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Altered hippocampal kynurenine pathway metabolism contribute to hyperexcitability in mesial temporal lobe epilepsy-hippocampal sclerosis
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  • Soumil Dey,
  • Aparna Banerjee Dixit,
  • Manjari Tripathi,
  • Ramesh Doddamani,
  • Meher Sharma,
  • Sanjeev Lalwani,
  • Sarat Chandra,
  • Jyotirmoy Banerjee
Soumil Dey
All India Institute of Medical Sciences
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Aparna Banerjee Dixit
University of Delhi
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Manjari Tripathi
All India Institute of Medical Sciences
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Ramesh Doddamani
All India Institute of Medical Sciences
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Meher Sharma
All India Institute of Medical Sciences
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Sanjeev Lalwani
All India Institute of Medical Sciences
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Sarat Chandra
All India Institute of Medical Sciences
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Jyotirmoy Banerjee
All India Institute of Medical Sciences
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Abstract

Background and Purpose Glutamate receptor mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid (KYNA) and quinolinic acid (QUIN) are two important tryptophan-kynurenine pathway (KP) metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of KP metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission. Experimental Approach TKP metabolites level were determined using HPLC and LC-MS/MS in the hippocampal samples of patients with MTLE-HS compared to autopsy and non-seizure control samples. mRNA and protein expression of TKP enzymes were determined by qPCR and western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in presence of kynurenine (KYN) and KYNA using whole cell patch clamp. Key Results We observed significantly reduced KYNA and elevated QUIN levels in the hippocampal samples, while KYN level remains unaltered. Spontaneous glutamatergic activity in the hippocampal samples was higher compared to that in non-seizure controls. Treatment with kynurenine inhibited the glutamatergic activity in non-seizure control samples but not in case of the hippocampal samples. However, exogenously applied KYNA inhibited glutamatergic activity in both non-seizure control and hippocampal samples. We also observed reduced levels of enzyme kynurenine aminotransferase II and its co-factor pyridoxal phosphate in the hippocampal samples. Conclusion Our findings indicate that altered metabolism of TKP metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS.

Peer review status:ACCEPTED

24 Sep 2020Submitted to British Journal of Pharmacology
25 Sep 2020Submission Checks Completed
25 Sep 2020Assigned to Editor
12 Oct 2020Reviewer(s) Assigned
16 Nov 2020Review(s) Completed, Editorial Evaluation Pending
24 Nov 2020Editorial Decision: Revise Minor
22 Jan 20211st Revision Received
22 Jan 2021Submission Checks Completed
22 Jan 2021Assigned to Editor
25 Jan 2021Reviewer(s) Assigned
19 Apr 2021Review(s) Completed, Editorial Evaluation Pending
20 Apr 2021Editorial Decision: Revise Minor
29 Apr 20212nd Revision Received
30 Apr 2021Submission Checks Completed
30 Apr 2021Assigned to Editor
03 May 2021Editorial Decision: Accept