Early administration of pyrrolidine dithiocarbamate extends the therapeutic time window of tissue plasminogen activator in a male rat model of embolic stroke. Issue 3 (4th October 2017)

• Record Type: Journal Article
• Authors: Wang, Zhongxing; Shan, Weiran; Cao, Jiangbei; Wintermark, Max; Huang, Wenqi; Zuo, Zhiyi
• Is Part Of: Journal of neuroscience research. Volume 96:Issue 3(2018)
• Page Start: 449
• Page End: 458
• Publication Date: 2017-10-04
• Subjects: embolic stroke -- hemorrhagic transformation -- neuroprotection -- plasminogen activator -- pyrrolidine dithiocarbamate -- tissue; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24186
• Languages: English
• ISSNs: 0360-4012

Abstract

Abstract: 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. Abstract : Rats treated with tPA 4 h after the onset of embolic stroke had increased hemorrhagic volumes compared to rats only with embolic stroke. The increased hemorrhagic volumes were attenuated by PDTC applied 30 min after the onset of embolic stroke but not by PDTC applied 4 h after the stroke.