PROTECTION AND REPAIR OF THE NIGROSTRIATAL DOPAMINERGIC SYSTEM BY GDNF IN-VIVO

GLIAL-CELL-LINE-DERIVED neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promote s survival of cultured fetal mesencephalic dopamine neurons(1) and is expressed in the developing striatum(2,3). There have, however, been n o reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF migh t exert protective or regenerative effects in vivo in the adult nigros triatal dopamine system in C57/Bl mice. GDNF injected over the substan tia nigra or in striatum before MPTP potently protects the dopamine sy stem, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is g iven after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above,normal le vels. We conclude that intracerebral GDNF administration exerts both p rotective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment stra tegies for Parkinson's disease.