L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome.
Administration, Oral
Adolescent
Arginine
/ blood
Brain
/ blood supply
Brain Mapping
Carbon Dioxide
/ blood
Cerebrovascular Circulation
/ drug effects
Female
Humans
MELAS Syndrome
/ drug therapy
Magnetic Resonance Imaging
Male
Neurovascular Coupling
/ drug effects
Ornithine
/ blood
Oxygen
/ blood
Pilot Projects
Prospective Studies
Treatment Outcome
Visual Cortex
/ drug effects
Young Adult
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
26
07
2019
accepted:
11
08
2020
entrez:
4
9
2020
pubmed:
4
9
2020
medline:
23
10
2020
Statut:
epublish
Résumé
We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p≤ 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling. Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls. Following L-Arg, there was restoration of serum Arg (76-230 μM) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg. Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state. This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus. NCT01603446.
Identifiants
pubmed: 32881886
doi: 10.1371/journal.pone.0238224
pii: PONE-D-19-17710
pmc: PMC7470264
doi:
Substances chimiques
Carbon Dioxide
142M471B3J
Arginine
94ZLA3W45F
Ornithine
E524N2IXA3
Oxygen
S88TT14065
Banques de données
ClinicalTrials.gov
['NCT01603446']
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0238224Déclaration de conflit d'intérêts
Joseph A. Fisher MD reports personal fees from Thornhill Medical Inc. (TMI) during the conduct of the study. TMI is a spin off from the University Health Network and has designed and constructed the RespirACT used for this study. In addition, Dr. Fisher has a patent (issued) for the underlying principles of the RespirACTTM used in this work. All patents are owned by the University Health Network and licensed to TMI. Dr. Fisher is one of the inventors of the device. TMI has not otherwise commissioned or supported this study. Olivia Sobczyk PhD reports personal fees from Thornhill Medical Inc., outside the submitted work. She is a consultant of TMI whose parent company own IP on the RespirACT device used in the study. David Mikulis MD has a patent (issued) for the underlying principles of the RespirACTTM application used in this work and reports minor equity ownership in TMI. Dr. Tein reports an operating grant from the United Mitochondrial Disease Foundation supporting in part this study. No personal fees were obtained. The UMDF had no role in the study design, analysis of data or writing of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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