GDNF IS A TROPHIC FACTOR FOR ADULT-RAT CORTICOSPINAL NEURONS AND PROMOTES THEIR LONG-TERM SURVIVAL AFTER AXOTOMY IN-VIVO

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for several neuronal populations involved in motor control. The prese nt study evaluates the trophic actions of GDNF on corticospinal neuron s, an important central nervous system motor projection into the spina l cord. Death of spinal motoneurons and corticospinal neurons is obser ved in the neurodegenerative disease amyotrophic lateral sclerosis. Ax otomy of adult rat corticospinal neurons at internal capsule levels in duces half of them to die, and the surviving population displays sever e atrophy. To examine the trophic effects of GDNF on corticospinal neu rons, Fast Blue-labelled corticospinal neurons were stereotaxically ax otomized at internal capsule levels and GDNF was infused intracortical ly to lesioned corticospinal neurons at total doses of 2, 4, 10, 20, 4 0, 100 and 300 mu g for 7 days. GDNF prevented axotomy-induced death o f corticospinal neurons al doses between 2 and 40 mu g and abolished o r attenuated their atrophy at all doses examined. In addition, treatme nt with 8 mu g GDNF for the first 2 weeks after axotomy resulted in th e long-term survival of corticospinal neurons for 42 days. With regard to the development of treatment strategies for upper motoneuron degen eration in amyotrophic lateral sclerosis, application of GDNF via the cerebrospinal fluid may be more relevant than intracortical delivery a s its diffusion within the brain parenchyma is limited. Intraventricul ar as well as intracisternal infusion of GDNF (300 mu g over 7 days) c ompletely prevented corticospinal neuron death. These results show tha t GDNF promotes the long-term survival of corticospinal neurons and ha s a positive effect on their size in vivo. Furthermore, the survival-p romoting effect of GDNF on corticospinal neurons after delivery via ce rebrospinal fluid has important clinical implications for potential tr eatment of the upper motoneuron degeneration seen in amyotrophic later al sclerosis.