TOPOGRAPHICAL DISTRIBUTION OF [I-125] GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IN UNLESIONED AND MPTP-LESIONED RHESUS-MONKEY BRAIN FOLLOWING A BOLUS INTRAVENTRICULAR-INJECTION

The present study determined the topographical distribution profile fo r [I-125]-glial cell Line-derived neurotrophic factor in unlesioned an d MPTP-lesioned (unilateral intracarotid injection) rhesus monkeys fol lowing an intraventricular injection. Autoradiographic analysis showed that following a bolus intraventricular injection, there was widespre ad distribution of [I-125]-glial cell line-derived neurotrophic factor throughout the ventricular system (walls of lateral, third, and fourt h ventricles and aqueduct), with some accumulation at the lateral vent ricle injection site, possibly associated with the ependymal cell laye r. In both unlesioned and MPTP-lesioned monkeys, there was labelling o f the cerebral cortex, substantia nigra/ventral tegmental area and seq uestration of [I-125]-glial cell line-derived neurotrophic factor adja cent to the hippocampal formation, globus pallidus, ventral to and in the substantia nigra. However, [I-125]-glial cell line-derived neurotr ophic factor did not appear to diffuse readily or accumulate in the ca udate-putamen even though there was some penetration away from the ven tricular walls. Throughout the brain, there was also substantial non-p arenchymal labelling of [I-125]-glial cell line-derived neurotrophic f actor, possibly associated with extracellular matrix components, menin ges and vasculature due to the heparin binding properties of glial cel l line-derived neurotrophic factor. In addition to the extensive loss of tyrosine hydroxy]ase immunoreactivity within the substantia nigra, there was also decreased accumulation of [I-125]-glial cell line-deriv ed neurotrophic factor and reduced glial cell line-derived neurotrophi c factor immunoreactivity ipsilateral to the lesion. Microscopic analy sis showed that glial cell line-derived neurotrophic factor immunoreac tivity was associated with upper cortical layers including a high dens ity of immunoreactivity at the surface of the cortex (meningeal, pial layer, vasculature) and around the ventricular walls (with some cellul ar labelling and labelling of vasculature). Moderate staining was obse rved in nigral cells contralateral to the MPTP-lesion, whereas only mi nimal levels of that glial cell Line-derived neurotrophic factor immun oreactivity were detected ipsilateral to the lesion. This study shows that intraventricularly injected glial cell line-derived neurotrophic factor accumulates not only around the ventricular walls, but also in specific brain regions in which sub-populations of cells are more read ily accessible than others. The presence of cells labelled with [I-125 ] and immunopositive for glial cell line-derived neurotrophic factor i n the substantia nigra indicates that these cells are a target for the trophic factor following intraventricular administration. Thus, the b ehavioral improvement observed in MPTP-lesioned monkeys following an i ntraventricular injection of glial cell line-derived neurotrophic fact or is likely the result of activation of nigral cells. (C) 1998 Elsevi er Science B.V.