Intracortical injection of endothelin-1 induces cortical infarcts in mice: effect of neuronal expression of an adenosine transporter

Mice underwent stereotaxic intracortical injection of ET-1 (1 μl; 400 pmol) or saline (1 μl). Some mice received the adenosine receptor antagonist caffeine (25 mg/kg, intraperitoneal) 30 minutes prior to ET-1. Perfusion and T2-weighted magnetic resonance imaging (MRI) were used to measure cerebral blood flow (CBF) and subsequent infarct size, respectively.ET-1 reduced CBF at the injection site to 7.3 ± 1.3% (n = 12) in hENT1 transgenic (Tg) and 12.5 ± 2.0% (n = 13) in wild type (Wt) mice. At 48 hours following ET-1 injection, CBF was partially restored to 35.8 ± 4.5% in Tg and to 45.2 ± 6.3% in Wt mice; infarct sizes were significantly greater in Tg (9 ± 1.1 mm3) than Wt (5.4 ± 0.8 mm3) mice. Saline-treated Tg and Wt mice had modest decreases in CBF and infarcts were less than 1 mm3. For mice treated with caffeine, CBF values and infarct sizes were not significantly different between Tg and Wt mice.ET-1 produced greater ischemic injury in hENT1 Tg than in Wt mice. This genotype difference was not observed in mice that had received caffeine. These data indicate that hENT1 Tg mice have reduced ischemia-evoked increases in adenosine receptor activity compared to Wt mice.Stroke is a leading cause of death and disabilities in developed countries. During stroke, a rapid depletion of ATP, dysregulation of ion channels and pumps, collapse of ion homeostasis, release of excitotoxic neurotransmitters, and intracellular calcium overload triggers a series of enzymatic cascades that result in neuronal death [1,2]. Unfortunately, with the exception of tissue plasminogen activator, there are as yet no clear evidence-based strategies for treatment [2].Adenosine is a neuromodulator that acts through a family of metabotropic receptors. Activation of adenosine A1 receptors, which are widely distributed in brain, has neuroprotective effects. In contrast, activation of A2A receptors, which are most abundant in basal ganglia, can promote cell injury [3]. Adenosine can be formed extracell