Effects of single versus combinatorial treatment strategies on beta II-tubulin gene expression in axotomized hamster rubrospinal motoneurons.

PURPOSE: betaII-tubulin, a regeneration-associated gene, is upregulated in injured peripheral neurons, but significantly less so in injured central neurons. Using a hamster dorsal spinal cord injury (SCI), the ability of single versus combinatorial treatment strategies to alter betaII-tubulin mRNA expression in rubrospinal motoneurons (RSMN) was examined. We have shown that systemic testosterone propionate (TP) treatment in combination with peripheral nerve grafting into a SCI site produces a peripheral-like pattern of betaII-tubulin mRNA expression in injured RSMN. In the present study, selected single- and combinatorial-therapy strategies were tested for their ability to promote a sustained upregulation of betaII-tubulin mRNA levels in injured RSMN.

METHODS: Single treatments of olfactory ensheathing cells (OEC), brain-derived neurotrophic factor (BDNF), or Schwann cells (SC) vs combinatorial treatments (SC+TP, OEC+TP, and OEC+BDNF) were administered to hamsters following a dorsal SCI. Quantitative in situ hybridization in conjunction with a betaII-tubulin cDNA probe was accomplished.

RESULTS: All of the single-therapy treatments tested were able to prevent the downregulation of betaII-tubulin mRNA that occurred a week after injury alone, but only BDNF maintained high levels of betaII-tubulin mRNA. In contrast, all combinatorial treatments tested maintained the upregulation of betaII-tubulin mRNA expression in injured RSMN 1 week post-SCI.

CONCLUSIONS: Targeting both intrinsic and extrinsic components of CNS injury can re-program elements of the molecular response of injured central motoneurons.