Cnicin promotes functional nerve regeneration.

Background: The limited regenerative capacity of injured axons hinders functional recovery after nerve injury. Although no drugs are currently available in the clinic to accelerate axon regeneration, recent studies show the potential of vasohibin inhibition by parthenolide, produced in Tanacetum parthenium, to accelerate axon regeneration. However, due to its poor oral bioavailability, parthenolide is limited to parenteral administration.

Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration.

Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury.

Transneuronal Delivery of Cytokines to Stimulate Mammalian Spinal Cord Regeneration.

The spinal cord contains multiple fiber tracts necessary for locomotion. However, as a part of the central nervous system, they are extremely limited in regenerating after injury. Many of these key fiber tracts originate from deep brain stem nuclei that are difficult to access.

[Regeneration of the optic nerve-Will it one day be reality?].

Background: Adult mammalian and human neurons of the central nervous system (CNS) lack the ability to spontaneously regenerate damaged axons. This dilemma of many CNS diseases is still an unsolved problem.

Objective: The purpose of this article is to examine the question which options have been investigated in more detail in recent years and offer approaches.

CXCR4/CXCL12-mediated entrapment of axons at the injury site compromises optic nerve regeneration.

Regenerative failure in the mammalian optic nerve is generally attributed to axotomy-induced retinal ganglion cell (RGC) death, an insufficient intrinsic regenerative capacity, and an extrinsic inhibitory environment. Here, we show that a chemoattractive CXCL12/CXCR4-dependent mechanism prevents the extension of growth-stimulated axons into the distal nerve. The chemokine CXCL12 is chemoattractive toward axonal growth cones in an inhibitory environment, and these effects are entirely abolished by the specific knockout of its receptor, CXCR4 (CXCR4), in cultured regenerating RGCs.

Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice.

Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration.

GSK3-CRMP2 signaling mediates axonal regeneration induced by knockout.

Knockout of phosphatase and tensin homolog (PTEN) is neuroprotective and promotes axon regeneration in mature neurons. Elevation of mTOR activity in injured neurons has been proposed as the primary underlying mechanism. Here we demonstrate that PTEN also abrogates the inhibitory activity of GSK3 on collapsin response mediator protein 2 (CRMP2) in retinal ganglion cell (RGC) axons.

Muscle LIM Protein Is Expressed in the Injured Adult CNS and Promotes Axon Regeneration.

Muscle LIM protein (MLP) has long been regarded as a muscle-specific protein. Here, we report that MLP expression is induced in adult rat retinal ganglion cells (RGCs) upon axotomy, and its expression is correlated with their ability to regenerate injured axons. Specific knockdown of MLP in RGCs compromises axon regeneration, while overexpression in vivo facilitates optic nerve regeneration and regrowth of sensory neurons without affecting neuronal survival.

Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity.

Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3 knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice.

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling.

Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines.

Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination.

Unlabelled: Functional recovery of injured peripheral neurons often remains incomplete, but the clinical outcome can be improved by increasing the axonal growth rate. Adult transgenic GSK3α(S/A)/β(S/A) knock-in mice with sustained GSK3 activity show markedly accelerated sciatic nerve regeneration. Here, we unraveled the molecular mechanism underlying this phenomenon, which led to a novel pharmacological approach for the promotion of functional recovery after nerve injury.

Sustained GSK3 activity markedly facilitates nerve regeneration.

Promotion of axonal growth of injured DRG neurons improves the functional recovery associated with peripheral nerve regeneration. Both isoforms of glycogen synthase kinase 3 (GSK3; α and β) are phosphorylated and inactivated via phosphatidylinositide 3-kinase (PI3K)/AKT signalling upon sciatic nerve crush (SNC). However, the role of GSK3 phosphorylation in this context is highly controversial.

Neuronal expression of muscle LIM protein in postnatal retinae of rodents.

Muscle LIM protein (MLP) is a member of the cysteine rich protein family and has so far been regarded as a muscle-specific protein that is mainly involved in myogenesis and the organization of cytoskeletal structure in myocytes, respectively. The current study demonstrates for the first time that MLP expression is not restricted to muscle tissue, but is also found in the rat naive central nervous system. Using quantitative PCR, Western blot and immunohistochemical analyses we detected MLP in the postnatal rat retina, specifically in the somas and dendritic arbors of cholinergic amacrine cells (AC) of the inner nuclear layer and the ganglion cell layer (displaced AC).

TGF-β signaling protects retinal neurons from programmed cell death during the development of the mammalian eye.

We investigated the influence of transforming growth factor-β (TGF-β) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-β type II receptor (TβRII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the TβRII in cells that originate from the inner layer of the optic cup. The animals showed a significant decrease of phosphorylated Smad3 in both the central and peripheral retina, which indicates the diminished activity of TGF-β signaling.

Do growth-stimulated retinal ganglion cell axons find their central targets after optic nerve injury? New insights by three-dimensional imaging of the visual pathway.

Retinal ganglion cells (RGCs) do not normally regenerate injured axons. However, several strategies to transform RGCs into a potent regenerative state have been developed in recent years. Intravitreal CNTF application combined with conditional PTEN and SOCS3 deletion or zymosan-induced inflammatory stimulation together with cAMP analogue injection and PTEN-deletion in RGCs induce long-distance regeneration into the optic nerve of adult mice.

CXCL12/SDF-1 facilitates optic nerve regeneration.

Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but undergo apoptosis soon after axotomy. Besides the insufficient intrinsic capability of mature neurons to regrow axons inhibitory molecules located in myelin of the central nervous system as well as the glial scar forming at the site of injury strongly limit axon regeneration. Nevertheless, RGCs can be transformed into a regenerative state upon inflammatory stimulation (IS), enabling these neurons to grow axons into the injured optic nerve.

Promoting optic nerve regeneration.

Vision is the most important sense for humans and it is irreversibly impaired by axonal damage of retinal ganglion cells (RGCs) in the optic nerve due to the lack of axonal regeneration. The failure of regeneration is partially attributable to factors located in the inhibitory environment of the forming glial scar and myelin as well as an insufficient intrinsic ability for axonal regrowth. Moreover, RGCs undergo apoptotic cell death after optic nerve injury, eliminating any chance for regeneration.

Role of mTOR in neuroprotection and axon regeneration after inflammatory stimulation.

Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but degenerate after axotomy. However, inflammatory stimulation (IS) enables RGCs to survive axotomy and regenerate axons in the injured optic nerve. Similar effects are achieved by the genetic deletion of phosphatase and tensin homolog (PTEN) and subsequent mammalian target of rapamycin (mTOR) activation.

Taxol facilitates axon regeneration in the mature CNS.

Mature retinal ganglion cells (RGCs) cannot normally regenerate axons into the injured optic nerve but can do so after lens injury. Astrocyte-derived ciliary neurotrophic factor and leukemia inhibitory factor have been identified as essential key factors mediating this effect. However, the outcome of this regeneration is still limited by inhibitors associated with the CNS myelin and the glial scar.

A method for preparing primary retinal cell cultures for evaluating the neuroprotective and neuritogenic effect of factors on axotomized mature CNS neurons.

Retinal ganglion cells (RGCs) are central nervous system neurons with a very limited ability for axon regeneration. This unit details a cell culture technique, which can be used to functionally screen factors/compounds for their neuritogenic and neuroprotective effects on RGCs. In this protocol, the retina is isolated, digested in a papain solution, and after trituration, the RGCs are cultured.

Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor.

After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI.

Stimulation of axon regeneration in the mature optic nerve by intravitreal application of the toll-like receptor 2 agonist Pam3Cys.

Purpose: After injury of the optic nerve, mature retinal ganglion cells (RGCs) are normally unable to regenerate axons and undergo apoptosis. However, inflammatory stimulation in the eye induced by the release of beta/gamma-crystallins from the injured lens or intravitreal zymosan injection transforms RGCs into an active regenerative state, protecting these neurons from cell death and allowing them to regenerate axons back into the optic nerve.

Methods: The authors tested whether intravitreal application of the selective, water-soluble, toll-like receptor 2 agonist Pam(3)Cys can delay axotomized RGC cell death and stimulate the regeneration of axons using an in vitro and in vivo paradigm.

Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF.

Intravitreal injections of exogenous CNTF stimulate axon regeneration of RGCs in vivo. Nevertheless, controversy exists over the ability of exogenous CNTF to directly stimulate axon regeneration of mature RGCs. Here we demonstrate that CNTF potently stimulated axon outgrowth of mature RGCs in culture in a JAK/STAT3- and PI3K/AKT-signaling pathway-dependent fashion and stronger than oncomodulin.