Protective effect of new nitrosothiols on the early inflammatory response to kidney ischemia/Reperfusion and transplantation in rats

[EN]Renal ischemia/reperfusion (I/R) is characterized by severe inflammatory damage. We assessed the effect of administrating recently developed nitrosothiol compounds acting as nitric oxide (NO) donors on the production of cytokines and other markers of acute inflammatory reaction in an experimental model of warm (I/R), and in a model of cold ischemia and transplant in rats. Warm ischemia was achieved by ligation of left renal pedicle for 60 min, followed by contralateral nephrectomy. NO-donors LA-803, LA-807, LA-810 were administered i.v. (1.8 μmol/kg) during 30 min before reperfusion. Cold ischemia was achieved by preservating the kidney for 24 h in Euro Collins and grafting it in consanguineous Fisher 344/Ico rats. LA-803 was administered in the preservation fluid and in the recipient rat. Reperfusion time was 4 h in warm ischemia and 3 h in cold ischemia + transplantation. Administration of LA-803, LA-807 and, in a lower proportion, LA-810 prevented from the enhanced production of tumor necrosis factor (TNF), interferon-γ (IFN-γ), and interleukin-1β (IL-1β), the decrease in interleukin-6 (IL-6) and interleukin-10 (IL-10), the increase in tissue level of superoxide anion (SOA) and superoxide dismutase (SOD), and the increase in neutrophil infiltration induced by warm I/R. Treatment with LA-803 in animals with renal transplantation after cold ischemia was also associated with reduced plasma levels of TNF, IFN-γ, and IL-1β, increased plasma levels of IL-6 and IL-10, reduced renal levels of SOA and SOD, and reduced neutrophil infiltration. These data demonstrate that systemic administration of new NO-donors with nitrosothiol structure diminished inflammatory responses in a kidney subjected to warm I/R or cold ischemia and transplantation

Modulation of serotonergic function in rat brain by VN2222, a 5-HT reuptake inhibitor with 5-HT1A receptor agonist

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 g/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 g/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.Peer reviewe