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Abstract
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. The loss of dopaminergic neurons in the substantia nigra leads to a disinhibition of cholinergic interneurons in the striatum. Pharmacotherapeutical strategies of PD-related hypercholinism have numerous adverse side effects. We previously showed that ipsilateral intrastriatal injections of 1 ng in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats inhibit apomorphine-induced rotation behavior significantly up to 6 months. In this study, we extended the behavioral testing of ipsilateral botulinum neurotoxin A (BoNT-A)-injection and additionally investigated the impact of intrastriatal BoNT-A-injections contralateral to the 6-OHDA-lesioned hemisphere on the basal ganglia circuity and motor functions. We hypothesized that the interhemispheric differences of acetylcholine (ACh) concentration seen in unilateral hemi-PD should be differentially and temporally influenced by the ipsilateral or contralateral injection of BoNT-A. Hemi-PD rats were injected with 1 ng BoNT-A or vehicle substance into either the ipsilateral or contralateral striatum 6 weeks after 6-OHDA-lesion and various behaviors were tested. In hemi-PD rats intrastriatal ipsilateral BoNT-A-injections significantly reduced apomorphine-induced rotations and increased amphetamine-induced rotations, but showed no significant improvement of forelimb usage and akinesia, lateralized sensorimotor integration and also no effect on spontaneous locomotor activity. However, intrastriatal BoNT-A-injections contralateral to the lesion led to a significant increase of the apomorphine-induced turning rate only 2 weeks after the treatment. The apomorphine-induced rotation rate decreases thereafter to a value below the initial rotation rate. Amphetamine-induced rotations were not significantly changed after BoNT-A-application in comparison to sham-treated animals. Forelimb usage was temporally improved by contralateral BoNT-A-injection at 2 weeks after BoNT-A. Akinesia and lateralized sensorimotor integration were also improved, but contralateral BoNT-A-injection had no significant effect on spontaneous locomotor activity. These long-ranging and different effects suggest that intrastriatally applied BoNT-A acts not only as an inhibitor of ACh release but also has long-lasting impact on transmitter expression and thereby on the basal ganglia circuitry. Evaluation of changes of transmitter receptors is subject of ongoing studies of our group.
Highlights
Parkinson’s disease (PD) is one of the most prevalent debilitating chronic progressive neurodegenerative movement disorders and mainly caused by degeneration of dopaminergic neurons especially in the substantia nigra pars compacta (SNC; Hornykiewicz and Kish, 1987; Braak et al, 2004)
Ipsilateral botulinum neurotoxin A (BoNT-A)-Injection Ipsilateral BoNT-A-injection caused a significant decrease in rotational behavior 4 weeks and 3 months after BoNT-A, thereafter rotations of BoNT-A-injected rats equaled those after sham-injection (Figure 3A)
Contralateral BoNT-A-Injection The injection of 1 ng BoNT-A into the left striatum of right sided 6-OHDA-lesioned rats caused a significant increase of the turning rate 2 weeks after surgery
Summary
Parkinson’s disease (PD) is one of the most prevalent debilitating chronic progressive neurodegenerative movement disorders and mainly caused by degeneration of dopaminergic neurons especially in the substantia nigra pars compacta (SNC; Hornykiewicz and Kish, 1987; Braak et al, 2004). Systemic application of anti-cholinergics has some peripheral and central side effects (Clarke, 2002; Fernandez, 2012; Connolly and Lang, 2014). To avoid these undesirable effects connected with systematic administration of anti-cholinergic drugs, we tested a local anti-cholinergic treatment by injecting botulinum neurotoxin A (BoNT-A) directly into the caudate putamen (CPu; Wree et al, 2011; Holzmann et al, 2012; Antipova et al, 2013; Hawlitschka et al, 2013; Mehlan et al, 2016) as a possible therapeutic option in experimental PD-model. We hypothesized that due to the BoNT-Aapplication into the hypo-dopaminergic and hyper-cholinergic striatum of hemi-PD rats the cholinergic transmission is blocked leading to reduced pathological compensatory effects in this model
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