Embryonic substantia nigra grafts show directional outgrowth to cografted striatal grafts and potential for pathway reconstruction in nonhuman primate.

Transplantation of embryonic dopamine (DA) neurons has been tested as a therapy for Parkinson's disease. Most studies placed DA neurons into the striatum instead of the substantia nigra (SN). Reconstruction of this DA pathway could serve to establish a more favorable environment for control of DA release by grafted neurons. To test this we used cografts of striatum to stimulate growth of DA axons from embryonic SN that was implanted adjacent to the host SN in African green monkeys. Embryonic striatum was implanted at one of three progressive distances rostral to the SN. Immunohistochemical analysis revealed DA neuron survival and neuritic outgrowth from the SN grafts at 12-36 weeks after grafting. Each animal showed survival of substantial numbers of DA neurons. Most fibers that exited SN grafts coursed rostrally. Striatal grafts showed evidence of target-directed outgrowth and contained dense patterns of DA axons that could be traced from their origin in the SN grafts. A polarity existed for DA neurites that exited the grafts; that is, those seen caudal to the grafts did not appear to be organized into a directional outflow while those on the rostral side were arranged in linear profiles coursing toward the striatal grafts. Some TH fibers that reached the striatal grafts appeared to arise from the residual DA neurons of the SN. These findings suggest that grafted DA neurons can extend neurites toward a desired target over several millimeters through the brain stem and caudal diencephalon of the monkey brain, which favors the prospect of circuit reconstruction from grafted neurons placed into appropriate locations in their neural circuitry. Further study will assess the degree to which this approach can be used to restore motor balance in the nonhuman primate following neural transplantation.

Tissue distribution of synthetic heme analogues: studies with tin, chromium, and zinc mesoporphyrins.

The uptake in tissue of Sn-mesoporphyrin (SnMP), Cr-mesoporphyrin (CrMP) and Zn-mesoporphyrin (ZnMP) administered at doses ranging from 1 to 10 mu mol/kg BW and the effects of these compounds on heme oxygenase activity were examined in both adult and neonatal rats. SnMP and CrMP, but not ZnMP, were rapidly cleared from blood and taken up by liver, spleen and kidney where marked inhibition of heme oxygenase activity was demonstrated. None of the metalloporphyrins were detectable in brain, and no inhibition of heme oxygenase activity was demonstrable in this tissue after administration of the compounds to both adult and neonatal rats. These results demonstrate that SnMP, CrMP and ZnMP do not cross the blood brain barrier, a fact of interest in relation to the potential use of these compounds clinically.