RESUMEN
Encephalopathy of prematurity (EoP) affects approximately 30% of infants born < 32 weeks gestation and is highly associated with inflammation in the foetus. Here we evaluated the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist widely used to treat asthma in children, to ameliorate peripheral and central inflammation, and subsequent grey matter neuropathology and behaviour deficits in a mouse model of EoP. Male CD-1 mice were treated with intraperitoneal (i.p.) saline or interleukin-1beta (IL-1ß, 40 µg/kg, 5 µL/g body weight) from postnatal day (P)1-5 ± concomitant montelukast (1-30 mg/kg). Saline or montelukast treatment was continued for a further 5 days post-injury. Assessment of systemic and central inflammation and short-term neuropathology was performed from 4 h following treatment through to P10. Behavioural testing, MRI and neuropathological assessments were made on a second cohort of animals from P36 to 54. Montelukast was found to attenuate both peripheral and central inflammation, reducing the expression of pro-inflammatory molecules (IL-1ß, IL-6, TNF) in the brain. Inflammation induced a reduction in parvalbumin-positive interneuron density in the cortex, which was normalised with high-dose montelukast. The lowest effective dose, 3 mg/kg, was able to improve anxiety and spatial learning deficits in this model of inflammatory injury, and alterations in cortical mean diffusivity were not present in animals that received this dose of montelukast. Repurposed montelukast administered early after preterm birth may, therefore, improve grey matter development and outcome in EoP.
Asunto(s)
Encefalopatías , Nacimiento Prematuro , Quinolinas , Recién Nacido , Humanos , Femenino , Masculino , Animales , Ratones , Sustancia Gris , Nacimiento Prematuro/tratamiento farmacológico , Acetatos/uso terapéutico , Acetatos/farmacología , Quinolinas/uso terapéutico , Quinolinas/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológicoRESUMEN
The mechanism underlying depression, anxiety, and stress-related psychiatric disorders is far from understood. The utilization of animal models of anxiety and stress can improve our knowledge of the pathology of these disorders as well as aiding in the identification of pharmacological therapeutic targets. The involvement of inflammation in the pathology of stress-related disorders is widely acknowledged. This study was therefore undertaken to assess depressive and anxiety-like behavior as well as neuroinflammation in acute-isolated rats. The study design comprised two main groups:1) rats in acute isolation (one rat per cage) and 2) standard housing (two rats per cage). Within ten days of acute isolation, we carried behavioral tests including Sucrose Neophobia (SNP), Sucrose Preference Test (SPT), Open field (OPF), and a Forced swim test (FST). In a separate set of experiments, we examined the molecular changes after five days of isolations, we examined the mRNA expression of Toll-like receptors (TLRs) and inflammatory markers in the hippocampal brain region. We found that acute social isolation did not have profound functional effects and the behavioral analysis revealed similarities between the isolated and standard housed rats. However, the molecular studies showed a significant increase in TLRs. An increase in Interleukin 6 (IL-6) and Tumor necrosis factor-alpha (TNF-alpha) was observed in the hippocampus of isolated rats but not the control rats. The results suggest that acute environmental isolation does not significantly affect depressive and anxiety-like behavior but does contribute to upregulations in neuroinflammatory responses. This indicates the initiation of neuronal insults following exposure to short-term isolation.