Olfactory Bulb D2/D3 Receptor Availability after Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Abstract

Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB.

Subthalamic nucleus but not entopeduncular nucleus deep brain stimulation enhances neurogenesis in the SVZ-olfactory bulb system of Parkinsonian rats

“…However, such behavioral studies cannot be conducted in a unilateral model of dopaminergic deficiency, as the unaffected hemisphere partly fills in for the unilateral deficit. This has already been shown in behavioral studies on olfaction in 6-OHDA rats, in which no signs of hyposmia could be detected ( Ilkiw et al, 2019 ; Alberts et al, 2022 ). However, other NMSs, such as anhedonia or depression, are present in unilaterally lesioned animals ( Ilkiw et al, 2019 ).…”

Distribution of Cleaved SNAP-25 in the Rat Brain, following Unilateral Injection of Botulinum Neurotoxin-A into the Striatum

“…It cannot be ruled out that an intrastriatal BoNT-A treatment influences the olfactory abilities by BoNT-A-mediated blockade of transmitter release in structures which are important for smelling. Our group demonstrated an improvement in the olfactory abilities of hemi-Parkinsonian rats after unilateral BoNT-A injection into the CPu [ 91 ].…”

“…In the 6-OHDA-induced hemi-Parkinson model of the rat, our research group could not detect any negative effects of intrastriatal application of BoNT-A on olfactory abilities of the animals. On the contrary, these properties were improved [ 91 ].…”

The Effect of Two Different Botulinum Neurotoxin A On The Cortical Neuron Cells In Terms of Apoptosis and MMP 2, MMP 7, and MMP9 Localizations

“…These toxins reduce the release of acetylcholine on the nerve terminals and inhibit neuromuscular connection. Seven similar subtypes (A, B, C, D, E, F, G) of BoNTs that act with the hyperactivity of cholinergic nerve terminals for a long time are described [1,2]. It has been shown that botulinum neurotoxin A (BoNTA) is widely preferred in clinical application.…”

“…It has been shown that botulinum neurotoxin A (BoNTA) is widely preferred in clinical application. BoNTs have been used effectively in the treatment of many diseases [2]. However, some undesirable side effects might be seen, in addition to its therapeutic effects.…”