bovine retina was assessed for its ability to support nerve fiber regeneration from proximal stumps of transected sciatic nerves. Proximal stumps of transected rat peripheral nerves were inserted into the single inlet end of a 6 mm long Y-shaped Silastic implant. One of the paired outlets was attached to an Elvax pellet containing the retina-derived growth extract, and the other outlet to a pellet containing an equivalent amount of tissue extract-free Hank's balanced salt solution. At 3 weeks postoperatively, the number of axons and blood vessels in the midportion of implant forks was assessed. The extent of axonal regeneration and blood vessel formation induced were similar to each other and dose-dependent. Results indicate preferential and dose-dependent growth of axons toward pellets containing the retina-derived growth-promoting extract.     

Overcoming inhibitors in myelin to promote axonal regeneration

The lack of axonal growth after injury in the adult central nervous system (CNS) is due to several factors including the formation of a glial scar, the absence of neurotrophic factors, the presence of growth-inhibitory molecules associated with myelin and the intrinsic growth-state of the neurons. To date, three inhibitors have been identified in myelin: Myelin-Associated Glycoprotein (MAG), Nogo-A, and Oligodendrocyte-Myelin glycoprotein (OMgp). In previous studies we reported that MAG inhibits axonal regeneration by high affinity interaction (K(D) 8 nM) with the Nogo66 receptor (NgR) and activation of a p75 neurotrophin receptor (p75NTR)-mediated signaling pathway. Similar to other axon guidance molecules, MAG is bifunctional. When cultured on MAG-expressing cells, dorsal root ganglia neurons (DRG) older than post-natal day 4 (PND4) extend neurites 50% shorter on average than when cultured on control cells. In contrast, MAG promotes neurite outgrowth from DRG neurons from animals younger than PND4. The response switch, which is also seen in retinal ganglia (RGC) and Raphe nucleus neurons, is concomitant with a developmental decrease in the endogenous neuronal cAMP levels. We report that artificially increasing cAMP levels in older neurons can alter their growth-state and induce axonal growth in the presence of myelin-associated inhibitors.     

Promotion of axonal regeneration in the injured CNS

Molecules that are found in the extracellular environment at a CNS lesion site, or that are associated with myelin, inhibit axon growth. In addition, neuronal changes--such as an age-dependent reduction in concentrations of cyclic AMP--render the neuron less able to respond to axotomy by a rapid, forward, actin-dependent movement. An alternative mechanism, based on the protrusive forces generated by microtubule elongation or the anterograde transport of cytoskeletal elements, may underlie a slower form of axon elongation that happens during regeneration in the mature CNS. Therapeutic approaches that restore the extracellular CNS environment or the neuron's characteristics back to a more embryonic state increase axon regeneration and improve functional recovery after injury. These advances in the understanding of regeneration in the CNS have major implications for neurorehabilitation and for the use of axonal regeneration as a therapeutic approach to disorders of the CNS such as spinal-cord injury.     

Acetylation as a mechanism that regulates axonal regeneration

<正>The capacity for adult axons to regenerate after injury is diminished compared with developing axons.In the case of central nervous system(CNS)axons,injury causes a total failure to regenerate.This failure is due to both the intrinsic developmental decrease in growth capacity and the extrinsic inhibitory environment formed because of the injury.One way to re-invigorate mature axons into a regrowth state is to induce regenerative gene expression in the nucleus to increase the intrinsic growth state of the neuron.One potential mechanism is through changes in epigenetic factors.Another possible method is to alter posttranslational modifications in axonal and growth cone microtubules of the axonal cytoplasm(Trakhtenberg and Goldberg,2012;Cho and