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.
Highlights
Acute unilateral lesions of a peripheral vestibular organ induce characteristic ocular motor and postural deficits, e.g., spontaneous nystagmus, head roll tilt and falling to the lesion side [1, 2]
To further clarify these mechanisms, a μPET-based whole brain visualization of mechanisms operating during vestibular compensation (VC) was recently established in a rat model of unilateral labyrinthectomy (UL)
There were no differences in extent of nystagmus or head roll tilt between the UL-groups treated with N-acetyl-DL-leucine (DL-group), N-acetylL-leucine (L-group) or N-acetyl-D-leucine (D-group) and the sham-treated group (SH-group) at any time point
Summary
Acute unilateral lesions of a peripheral vestibular organ induce characteristic ocular motor and postural deficits, e.g., spontaneous nystagmus, head roll tilt and falling to the lesion side [1, 2]. Current concepts of VC emphasize the importance of the commissural connections between the vestibular nuclei (VN), the spinal projections to the VN, the vestibulocerebellar pathways, the multisensory thalamo-cortical networks and the stress-axis activation [4, 6,7,8,9,10,11,12]. To further clarify these mechanisms, a μPET-based whole brain visualization of mechanisms operating during VC was recently established in a rat model of unilateral labyrinthectomy (UL). It showed several sequential changes of the regional cerebral glucose metabolism (rCGM) over time during VC including adjustment or rCGM symmetry between the vestibular nuclei, increase of rCGM in the ipsilesional spinal trigeminal nucleus and in the vestibulocerebellum bilaterally [13]
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