Experimental Intrastriatal Applications of Botulinum Neurotoxin-A: A Review

Abstract

Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders. Its main pathophysiological characteristic is the loss of dopaminergic neurons in the substantia nigra pars compacta followed by a lack of striatal dopaminergic input and a consequent disinhibition of tonically active cholinergic interneurons. The resulting striatal hypercholinism causes major motor symptoms in PD. Anticholinergic pharmacotherapies have antiparkinsonian effects on motor symptoms, but, due to systemic actions, also numerous severe side effects occur on a regular basis. To circumvent these side effects, a local anticholinergic therapy acting exclusively in the striatum would be reasonable. Botulinum neurotoxin-A (BoNT-A) is synthesized by Clostridium botulinum and blocks the release of acetylcholine from the presynaptic bouton. For several decades, BoNT-A has been used successfully for medical and cosmetic purposes to induce controlled paralyses of single muscles. Our group and others investigated the experimental treatment of striatal hypercholinism by the direct injection of BoNT-A into the striatum of rats and mice as well as of hemiparkinsonian animal models. This review gives an overview of the most important results of the experimental intrastriatal BoNT-A application, with a focus on hemiparkinsonian rats.

Botulinum Neurotoxin-A Injected Intrastriatally into Hemiparkinsonian Rats Improves the Initiation Time for Left and Right Forelimbs in Both Forehand and Backhand Directions

“…Three months after a second intrastriatal BoNT-A injection, IT decreased again, followed by a recurrent impairment that lasted up to a further 12 months ( Figure 2 A,B). Concerning the time-dependent outcome of BoNT-A application, these findings correspond to our prior results in an apomorphine-induced rotation test: injection of BoNT-A into the CPu of hemi-PD rats reduced apomorphine-induced rotation behavior significantly for at least 3 months [ 38 , 39 , 40 , 42 , 43 , 44 , 87 ]. In addition, compared with sham injections, a second BoNT-A again significantly decreased apomorphine-induced rotations, whereas the beneficial effect faded with longer post-injection survival times [ 58 ].…”

“…We applied our new approach for the determination of the IT in the model of hemi-PD rats which were intrastriatally treated with botulinum neurotoxin-A (BoNT-A) [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. The hypothesis tested is whether intrastriatal BoNT-A could improve the initiation time of stepping in hemi-PD rats.…”

“…In PD, DA depletion leads to hyperactivity of cholinergic interneurons in the CPu [ 46 , 47 , 48 , 49 ] which likely contributes to major motor symptoms [ 50 , 51 ]. BoNT-A is thought to act as a local anticholinergic drug [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. As shown, unilateral injection of 1 ng BoNT-A into the CPu of hemi-PD rats temporarily reduced apomorphine-induced rotation behavior significantly for at least 3 months [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

“…BoNT-A is thought to act as a local anticholinergic drug [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. As shown, unilateral injection of 1 ng BoNT-A into the CPu of hemi-PD rats temporarily reduced apomorphine-induced rotation behavior significantly for at least 3 months [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. As shown in various studies, 1 ng BoNT-A intrastriatally injected into hemi-PD rats is a well-tolerated and a therapeutically adequate dose (reviewed in [ 43 ]).…”

Antidepressant-Like Properties of Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson’s Disease

“…Botulinum neurotoxin-A (BoNT-A) inhibits the release of acetylcholine (ACh) in the peripheral nervous system and is also thought to act as a local anticholinergic drug when injected intrastriatally, i.e., into the CPu in hemiparkinsonian (hemi-) PD rats. In hemi-PD rats, injection of 1 ng BoNT-A into the DA-depleted CPu significantly diminished apomorphine-induced rotational behavior for at least 3 months, the effect fading thereafter [ 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ].…”