Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson's disease.
Central pathophysiological pathways of basal ganglia dysfunction imply a disturbed interaction of dopaminergic and cholinergic circuits. In Parkinson's disease (PD) imbalanced cholinergic hyperactivity prevails in the striatum. Interruption of acetylcholine (ACh) release in the striatum by locally injected botulinum neurotoxin A (BoNT-A) has been studied in the rat 6-hydroxydopamine (6-OHDA) model of PD (hemi-PD). The hemi-PD was induced by injection of 6-OHDA into the right medial forebrain bundle. Motor dysfunction provoked by apomorphine-induced contralateral rotation was completely reversed for more than 3 months by ipsilateral intrastriatal application of 1-2 ng BoNT-A. Interestingly, BoNT-A injected alone into the right striatum of naïve rats caused a slight transient ipsilateral apomorphine-induced rotation, which lasted only for about one month. Immunohistochemically, large axonal swellings appeared within the striatum injected with BoNT-A, which we tentatively named BoNT-A-induced varicosities. They contained either choline acetyltransferase or tyrosine hydroxylase. These findings suggest a selective inhibition of evoked release of ACh by locally applied BoNT-A. Intrastriatal application of BoNT-A may antagonize localized relative functional disinhibited hypercholinergic activity in neurodegenerative diseases such as PD avoiding side effects of systemic anti-cholinergic treatment.
Department of Anatomy, University of Rostock, Gertrudenstr. 9, 18057 Rostock, Germany.
Andreas
A
Wree
Eilhard
E
Mix
Alexander
A
Hawlitschka
Veronica
V
Antipova
Martin
M
Witt
Oliver
O
Schmitt
Reiner
R
Benecke
D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology; D019274:Botulinum Toxins, Type A / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020439:Growth Cones / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012399:Rotation / Q000009:adverse effects*
D009498:Neurotoxins; D016627:Oxidopamine; D019274:Botulinum Toxins, Type A