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Volume 17, Number 18, Issue of September 15, 1997 pp. 7111-7118
Copyright ©1997 Society for Neuroscience

GDNF Protection against 6-OHDA: Time Dependence and Requirement for Protein Synthesis

Received May 12, 1997; revised June 24, 1997; accepted June 30, 1997.

Cecilia M. Kearns¹, Wayne A. Cass¹, Kyle Smoot¹, Richard Kryscio², and Don M. Gash¹

¹ Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, Kentucky 40536, and ² Department of Biostatistics, University of Kentucky Medical Center, Lexington, Kentucky 40536

Glial cell line-derived neurotrophic factor (GDNF) injected intranigrally protects midbrain dopamine neurons against 6-hydroxydopamine (6-OHDA) toxicity. The timing between GDNF administration and exposure to 6-OHDA is critical in achieving optimal protection. When injected 6 hr before an intranigral injection of 6-OHDA, GDNF provides complete protection as measured by the number of surviving neurons in the substantia nigra of adult rats. The surviving neuronal population decreases by ~50% with 12 and 24 hr separating GDNF and 6-OHDA administrations. In controls with 6-OHDA lesions, there is <10% survival of nigral dopamine neurons. No significant increase in survival is seen with either concurrent injections of GDNF and 6-OHDA or 1 hr GDNF pretreatment. 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. Protein synthesis is necessary for GDNF-induced neuroprotective effects because cycloheximide pretreatment that inhibits protein synthesis also blocks neuroprotection.

Key words: GDNF; 6-OHDA; neuroprotection; substantia nigra; dopamine neurons; cycloheximide

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