GDNF protection against 6-OHDA: time dependence and requirement for protein synthesis.
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 approximately 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.
Kearns
C M
CM
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Cass
W A
WA
Smoot
K
K
Kryscio
R
R
Gash
D M
DM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003513:Cycloheximide / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007276:Injections, Intraventricular; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D003513:Cycloheximide; D004298:Dopamine