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Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior

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Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior toxins Article Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior Alexander Hawlitschka 1, Carsten Holzmann 2 , Andreas Wree 1,* and Veronica Antipova 1,3 1 Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany; [email protected] (A.H.); [email protected] (V.A.) 2 Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany; [email protected] 3 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Macroscopic and Clinical Anatomy, Medical University of Graz, A-8010 Graz, Austria * Correspondence: [email protected]; Tel.: +49-3814948400 Received: 22 August 2018; Accepted: 8 September 2018; Published: 11 September 2018 Abstract: Injection of botulinum neurotoxin-A (BoNT-A) into the striatum of hemiparkinsonian (hemi-PD) rats reduced apomorphine-induced rotation behavior significantly, for at least 3 months. Thereafter, rotation behavior increased again. We injected hemi-PD rats with 1 ng BoNT-A twice, the second injection following 6 months after the first one and tested the rats for apomorphine-induced rotations and spontaneous motor behaviors, i.e., corridor task and stepping test. To test the hypothesis that BoNT-A reduced striatal hypercholinism in hemi-PD rats, the acetylcholinesterase inhibitor donepezil was injected prior to separate apomorphine-induced rotation tests. In hemi-PD rats, the first BoNT-A injection led to a clear reduction of the apomorphine-induced rotations, and the second BoNT-A injection to a more massive and prolonged reaction. In hemi-PD rats whose apomorphine-induced rotation behavior was strongly reduced by an intrastriatal BoNT-A, subsequent donepezil injections led to significant increases of the rotation rate. Concerning corridor task and stepping test, neither first nor second BoNT-A injections changed hemi-PD rats’ behavior significantly. The data give evidence for the possibility of repeated intrastriatal administrations of BoNT-A, for treatment of motor symptoms in experimental hemi-PD over a longer time. Keywords: botulinum neurotoxin-A; striatum; basal ganglia; donepezil; acetylcholine; 6-OHDA Key Contribution: In hemiparkinsonian rats the temporal positive effect of repeated intrastriatal BoNT-A application on apomorphine-induced rotations and spontaneous motor behaviors was studied for the first time. 1. Introduction Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder, which mainly affects movement ability. PD is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a lack of dopaminergic inhibition of tonically active cholinergic interneurons in the striatum (CPu) (Figure1A,B). This causes a hypercholinism in the CPu, which is thought to contribute to the majority of motor symptoms in PD [1–5] (Figure1B). Classic anticholinergic treatments ameliorate motor symptoms of PD, but acting systemically they also entail numerous unwanted side effects [6–9]. Botulinum neurotoxin-A (BoNT-A) cleaves synaptosomal-associated protein-25 (SNAP-25), a component of the vesicle fusion apparatus of the cholinergic presynaptic membrane. Therefore, Toxins 2018, 10, 368; doi:10.3390/toxins10090368 www.mdpi.com/journal/toxins Toxins Toxins2018, 102018, 368, 10, x FOR PEER REVIEW 2 of 232 of 22 Botulinum neurotoxin-A (BoNT-A) cleaves synaptosomal-associated protein-25 (SNAP-25), a it inhibitscomponent the release of the vesicle of acetylcholine fusion apparatus (ACh) of in the the cholinergic peripheral presynaptic nervous membrane. system [10 There,11],fore, and it as we hypothesizedinhibits the in release the central of acetylcholine nervous system (ACh) asin the well peripheral [12] (Figure nervous1C). Intrastriatalsystem [10,11] injection, and as ofwe 1 ng BoNT-Ahypothesized in hemiparkinsonian in the central nervous (hemi-PD) system rats as reverses well [12] apomorphine-induced (Figure 1C). Intrastriatal rotationsinjection of for 1 ng at least 3 monthsBoNT [-12A –in17 hemiparkinsonian]. During a time (hemi frame-PD) of 12 rats months reverses after apomorphine BoNT-A treatment,-induced rotations hemi-PD for rats at least showed 3 a months [12–17]. During a time frame of 12 months after BoNT-A treatment, hemi-PD rats showed a gradual recurrence of the apomorphine-induced rotation rate [12–14]. gradual recurrence of the apomorphine-induced rotation rate [12–14]. Figure 1. Theoretical concept of the ACh-dependency of the reduction of the apomorphine-induced Figure 1. Theoretical concept of the ACh-dependency of the reduction of the apomorphine-induced rotation rate after unilateral BoNT-A treatment of hemiparkinsonian (hemi-PD) rats. (A–D) Scheme rotation rate after unilateral BoNT-A treatment of hemiparkinsonian (hemi-PD) rats. (A–D) Scheme of of the indirect pathway of the basal ganglia circuitry. Neurons, efferences and afferences of the the indirect pathway of the basal ganglia circuitry. Neurons, efferences and afferences of the striatum striatum (green oval area) relevant for our experiments are shown. A large cholinergic interneuron is (greendepicted oval area) with relevant a stylized for presynapse our experiments (red), the are red shown. circles representing A large cholinergic ACh. The interneuron rectangles with is depicted an witharrow a stylized (SNARE) presynapse symbolize (red), the entirety the red of the circles N-ethylmaleimide representing-sensitive ACh. The-factor rectangles attachment with receptor an arrow (SNARE)complex symbolize, which theconveys entirety the offusion the N of-ethylmaleimide-sensitive-factor transmitter vesicles with the presynaptic attachment membrane. receptor complex,The whichscissors conveys named the fusionwith “AChE” of transmitter representvesicles acetylcholinesterase with the presynaptic which cleaves membrane. ACh, and Thethe blue scissors neuron named witha “AChE” medium representsized spinyacetylcholinesterase projection neuron (MSN) which, which cleaves inhibits ACh, the globus and the pallidus blue externus neuron a(EGP) medium sizedneurons spiny projectionby GABA. neuron(A) Under (MSN), normal which conditions inhibits tonically the globus active palliduscholinergic externus interneurons (EGP) excite neurons by GABA.MSNs by (A release) Under of ACh. normal These conditions cholinergic tonically interneurons active are cholinergicexcited by glutamatergic interneurons input excite of motor, MSNs by releasesensory of ACh., and These prefrontal cholinergic cortices and interneurons thalamus. Owing are excited to their by D glutamatergic2 receptors, cholinergic input of interneurons motor, sensory, are inhibited by dopaminergic input from the substantia nigra pars compacta (SNpc). (B) After lesion and prefrontal cortices and thalamus. Owing to their D2 receptors, cholinergic interneurons are of the SNpc with 6-OHDA the dopaminergic input to the striatum, and consequently, the inhibition inhibited by dopaminergic input from the substantia nigra pars compacta (SNpc). (B) After lesion of of cholinergic interneurons is reduced, leading to a striatal extracellular hypercholinism, symbolized the SNpcby a withhigher 6-OHDA number of the red dopaminergic circles. Therefore input, GABA to the-ergic striatum, projection and neurons consequently, to the EGP the inhibitionbecome of cholinergicoveractive. interneurons (C) The injection is reduced, of BoNT leading-A directly to a striatal into th extracellulare striatum cleaves hypercholinism, the SNAP-25, symbolizedan essential by a highercomponent number ofof red the circles. SNARE Therefore, complex GABA-ergicin cholinergic projection presynaptic neurons boutons. to the In EGP consequence, become overactive. the (C) Theextracellular injection ofamount BoNT-A of directlyACh and into the the inhibition striatum cleavesof the theEGP SNAP-25, should annormalize. essential ( componentD) After of the SNAREadministration complex of inthe cholinergic blood-brain presynaptic barrier passing boutons. acethylcholinesterase In consequence, inhibitor the extracellular donepezil amount, the of ACh andBoNT the-A- inhibitioninduced reduction of the EGP of extracellular should normalize. ACh in hemi (D) After-PD rat administration striatum should of be the at blood-brain least partially barrier passingreversed acethylcholinesterase, and the extracellular inhibitor ACh concentration donepezil, the in the BoNT-A-induced striatum increased reduction again. of extracellular ACh in hemi-PD rat striatum should be at least partially reversed, and the extracellular ACh concentration in the striatum increased again. Toxins 2018, 10, 368 3 of 22 Toxins 2018, 10, x FOR PEER REVIEW 3 of 23 In this study, two aspects of hemi-PD and BoNT treatment were evaluated. First, we tested In this study, two aspects of hemi-PD and BoNT treatment were evaluated. First, we tested whether repeated intrastriatal BoNT-A injections were able to improve motor behavior in hemi-PD rats whether repeated intrastriatal BoNT-A injections were able to improve motor behavior in hemi-PD for a longer time period, resembling used clinical practice for BoNT-A treatments [18,19]. Thus, rats for a longer time period, resembling used clinical practice for BoNT-A treatments [18,19]. Thus, hemi-PD rats were intrastriatally injected with 1 ng BoNT-A 1 month and 7 months following hemi-PD rats were intrastriatally injected with 1 ng BoNT-A 1 month and 7 months following 6-hydroxydopamine
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