Suramin reduces infarct volume in a model of focal brain ischemia in rats.
Extracellular adenosine 5'-triphosphate (ATP) provides excitatory transmission in the central nervous system. Stimulation by ATP of ionotropic ligand-gated ion channel purinoceptors (P(2X)) leads to increased intracellular calcium levels, and activation of P(2X) receptors may be involved in the process of excitotoxic neuronal injury caused by stroke. Suramin, as an agent that is known to block P(2X) receptors at a specific concentration, was assessed for its neuroprotective potential in a model of experimental stroke in the rat. We propose that the effectiveness of suramin is limited to those concentrations where it is an effective P(2X) receptor antagonist. Focal brain ischemia was produced by unilateral occlusion and transection of the middle cerebral artery (MCAT) and bilateral occlusion of the common carotid arteries (CCA). Thirty-four male Sprague-Dawley rats were randomly separated into five groups. Changes in regional cerebral blood flow in the ischemic region were verified by laser Doppler flowmetry. All rats received, over a period of 30 min before MCAT, a dose of suramin at 0 (saline), 25, 50, 100, or 250 mg/kg intravenously in a volume of 1 ml using an infusion pump. Six hours after ischemia onset, evaluation of the neurologic status and cerebral blood flow was followed by morphometric analysis of infarct volume. During the surgical procedure mean arterial pressure, blood gases (PaCO(2), PaO(2)), and pH were monitored. A dose-dependent decrease in infarct volume (slope -0.049, SE 0.009, P<0.001) was observed in groups treated over the dose range of 0 to 100 mg/kg (r(2)=0.55). Suramin at a dose of 100 mg/kg significantly decreased infarct volume (n=9, P<0.001) and edema volume (P=0.003). The neuroprotective effect of suramin at a dose of 100 mg/kg was supported by an improved neurologic score in this group (median 0) compared with a median of 3 in control animals (P=0.02). These findings indicate that suramin at 100 mg/kg is an effective pre-treatment neuroprotective agent. As the estimated brain concentration of 10 microM (from McNally et al., 2000, Life Sci 67:1847-1857) is the IC(50) for suramin-mediated P(2X) antagonism, these results suggest that interference with the ATP excitatory system could provide neuroprotection from brain ischemia.
Kharlamov
Alexander
A
Department of Anesthesiology, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212-4772, USA.
Jones
Stephen C
SC
Kim
D Kyle
DK
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy*; D002339:Carotid Arteries / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema; D007150:Immunohistochemistry; D007238:Infarction; D008297:Male; D020768:Middle Cerebral Artery / Q000293:injuries; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013498:Suramin / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D058919:Purinergic P2 Receptor Antagonists; D058469:Receptors, Purinergic P2X; D013498:Suramin