Early administration of pyrrolidine dithiocarbamate extends the therapeutic time window of tissue plasminogen activator in a male rat model of embolic stroke

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Stroke is a leading cause of mortality and morbidity. A fundamental pathophysiological process of stroke is ischemic brain injury (Lipton, 1999; Martin, Smith, Matthews, & Ventura, 1999). Despite intensive research, clinically effective and safe methods for reducing ischemic brain injury have yet to be established. Reopening the occluded cerebral vessels within a certain time frame represents an effective way to improve neurological outcome after the onset of ischemic stroke (Berkhemer et al., 2015; Goyal, Pradhan, Gupta, & Kapoor, 2015).
Tissue plasminogen activator (tPA) is the only drug therapy approved by the Food and Drug Administration for ischemic stroke. It has a narrow therapeutic time window because its side effects will outweigh its benefits if it is used at a time point that is more than 3 h after the onset of brain ischemia (Adams et al., 2007), although this therapeutic time window may be extended to 4.5 h in selective cases (Del Zoppo, Saver, Jauch, & Adams, 2009). The major side effects of tPA include hemorrhagic transformation (HT), an effect that may be mediated by activation of matrix metalloprotease (MMP; Montaner et al., 2003), and direct neurovascular toxicity (Liu et al., 2004; NINDS, 1997; Wang et al., 2012; Wang et al., 1998). Due to this narrow therapeutic time window, intravenous tPA is currently used only in fewer than 4% of patients with ischemic stroke (Kleindorfer, Lindsell, Brass, Koroshetz, & Broderick, 2008). Methods to extend the therapeutic time window of tPA are highly sought to improve the outcome of patients with ischemic stroke.
Pyrrolidine dithiocarbamate (PDTC) is a small molecule with anti‐oxidant and anti‐inflammatory properties (Liu, Ye, Malik, 1999). PDTC has been shown to activate Akt, a protein that is considered to be pro‐survival. PDTC can reduce focal brain ischemic injury in young adult rats (Nurmi et al., 2004a; Nurmi et al., 2004b). This protective effect occurs even if the application of PDTC is at 6 h after the onset of transient focal brain ischemia in those rats (Nurmi et al., 2004b). Our recent study showed that oral PDTC started at 10 min after brain ischemia improved neurological outcome assessed at 1 or 2 months later in young adult rats (Li, Sheng, Feng, & Zuo, 2012). PDTC also reduced brain injury after ischemia and hypoxia in neonatal rats (Nurmi et al., 2006; Wang, Zhao, Peng, & Zuo, 2013). Thus, we hypothesize that PDTC can be used to extend the therapeutic time window of tPA. To test this hypothesis, rats were subjected to embolic stroke and then treated with tPA in the presence or absence of PDTC. Their neurological outcome was assessed.

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