TY - JOUR
T1 - Montelukast reduces grey matter abnormalities and functional deficits in a mouse model of inflammation-induced encephalopathy of prematurity
AU - Yates, Abi G
AU - Kislitsyna, Elena
AU - Alfonso Martin, Carla
AU - Zhang, Jiaying
AU - Sewell, Amy L
AU - Goikolea-Vives, Ane
AU - Cai, Valerie
AU - Alkhader, Lama F
AU - Skaland, Aleksander
AU - Hammond, Basil
AU - Dimitrova, Ralica
AU - Batalle, Dafnis
AU - Fernandes, Cathy
AU - Edwards, A David
AU - Gressens, Pierre
AU - Thornton, Claire
AU - Stolp, Helen B
N1 - Funding Information:
We would like to acknowledge staff at the Centre for the Developing Brain for their advice on ex vivo MRI acquisition and processing. Tom Eykyn from BMEIS for 9.4T technical support. Rianne Wester from the BRC Flow Core for support with use of the FlexMap 3D. Steve Levison, Gareth Ball, Henrik Hagberg for their early involvement in discussion of the concepts and potential experimental approaches. Kate Dziegielewska, Norman Saunders and Laura Jacobson (University of Melbourne) for early discussions regarding potential therapeutic agents for early inflammatory-induced brain injury. The MRC Centre for Neurodevelopmental Disorders, Wellcome EPSRC Medical Engineering Centre. GSTT NIHR Biomedical Research Centre.
Funding Information:
This research was supported by Sparks Children’s Medical Research (15KCL05), King’s Health Partners (R170506), Rosetrees Trust (CM833) and the Medical Research Council (MR/K006355/1). The authors acknowledge infrastructure support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre (BRC) at South London, Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King's College London and the NIHR-BRC at Guys and St Thomas’ Hospitals NHS Foundation Trust (GSTFT). The authors also acknowledge support in part from the Wellcome Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering at Kings College London [WT 203148/Z/16/Z], and the Department of Health through an NIHR Comprehensive Biomedical Research Centre Award (to Guy’s and St. Thomas’ National Health Service (NHS) Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10/29
Y1 - 2022/10/29
N2 - 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-1β, 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-1β, 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.
AB - 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-1β, 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-1β, 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.
UR - http://www.scopus.com/inward/record.url?scp=85140929032&partnerID=8YFLogxK
U2 - 10.1186/s12974-022-02625-5
DO - 10.1186/s12974-022-02625-5
M3 - Article
C2 - 36309753
SN - 1742-2094
VL - 19
SP - 265
JO - Journal of neuroinflammation
JF - Journal of neuroinflammation
IS - 1
M1 - 265
ER -