Combination treatment with dipyridamole, aspirin, and tPA in an embolic model of stroke in rats Samer Aldandashi, Raza Noor, Chen Xu Wang, Ghias Uddin, Ashfaq Shuaib ⁎ Stroke Research Laboratory, University of Alberta, 533 HMRC, Edmonton, Alberta, Canada T6G 2S2 Received 7 December 2006; revised 5 March 2007; accepted 17 March 2007 Available online 27 March 2007 Abstract Antithrombotic therapy has been shown to be effective in preventing secondary strokes. Inhibition of platelet function may reduce formation of thrombi thereby reducing the incidence of stroke. However, stronger inhibition of platelets is correlated with increased risk of bleeding events. The purpose of this study was to test the protective effects of combination therapy with dipyridamole and acetylsalicylic acid (ASA) in comparison to ASA alone, and whether such combination treatment may produce any added benefits when tissue plasminogen activator (tPA) treatment is also used. The study was divided into three parts. In part A, effect of antiplatelets on infarct volume was assessed. In part B, perfusion deficits were measured. In part C, efficacy of antiplatelet therapy in combination with tPA was assessed. In part A, dipyridamole and aspirin treatment significantly reduced infarct volume (P < 0.05). In part B, treatment with dipyridamole significantly reduced the perfusion deficits as compared to control (P <0.05). In part C, dipyridamole plus tPA or dipyridamole and aspirin plus tPA significantly decreased infarct volume as compared to tPA alone (P < 0.05). The present study suggests that there is significant protection with dipyridamole as both infarct volume and perfusion deficits are significantly reduced. Dipyridamole with tPA also significantly reduced infarct volume as compared to tPA alone. Our data suggests that higher doses of antithrombotic therapy with dipyridamole offer best neuroprotection. © 2007 Elsevier Inc. All rights reserved. Keywords: Antiplatelets; Antithrombotic; Brain injury; Cerebral ischemia Introduction Thrombosis and thromboembolic occlusions of major and minor blood vessels are involved in various illnesses. If such an occlusion happens within the arterial tree of the vasculature, the onset of clinical symptoms in most cases is rapid and with devastating consequences (Eisert, 2001a). The observation by pathologists that the occluding thrombi in the arteries are platelet-rich in content promoted the strategy of preventing the untimely occlusion by inhibiting platelets from forming aggregates. Aspirin is a member of the antiplatelet class of drugs and it inhibits platelet aggregation by irreversibly blocking cyclooxygenase in all cells. Dipyridamole, previously only known for its antithrombotic activity, also inhibits platelet aggregation via a number of mechanisms including inhibition of cellular uptake and metabolism of adenosine leading to increased adenosine concentration at the platelet/vessel wall interface resulting in reduced platelet aggregation and adhesion. Dipyridamole also increases intracellular cGMP through inhibition of cGMP phosphodiesterase leading to potentiation of effects of nitric oxide (NO) on platelets, resulting in inhibition of platelet aggregation and adhesion (Eisert, 2002; Bult et al., 1991a; Sakuma et al., 1991). Many studies have demonstrated that dipyridamole is not purely an antiplatelet agent like acetylsalicylic acid (ASA) (Eisert, 2001b, 2002; Uddin et al., 2003), but it also enhances the antithrombotic mechanisms of the local vasculature by a variety of mechanisms which include, direct stimulation of the vascular endothelium to cause PGI 2 (Eisert, 2001b, 2002; Uddin et al., 2003; Neri Serneri et al., 1981) and tPA (Kim et al., 2005) release. Dipyridamole is a scavenger for oxy as well as peroxy radicals, which is known to inhibit damage to tissue under oxidative and metabolic stress (Chakrabarti et al., 2005). Dipyridamole also inhibits smooth muscle cell proliferation resulting in inhibition of restenosis (Eisert, 2002). Very recent Experimental Neurology 205 (2007) 563 – 568 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Fax: +1 780 492 1617. E-mail address: Ashfaq.shauib@ualberta.ca (A. Shuaib). 0014-4886/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2007.03.018