LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia.

摘要: Bradykinin promotes neuronal damage and brain edema through the activation of B2 receptor. The neuroprotective effect LF 16-0687 Ms, a receptor antagonist, has been described when given prior to induction transient focal cerebral ischemia in rat, but there are no data regarding consequence treatment after injury. Therefore, murine model middle artery occlusion (MCAO), we evaluated Ms and/or onset on neurological deficit, infarct volume inflammatory responses including edema, blood–brain barrier (BBB) disruption neutrophil accumulation. LF (1, 2 4 mg kg−1) administered 0.5 h before and, 1.25 6 MCAO, decreased by maximum 33% significantly improved recovery. When at 0.25 6.25 (1.5, 3 25% score. Post-treatment with (1.5 (−28%), BBB (−60%) accumulation (−65%) induced ischemia. Physiological parameters were not modified Ms. These emphasize role bradykinin development lesion, deficit resulting from antagonist might represent new therapeutic approach pharmacological stroke. Keywords: ischemia, mice, neuroprotection, inflammation Introduction Bradykinin is generated plasma tissue kininogen action kallikrein (Bhoola et al., 1992). All components kallikrein–kinin system have identified various species human (Kizuki 1994; Walker 1995; Raidoo 1996). actions mediated G-protein coupled (constitutive) B1 (inducible) subtypes; however accounts for majority acute physiological effects (Marceau, Regoli 1998). located endothelial cells (Wahl 1996), neurons (Raidoo & Bhoola, 1997; Chen 2000), astrocytes microglia (Hosli Hosli, 1993). In neuroglial tissues, induces production release proinflammatory mediators such as reactive oxygen (Rosenblum, 1987; Ellis, 1990; Sobey 1997), nitric oxide (Katusic 1993; Gorlach Wahl, prostanoids (Gecse 1989), excitatory amino-acid neurotransmitters (Parpura Jeftinija 1996) cytokines (Cunha triggers reactions arteriolar dilatation, loss cerebrovascular autoregulation, cell lesion increased vascular permeability (Whalley 1983; Unterberg 1984; Wahl These events lead formation, ultimately injury death (Unterberg 1986; Francel, 1992; 1995). considered an important mediator associated Baethmann, An increase levels was observed during global rat (Kamiya 1993) pathway reported patients (Wagner 2002). Although number experimental studies showed that nonpeptide (Pruneau 1999b), reduced function rodent models traumatic closed head trauma 1999a; Verrecchia 2000; Rachinsky 2001; Kaplanski 2002), controlled cortical impact (Stover 2000) cold (Schulz Plesnila 2001), only few investigated contribution Relton al. (1997) demonstrated CP-0597, peptide swelling, size behavioral outcomes body weight Using same model, Zausinger (2002) neuroprotective, further supporting detrimental ischemic damage. However, this study, date, addition, study examining mice brain. Therefore, main purpose present evaluate potential value histological following (MCAO) mice.