| Parkinson's disease (PD) is the second most common neurodegenerative disease. The loss of dopaminergic neurons in the substantia nigra accounts for most symptoms in PD. Recently, intracerebral injection of thrombin (20 Units) has been shown to lesion those neurons, suggesting a potential role for this coagulation cascade protein in PD. However, lower doses of thrombin administered several days before lesioning are protective in stroke models; an effect termed thrombin preconditioning (TPC). While the mechanisms of TPC remain poorly understood, they may involve protection against oxidative stress and iron accumulation.;The primary goal of this dissertation was to evaluate TPC in rat experimental PD. 6-Hydroxydopamine (6-OHDA) selectively damages dopaminergic neurons and was used in these studies. TPC provided protection from 6-OHDA-elicited behavioral deficits. The effects were not mediated through sparing of striatal intracellular dopamine. Surprisingly, however, dopaminergic terminals were spared. TPC prevented striatal atrophy, indicating that the protective effects of TPC may be mediated through non-dopaminergic mechanisms.;Thrombin participates in cell signaling through activation of the protease-activated receptors (PARs). Here, it was determined that TPC-elicited protection was mediated through activation of PAR-1; while PAR-4 activation increased the lesion severity.;In contrast to preconditioning, thrombin or PAR-1 activation at the time of 6-OHDA lesioning increased behavioral deficits. Experiments on post administration of thrombin resulted in unexpected findings. Needle insertion with saline infusion after 6-OHDA strikingly increased the severity of behavioral and neurochemical deficits, an effect absent with thrombin infusion. These results raise questions over the role of physical trauma and thrombin in modulating the progression of PD.;The neurochemical effects of experimental intracerebral hemorrhage (ICH), where thrombin overload occurs, were also evaluated. Striking up-regulation of both ipsilateral and contralateral intracellular dopamine occurred in the striatum. Those effects were greater than for gamma-aminobutyric acid (GABA) and may indicate selective effects of ICH on dopaminergic neurons.;This dissertation provides some of the first published evidence that a form of preconditioning is protective in an animal model of PD and that low doses of thrombin at or after lesioning affect behavioral outcome. Future studies determining the mechanisms of thrombin action in PD may elucidate new therapeutic pathways. |
