GDNF PROTECTION AGAINST 6-OHDA - TIME-DEPENDENCE AND REQUIREMENT FOR PROTEIN-SYNTHESIS

Glial cell line-derived neurotrophic factor (GDNF) injected intranigra lly protects midbrain dopamine neurons against B-hydroxydopamine (6-OH DA) toxicity. The timing between GDNF administration and exposure to 6 -OHDA is critical in achieving optimal protection. When injected 6 hi before an intranigral injection of 6-OHDA, GDNF provides complete prot ection as measured by the number of surviving neurons in the substanti a nigra of adult rats. The surviving neuronal population decreases by similar to 50% with 12 and 24 hr separating GDNF and B-OHDA administra tions. In controls with 6-OHDA lesions, there is <10% survival of nigr al dopamine neurons. No significant increase in survival is seen with either concurrent injections of GDNF and 6-OHDA or 1 hr GDNF pretreatm ent. Based on HPLC measurements, striatal and midbrain dopamine levels are at least twofold higher on the lesioned side in animals receiving GDNF 6 hr before a 6-OHDA lesion compared with vehicle recipients. Pr otein synthesis is necessary for GDNF-induced neuroprotective effects because cycloheximide pretreatment that inhibits protein synthesis als o blocks neuroprotection.