Steinmetz, et al. (2005). Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mam

[Wise Young]

This study from Jerry Silver's laboratory reports that causing inflammation (with Zymosan) to sensory roots before injury and treatment with chondrotinase after injury allowed regeneration of sensory axons into the spinal cord. Chondroitinase (ChABC) breaks down chondroitin-6-sulfate-proteoglycan (CSPG) which inhibits axonal growth in the spinal cord. It is interesting that CSPG alone or Zymosan alone did not stimulate regeneration of the sensory roots. Also Zymosan treatment after injury did not help.

[*] Steinmetz MP, Horn KP, Tom VJ, Miller JH, Busch SA, Nair D, Silver DJ and Silver J (2005). Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mammalian spinal cord. J Neurosci 25: 8066-76. Peripherally conditioned sensory neurons have an increased capacity to regenerate their central processes. However, even conditioned axons struggle in the presence of a hostile CNS environment. We hypothesized that combining an aggressive conditioning strategy with modification of inhibitory reactive astroglial-associated extracellular matrix could enhance regeneration. We screened potential treatments using a model of the dorsal root entry zone (DREZ). In this assay, a gradient of inhibitory chondroitin sulfate proteoglycans (CSPGs) stimulates formation of dystrophic end bulbs on adult sensory axons, which mimics regeneration failure in vivo. Combining inflammation-induced preconditioning of dorsal root ganglia in vivo before harvest, with chondroitinase ABC (ChABC) digestion of proteoglycans in vitro allows for significant regeneration across a once potently inhibitory substrate. We then assessed regeneration through the DREZ after root crush in adult rats receiving the combination treatment, ChABC, or zymosan pretreatment alone or no treatment. Regeneration was never observed in untreated animals, and only minimal regeneration occurred in the ChABC- and zymosan-alone groups. However, remarkable regeneration was observed in a majority of animals that received the combination treatment. Regenerated fibers established functional synapses, as demonstrated electrophysiologically by the presence of an H-reflex. Two different postlesion treatment paradigms in which the timing of both zymosan and ChABC administration were varied after injury were ineffective in promoting regeneration. Therefore, zymosan pretreatment, but not posttreatment, of the sensory ganglia, combined with ChABC modification of CSPGs, resulted in robust and functional regeneration of sensory axons through the DREZ after root injury. Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16135764