Thrombin preconditioning provides protection in a 6-hydroxydopamine Parkinson's disease model

Abstract

Low-dose thrombin given several days before lesioning is neuroprotective in ischemic and hemorrhagic models of stroke, an effect termed thrombin preconditioning (TPC). Here, the ability of TPC to provide protection in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD) was evaluated. All animals received 10 μg 6-OHDA into the right medial forebrain bundle. Three days prior to 6-OHDA, the animals received either 1 U rat thrombin ( n = 17) or saline ( n = 14) 1 mm above the site of neurotoxin delivery. The animals were then evaluated for neurobehavioral deficits until 21 days post-injection. TPC animals performed significantly better on both a vibrissae-elicited forelimb placing test and a forelimb-use asymmetry test than the saline controls. The animals were then sacrificed for either catecholamine determination by HPLC with electrochemical detection or for histopathology to determine lateral ventricular volume or striatal tyrosine hydroxylase immunoreactivity. Although TPC did not protect against the dopamine depletion associated with this severe model, it did reduce dopaminergic terminal loss and ventricular enlargement as compared to saline-treated animals. This report presents the new finding that preconditioning (and TPC in particular) provides protection in a 6-OHDA PD model. Understanding the mechanisms involved in TPC-mediated protection may stimulate innovative therapeutic regimens.