Decreased cerebrospinal fluid kynurenic acid in epileptic spasms: A biomarker of response to corticosteroids.

3-Hydroxyanthranilic Acid Adrenal Cortex Hormones Animals Biomarkers Chromatography, Liquid Epilepsy / drug therapy Kynurenic Acid / cerebrospinal fluid Kynurenine / cerebrospinal fluid Male Quinolinic Acid / cerebrospinal fluid Spasm Tandem Mass Spectrometry Tryptophan / metabolism
Cerebrospinal fluid Epileptic spasms Infantile spasms Ketogenic diet Metabolomics Tryptophan-kynurenine pathway

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Oct 2022
Historique:
received: 24 06 2022
revised: 06 09 2022
accepted: 07 09 2022
pubmed: 30 9 2022
medline: 19 10 2022
entrez: 29 9 2022
Statut: ppublish

Résumé

Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs). There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively). This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored. Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

Sections du résumé

BACKGROUND BACKGROUND
Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations.
METHODS METHODS
A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs).
FINDINGS RESULTS
There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively).
INTERPRETATION CONCLUSIONS
This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored.
FUNDING BACKGROUND
Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.

Identifiants

DOI: 10.1016/j.ebiom.2022.104280 PMID: 36174397 PMC: PMC9515432
pubmed: 36174397
pii: S2352-3964(22)00462-5
doi: 10.1016/j.ebiom.2022.104280
pmc: PMC9515432
pii:
doi:

Substances chimiques

Adrenal Cortex Hormones 0
Biomarkers 0
3-Hydroxyanthranilic Acid 1UQB1BT4OT
Kynurenine 343-65-7
Tryptophan 8DUH1N11BX
Quinolinic Acid F6F0HK1URN
Kynurenic Acid H030S2S85J

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104280

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests DG has received honoraria for speaking from UCB, BioMarin and Eisai. The other authors have declared that no conflict of interest exists.

Auteurs

Jingya Yan (J)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Kavitha Kothur (K)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Emily A Innes (EA)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Velda X Han (VX)

Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.

Hannah F Jones (HF)

Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.

Shrujna Patel (S)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Erica Tsang (E)

Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Richard Webster (R)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Sachin Gupta (S)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Christopher Troedson (C)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Manoj P Menezes (MP)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Jayne Antony (J)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Simone Ardern-Holmes (S)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Esther Tantsis (E)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Shekeeb Mohammad (S)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Louise Wienholt (L)

Department of Clinical Immunology and Allergy, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Ananda S Pires (AS)

Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia.

Benjamin Heng (B)

Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia.

Gilles J Guillemin (GJ)

Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia.

Anna Guller (A)

Computational NeuroSurgery Lab, Macquarie University, Sydney, NSW, Australia.

Deepak Gill (D)

TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia.

Sushil Bandodkar (S)

Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Russell C Dale (RC)

Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia. Electronic address: russell.dale@health.nsw.gov.au.

Articles similaires

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Meal Timing and Anthropometric and Metabolic Outcomes: A Systematic Review and Meta-Analysis.

Hiu Yee Liu, Ashley A Eso, Nathan Cook et al.
1.00
Humans Meals Time Factors Female Adult

Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Aminobenzoates › ortho-Aminobenzoates › Acide 3-hydroxy-anthranilique › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Hormones corticosurrénaliennes › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Eucaryotes › Animaux › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Chromatographie › Chromatographie en phase liquide › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Hydroxyquinoléines › Acide kynurénique › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Cynurénine › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Acides quinoliniques › Acide quinolinique › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Manifestations neuromusculaires › Spasme › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Spectrométrie de masse › Spectrométrie de masse en tandem › Decreased cerebrospinal fluid kynurenic acid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés essentiels › Tryptophane › Decreased cerebrospinal fluid kynurenic acid...