The survival of injured adult dopaminergic substantia nigra pars compacta neurons can be promoted by various neurotrophic factors. Most neurotrophic factor receptors are activated by intracellular tyrosine phosphorylation upon ligand binding and are subsequently inactivated or dephosphorylated by protein tyrosine phosphatases. This raised the possibility that tyrosine phosphatase inhibition might improve neuronal survival. Here, we infused the stable water-soluble tyrosine phosphatase-specific inhibitor, peroxovanadium [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) (bpV(phen))], for 14 days close to the substantia nigra starting immediately after a unilateral moderate injury by injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the midbrain of adult Sprague-Dawley rats. The dopaminergic nigrostriatal neurons were identified by retrograde tracing with fluorogold 7 days prior to the injury. With infusion of 3 or 10 microm peroxovanadium, 75% of these neurons survived compared to 45% in vehicle-infused rats. Degeneration of the dopaminergic projections to the neostriatum was also reduced by 10 microm peroxovanadium. Twenty minutes after an acute injection of peroxovanadium into the substantia nigra, increased tyrosine phosphorylation in Western blots of nigral extracts was seen in the same protein bands as after injections of brain-derived neurotrophic factor (BDNF) or NT-4. This suggests that peroxovanadium enhances endogenous neurotrophic signalling resulting in improved neuronal survival. The neuroprotective effects of this small molecule protein tyrosine phosphatase inhibitor represent a proof-of-principle for a novel treatment strategy in a model for Parkinson's disease.

We previously established (Datskovskaia et al. [2001] J Comp Neurol 430:85-100) that roughly 40% of Y retinal terminals contact interneurons in the A lamina of the dorsal lateral geniculate nucleus (dLGN) of the cat. However, we did not establish whether the dendritic terminals of interneurons postsynaptic to Y retinal terminals subsequently contact Y thalamocortical cells. To begin to address this issue, we examined the synaptic targets of Y retinal terminals in the magnocellular C lamina of the dLGN, which is populated almost exclusively by Y thalamocortical cells and interneurons. We utilized material generated from our previous work, in which we injected the superior colliculus with biotinylated dextran amine to backfill the geniculate branches of Y retinogeniculate axons in the dLGN. Sections prepared for electron microscopy were stained for gamma aminobutyric acid (GABA) to distinguish interneurons from thalamocortical cells. We found that the majority of profiles postsynaptic to Y retinal axons were the GABA-negative dendrites of thalamocortical cells (116/200, 58%). The remainder were GABA-positive dendrites of interneurons (84/200, 42%), many of which contained vesicles (F2 profiles; 54/200, 27%). In addition, we examined the synaptic targets of F2 profiles and found that almost all contacts of F2 profiles in the magnocellular C lamina were made onto the GABA-negative dendrites of thalamocortical cells (199/200, 99.5%). Thus, Y retinogeniculate axons contact interneurons and interneurons contact Y thalamocortical cells in the magnocellular C lamina of the dLGN. This indicates that interneurons are involved in modulation of the Y pathway.