N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus

PLoS One. 2015 Mar 24;10(3):e0120891. doi: 10.1371/journal.pone.0120891. eCollection 2015.

Abstract

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-μPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-μPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / drug effects*
  • Leucine / analogs & derivatives*
  • Leucine / therapeutic use
  • Male
  • Nystagmus, Pathologic / complications
  • Postural Balance / drug effects*
  • Rats, Sprague-Dawley
  • Sensation Disorders / complications
  • Sensation Disorders / drug therapy*
  • Sensation Disorders / etiology
  • Thalamus / drug effects*
  • Vestibule, Labyrinth / injuries*

Substances

  • Leucine
  • acetylleucine

Grant support

This project was supported by the German Federal Ministry of Education and Research (grant number 01 EO 0901; funding volume: 730.000 €; funding initiative Integrated Center for Research and Treatment of Vertigo, Balance and Ocular Motor Disorders, University of Munich) and Pierre Fabre Laboratories (consumables, pharmaceuticals, chemicals, animal costs; funding volume 40.000 €). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.