Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson's disease

Wree, Andreas; Mix, Eilhard; Hawlitschka, Alexander; Antipova, Veronica; Witt, Martin; Schmitt, Oliver

doi:10.1016/j.nbd.2010.09.017

Cited by 36 publications

(119 citation statements)

References 31 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…In hemi-PD rats established by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB; Ungerstedt, 1968; Ungerstedt and Arbuthnott, 1970; Meredith et al, 2008), intraperitoneally applied atropine antagonized profound PD-typical akinesia (Schallert et al, 1978) and in combination with L-DOPA suppressed pathological circling of hemi-PD rats (Schallert et al, 1979). In our previous studies (Wree et al, 2011) application of BoNT-A into the CPu ipsilateral to the dopaminergic depletion caused a long-term abolition of the pathological apomorphine-induced rotations. We hypothesized that due to the BoNT-A-application into the hypo-dopaminergic and hyper-cholinergic striatum of hemi-PD rats the cholinergic transmission is blocked thus leading to reduced pathological compensatory effects in this model.…”

Section: Introductionmentioning

confidence: 78%

“…All animals displayed more than four contralateral rotations/min, indicating a unilateral death of about 97% of the nigrostriatal DAergic neurons (Ungerstedt and Arbuthnott, 1970) and, therefore, were tested further. As reported previously (Wree et al, 2011; Hawlitschka et al, 2013), 6 weeks after 6-OHDA-lesioning animals received injections of 2 × 1 μl BoNT-A solution (lot No. 13028A1A; List, Campbell, CA; purchased via Quadratech, Surrey, UK) containing a total of 1 ng BoNT-A dissolved in phosphate-buffered saline with 0.1% bovine serum albumin (PSA-BSA 0.1%) added into the right (ipsilateral) or left (contralateral) CPu.…”

Section: Methodsmentioning

confidence: 90%

“…In order to test our hypothesis that intrastriatal BoNT-A-application interferes with the 6-OHDA-induced hypercholinism (DeBoer et al, 1993) and/or the D 2 -receptor upregulation (Creese et al, 1977) in the CPu, we injected in the present study the “effective” dose of BoNT-A (Wree et al, 2011) either into the CPu ipsilateral or contralateral to the dopaminergic deprivation. Here we show that at least some of the behavioral effects seen after ipsilateral BoNT-A-applications in hemi-PD rats should be reversed or even changed to the opposite by contralateral BoNT-A-injection in hemi-PD rats.…”

Section: Introductionmentioning

confidence: 99%

“…However, 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. In hemi-PD rats established by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB; Ungerstedt, 1968; Ungerstedt and Arbuthnott, 1970; Meredith et al, 2008), intraperitoneally applied atropine antagonized profound PD-typical akinesia (Schallert et al, 1978) and in combination with L-DOPA suppressed pathological circling of hemi-PD rats (Schallert et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Antipova

Holzmann

Schmitt

et al. 2017

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Antipova

Holzmann

Schmitt

et al. 2017

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The disturbance of these neuronal circuits elicits parkinsonian motor symptoms, such as resting tremor, rigidity and akinesia [13, 16]. Several studies demonstrated that the intrastriatal injection of BoNT/A reduces pathologic behavior in the rat 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease model (rat 6-OHDA PD model) [1, 14, 24]. In addition, our recent report indicated that intrastriatal injection of BoNT/A2 reduces pathologic behavior, i.e.…”

mentioning

confidence: 99%

Botulinum Neurotoxin Type A Subtype 2 Confers Greater Safety than Subtype 1 in a Rat Parkinson’s Disease Model

Itakura

Kohda

Kubo

et al. 2014

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

Botulinum neurotoxin type A (BoNT/A) cleaves SNAP-25 and interrupts the release of acetylcholine. We previously reported that BoNT/A subtype 2 (BoNT/A2) ameliorates pathologic behavior more effectively than subtype 1 (BoNT/A1) in a rat Parkinson’s disease model. Here, we further show BoNT/A2 has fewer adverse effects than BoNT/A1. We first confirmed that intrastriatal treatments of both BoNT/As had no-effect on dopaminergic terminals in the striatum. SNAP-25 cleaved by BoNT/A2 was strictly localized to the striatum on the injected side; however, SNAP-25 cleaved by BoNT/A1 diffused contralaterally. Furthermore, treatment with BoNT/A1 caused a significant reduction in body weight, while BoNT/A2 treatment did not. These results suggest that BoNT/A2 is more beneficial for clinical application against Parkinson’s disease than BoNT/A1.

show abstract

Behavioral and structural effects of unilateral intrastriatal injections of botulinum neurotoxin a in the rat model of Parkinson's disease

Antipova

Hawlitschka

Mix

et al. 2013

J of Neuroscience Research

Self Cite

View full text Add to dashboard Cite

Botulinum neurotoxin (BoNT) inhibits the release of acetylcholine from presynaptic vesicles through its proteinase activity cleaving the SNARE complex. Parkinson's disease (PD) is associated with locally increased cholinergic activity in the striatum. Therefore, the present study investigates the effect of unilateral intrastriatal BoNT-A injection in naïve rats on striatal morphology; i.e., the total number of Nissl-stained neurons and the volume of caudate-putamen (CPu) were estimated. Furthermore, stainings for markers of gliosis (glial fibrillary acidic protein) and microglia (Iba1) were performed. In addition, the potential beneficial effects of a unilateral intrastriatal injection of BoNT-A on motor activity in the rat model of hemi-PD were evaluated. Hemi-PD was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle. Six weeks later, rats received an ipsilateral intrastriatal injection of BoNT-A. Behaviorally, motor performance was tested. The total number of CPu neurons and the striatal volume were not significantly different between the BoNT-A-injected right and the intact left hemispheres of naïve rats. In hemi-PD rats, intrastriatal BoNT-A abolished apomorphine-induced rotations, increased amphetamine-induced rotations, and tended to improve left forelimb usage. Forced motor function in the accelerod test was not significantly changed by BoNT-A, and open field activity was also unaltered compared with sham treatment. Thus, intrastriatal BoNT-A affects spontaneous motor activity of hemi-PD rats to a minor degree compared with drug-induced motor function. In the future, tests assessing the cognitive and emotional performance should be performed to ascertain finally the potential therapeutic usefulness of intrastriatal BoNT-A for PD.

show abstract

Intrastriatal botulinum toxin abolishes pathologic rotational behaviour and induces axonal varicosities in the 6-OHDA rat model of Parkinson's disease

Cited by 36 publications

References 31 publications

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

Botulinum Neurotoxin Type A Subtype 2 Confers Greater Safety than Subtype 1 in a Rat Parkinson’s Disease Model

Behavioral and structural effects of unilateral intrastriatal injections of botulinum neurotoxin a in the rat model of Parkinson's disease

Contact Info

Product

Resources

About