DIFFERENTIAL-EFFECTS OF PLATELET-DERIVED GROWTH-FACTOR ISOFORMS ON DOPAMINE NEURONS IN-VIVO - -BB SUPPORTS CELL-SURVIVAL, -AA ENHANCES FIBER FORMATION

Trophic effects of platelet-derived growth factor -AA and -BB on developing (embryonic day 14) ventral mesencephalon were studied using the in vivo model of intraocular transplantation to sympathetically denervated host eyes. This model enabled studies of survival and growth of grafted brain tissue, dopaminergic fiber outgrowth from the grafts onto the host iris as well as morphological effects of platelet-derived growth factor on grafted tissue using markers for tyrosine hydroxylase and glial fibrillary acid protein. Growth of grafts was followed by repeated observations directly through the cornea of the host using a stereomicroscope. This revealed that there was no apparent effect on volume increase of mesencephalic grafts after treatments with either platelet-derived growth factor-AA (100 ng/ml buffer), platelet-derived growth factor-BB (100 ng/ml buffer) or vehicle solution (high salt buffer) alone. Growth factor treatments were administered immediately prior to grafting by incubating the grafts in the appropriate factor as well as on days 5, 10 and 15 postgrafting by administration of 5-mu 1 intraocular injections of similiar solutions as used for incubation. Platelet-derived growth factor-AA significantly enhanced dopaminergic fiber outgrowth from mesencephalic grafts when compared to both platelet-derived growth factor-BB and controls, without an accompanying rise in the number of tyrosine hydroxylase-positive neurons. In contrast, a significantly greater number of tyrosine hydroxylase-positive neurons was seen in grafts treated with platelet-derived growth factor-BB but without an accompanying increase in outgrowth of dopamine-containing fibers. Both platelet-derived growth factor-AA and -BB treatments caused a slight but significant decrease (=normalization) in the GFAP-like immunoreactive elements within the grafts as compared to grafts treated with vehicle alone. These findings suggest that in vivo, the two platelet-derived growth factor isoforms both act on the ventral mesencephalic grafts, each in a distinct manner, -AA enhancing the formation of dopamine fibers and -BB acting as a maintenance factor for tyrosine hydroxylase-positive cells in this area. This leads to the conclusion that these two platelet-derived growth factor isoforms could act as trophic factors for mesencephalic dopamine neurons.