Tissue plasminogen activator (tPA) is used in fewer than 4% of patients after
ischemic stroke because of its narrow therapeutic time window. We tested whether
pyrrolidine dithiocarbamate (
PDTC), a drug with multiple mechanisms to provide neuroprotection, can be used to extend the therapeutic time window of tPA. Three-month-old male Sprague-Dawley rats were subjected to
embolic stroke in the area supplied by the right middle cerebral artery. tPA at 10 mg/kg was given intravenously 4 h after the onset of
stroke.
PDTC at 50 mg/kg was given via gastric gavage at 30 min or 4 h after the onset of
stroke. Two days after the
stroke, neurological outcome was evaluated and the right frontal cortex area 1 (Fr1), an ischemic penumbral region, was harvested for analysis.
PDTC given at 30 min after the
stroke reduced
infarct volumes and improved neurological functions no matter whether the rats received tPA.
PDTC also reduced tPA-increased hemorrhagic volumes. Consistent with these results,
PDTC in the presence or absence of tPA treatment attenuated the increase of proinflammatory
cytokines, oxidative stress and matrix
metalloprotease 2 activity in the right Fr1. However,
PDTC given at 4 h after the onset of
stroke did not improve the neurological outcome of rats treated with or without tPA. Our results suggest that
PDTC given at an early time point but not in a delayed phase provides neuroprotection against
embolic stroke and may be used to extend the therapeutic time window of tPA.