LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia

Abstract

Middle cerebral artery occlusion Behavioral Histopathology Local cerebral blood flow Platelet-activating factor (PAF) is a bioactive phospholipid that accumulates during ischemia-reperfusion and is involved in the activation of platelets, neutrophils, and pro-inflammatory signaling. PAF has been suggested to enhance brain ischemia-reperfusion damage. LAU-0901, a novel PAF receptor antagonist, was examined in models of focal cerebral ischemia in rats and mice. Sprague-Dawley rats were anesthetized and received 2-hour middle cerebral artery occlusion (MCAo) by intraluminal suture. LAU-0901 (30, 60, 90 mg/kg; n = 9-11) or vehicle (n = 11) was administered i.p. at 2 h after onset of MCAo. The neurological status was evaluated at 60 min, and on days 1, 2, 3 and 7 after MCAo. In the dose-response study in mice, C57BL/6 mice were anesthetized and received 1 h MCAo by intraluminal suture. LAU-0901 (15, 30, 60 mg/kg; n = 7-9) or vehicle (n = 8) was given i.p. at 1 h after onset of MCAo. Local cerebral blood flow (LCBF) was measured at 1, 2, 4, and 6 h after MCAo in mice. LAU-0901 treated rats showed improved neurological score throughout the 7-day survival period. LAU-0901 treatment (30, 60 and 90 mg/kg) reduced total corrected infarct volume compared to vehicle rats by 76, 88 and 90%, respectively. Mice treated with LAU-0901 (30 and 60 mg/kg) reduced total infarction by 29% and 66%, respectively. LCBF was improved by treatment with LAU-0901 (30 mg/kg) by 77% of baseline at 6 h. In conclusion, we demonstrate for the first time that LAU-0901 improves behavioral scores, LCBF and reduces infarct volume after focal cerebral ischemia in rats and mice. Thus, this PAF receptor antagonist exhibits potent and sustained neuroprotection that may be of value for the design of stroke therapies.

LAU-0901, a novel platelet-activating factor receptor antagonist, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat

“…LAU-0901 was also evaluated in animal models of focal cerebral ischemia in rats and mice and showed marked infarct volume reduction and neurobehavioral improvement at seven days of survival (Belayev et al 2008). LAU-0901 treatment (30, 60 and 90 mg/kg) significantly reduced total corrected infarct volume compared to vehicle rats by 76, 88 and 90%, respectively.…”

“…Recently, we have shown that LAU-0901 improved behavior and reduced brain infarction in focal cerebral ischemia in rats and mice (Belayev et al 2008). The dose-response studies in rat and mouse models of transient middle cerebral artery occlusion (MCAo) showed that 60 mg/kg dosage was highly neuroprotective; thus, this dose was applied in this study (Belayev et al 2008). The objective of the present study was to test the hypothesis that acute LAU-0901-induced neuroprotection endures in animals allowed to survive for several weeks after focal ischemic insult.…”

Pharmacokinetic studies of ginkgolide K in rat plasma and tissues after intravenous administration using ultra-high performance liquid chromatography-tandem mass spectrometry

“…At present time instinctively occurring PAF antagonist exists as a specific grade of therapeutic agents against different diseases either of immunological or non-immunological types [6]. Most important, activation of PAF could further aggravate cerebral neuronal damage induced by ischemic reperfusion [7]. Hence, PAF antagonist is frequently used to lessen cerebral neuron injury [8].…”

Loss of PAFR prevents neuroinflammation and brain dysfunction after traumatic brain injury

“…Furthermore, PAF has been reported to play an important role in many pathophysiological processes including cerebral edema and cerebral ischemia-reperfusion injury through interactions with PAFR1718. PAFR, which belongs to G protein coupled receptors superfamily, is a seven transmembrane proteins that expressed extensively throughout the brain including microglia and neurons and has been reported to be activated by interating with PAF1920.…”