Lesioned corticospinal tract axons regenerate in myelin-free rat spinal cord.

Abstract

In the adult central nervous system (CNS) of higher vertebrates lesioned axons seemed unable to regenerate and reach their former target regions due to influences of the CNS microenvironment. Evidence from in vitro and biochemical experiments has demonstrated the presence of inhibitory substrate components in CNS tissue, in particular in white matter. These CNS components, which strongly inhibit neurite growth, were identified as minor membrane proteins ofdefined molecular mass (35 and 250 kDa) in oligodendrocyte membranes and CNS myelin. Oligodendrocyte development and myelin formation can be prevented by x-irradiation ofnewborn rats. Here we show that in myelin-free spinal cords corticospinal tract fibers transected at 2 weeks of age show reelongation ofmany millimeters within 2-3 weeks after the lesion. In normally myelinated controls, regenerative sprouts grew less than 1.7 mm caudal to the lesion.

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

“…Indeed, several components from the disrupted myelin and extracellular matrix components produced by reactive astrocytes, microglia, and fibrocytes show strong inhibitory properties on axonal outgrowth and regeneration, limiting the recovery of motor function after injury (Savio and Schwab, 1990;Schnell and Schwab, 1990;McKerracher et al, 1994;Bregman et al, 1995;Davies et al, 1999;Chen et al, 2000;Bradbury et al, 2002;GrandPré et al, 2002;Kottis et al, 2002;Sroga et al, 2003;Silver and Miller, 2004;Yiu and He, 2006;Hellal et al, 2011;Wang et al, 2011). In p53 Ϫ/Ϫ injured cords, aberrant glial proliferation is accompanied by enhanced glial scar formation, as shown by GFAP-and fibronectin-positive scar tissue revealing a bigger reactive astrocyte area around the lesion site and an enlarged lesion core.…”

Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A

“…In the adult CNS, the most plastic regions are often the lowest in terms of myelin content (Benowitz and PerroneBizzozero, 1991;Kapfhammer and Schwab, 1994). In the postnatal or adult spinal cord and brainstem, suppression of myelin formation or the application of a Nogo-A neutralizing antibody restore plasticity and compensatory sprouting to a level that is normally seen exclusively within the first few days after birth (Dyer et al, 1998;Raineteau and Schwab, 2001;Savio and Schwab, 1990;Schwab, 2004;Thallmair et al, 1998). These results gave rise to the concept of a stabilizing role of Nogo-A for the adult CNS (Kapfhammer and Schwab, 1994;Schwab, 2004), probably assisted by other CNS myelin proteins with neurite growth inhibitory activities like myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), Semaphorin 4D and 5A, or certain chondroitin sulfate proteoglycans (Filbin, 2003;Moreau-Fauvarque et al, 2003;Goldberg et al, 2004;Niederöst et al, 1999).…”

White matter inhibitors in CNS axon regeneration failure

“…Two in vivo studies supported the hypothesis that myelin and oligodendrocytes are inhibitory to regeneration. First, regeneration of descending tract axons after lesion was enhanced in postnatal rats after depleting oligodendrocytes and CNS myelin with γ-irradiation (Savio and Schwab, 1990). Second, after adult mice were immunized with myelin so that their own immune system was stimulated to produce polyclonal antibodies including those that presumably block myelinassociated inhibitors, regeneration of corticospinal (CST) axons was observed following injury (Huang et al, 1999).…”