L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome

PLoS One. 2020 Sep 3;15(9):e0238224. doi: 10.1371/journal.pone.0238224. eCollection 2020.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Classification of evidence: 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.

Clinical trials.gov (nih): NCT01603446.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Arginine / blood
  • Arginine / pharmacology
  • Arginine / therapeutic use*
  • Brain / blood supply
  • Brain / diagnostic imaging
  • Brain Mapping
  • Carbon Dioxide / blood
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology*
  • Female
  • Humans
  • MELAS Syndrome / drug therapy*
  • Magnetic Resonance Imaging
  • Male
  • Neurovascular Coupling / drug effects
  • Neurovascular Coupling / physiology*
  • Ornithine / blood
  • Oxygen / blood
  • Pilot Projects
  • Prospective Studies
  • Treatment Outcome
  • Visual Cortex / drug effects
  • Young Adult

Substances

  • Carbon Dioxide
  • Arginine
  • Ornithine
  • Oxygen

Associated data

  • ClinicalTrials.gov/NCT01603446

Grants and funding

This work was supported in part by an operating grant from the United Mitochondrial Disease Foundation (IT). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. There was no additional external funding for this study.