Co-treatment with riluzole and GDNF is necessary for functional recovery after ventral root avulsion injury

Unilateral avulsion of lumbar ventral roots kills approximately 50% of injured motoneurons within 2 weeks of surgery. Immediate treatment involving surgical reimplantation of the ventral root (VRI) or intrathecal glial cell line-derived neurotrophic factor (GDNF) delivery or intraperitoneal injection of riluzole for 2 weeks ameliorates motoneuron death to 80% of control but combining the different treatment paradigms did not further enhance survival except when GDNF was combined with VRI. At 3 months, all combined treatments provided a neuroprotective effect compared to avulsion only, but the neuroprotective effect of surgical reimplantation alone was not maintained unless combined with riluzole and GDNF treatment. Analysis of regenerating motoneurons using retrograde labelling techniques showed that riluzole, but not GDNF, increased the number of dendrites per labelled motoneuron. However, when functional motor recovery was assessed using the BBB locomotor score and rotarod tests, only VRI animals treated with riluzole and GDNF application showed significantly improved locomotor function in both tests. Our results show that functional recovery appears related to a combination of enhanced dendrite formation, increased motoneuron survival and the neurotrophic actions of GDNF. Thus, combination treatment may offer a new therapeutic strategy for treating patients with avulsion injury.