Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice.

Parkinson's disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-ß-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.

Therapy with nonglycosaminoglycan-binding mutant CCL7: a novel strategy to limit allograft inflammation.

Chemokines are immobilized by binding to glycosaminoglycans (GAGs). A non-GAG-binding mutant CCL7 (mtCCL7) was developed that retained its affinity for chemokine receptors. This mtCCL7 induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration (p<0.01). Unlike wild-type CCL7, mtCCL7 persisted in the circulation of BALB/c mice for more than 6 h and prevented leukocyte infiltration of skin isografts (p<0.05). Treatment with mtCCL7 marginally increased the survival of C57BL/6 to BALB/c skin allografts and reduced graft infiltration by CD3+ cells (p<0.05). Importantly, mtCCL7 promoted long-term (>40 day) graft survival following minor histocompatibility (HY) antigen mismatched C57BL/6 skin transplantation; control grafts were rejected by day 24. Treatment with mtCCL7 produced a significant decrease in the frequency of IFN-gamma producing donor-reactive splenic T cells, reduced CCR2 expression by circulating leukocytes for 6 h (p<0.01) and blocked the normal increase in affinity of alpha4beta1 integrins for VCAM-1 following transient chemokine stimulation. These data suggest that mtCCL7 persists in the circulation and reduces both specific T-cell priming and the capacity of circulating immune cells to respond to GAG-bound chemokine at sites of developing inflammation.