Beyond neuromuscular activity: botulinum toxin type A exerts direct central action on spinal control of movement

Šoštarić, Petra; Matić, Magdalena; Nemanić, Dalia; Lučev Vasić, Željka; Cifrek, Mario; Pirazzini, Marco; Matak, Ivica

doi:10.1016/j.ejphar.2023.176242

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…Regarding neuromuscular diseases, the biological significance of SNAP25 cleavage in the spinal cord ventral horn after muscular administration is uncertain. This central action might participate in the mode of action [47][48][49], but nevertheless the present study clearly suggests that BoNT activity at the spinal cord level is biologically safe, as no histopathological tissular reactions were observed. Some authors hypothesize that the distant spread of BoNT, or at least some serotypes, occurs through neuronal transport to the spinal cord and then to contralateral muscles [27].…”

Section: Spread and Neuronal Transportmentioning

confidence: 46%

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat

Martin,

Carre,

Bilbault

et al. 2024

Toxins

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Botulinum neurotoxins E (BoNT/E) and A (BoNT/A) act by cleaving Synaptosome-Associated Protein 25 (SNAP25) at two different C-terminal sites, but they display very distinct durations of action, BoNT/E being short acting and BoNT/A long acting. We investigated the duration of action, spread and neuronal transport of BoNT/E (6.5 ng/kg) and BoNT/A (125 pg/kg) after single intramuscular administrations of high equivalent efficacious doses, in rats, over a 30- or 75-day periods, respectively. To achieve this, we used (i) digit abduction score assay, (ii) immunohistochemistry for SNAP25 (N-ter part; SNAP25N-ter and C-ter part; SNAP25C-ter) and its cleavage sites (cleaved SNAP25; c-SNAP25E and c-SNAP25A) and (iii) muscular changes in histopathology evaluation. Combined in vivo observation and immunohistochemistry analysis revealed that, compared to BoNT/A, BoNT/E induces minimal muscular changes, possesses a lower duration of action, a reduced ability to spread and a decreased capacity to be transported to the lumbar spinal cord. Interestingly, SNAP25C-ter completely disappeared for both toxins during the peak of efficacy, suggesting that the persistence of toxin effects is driven by the persistence of proteases in tissues. These data unveil some new molecular mechanisms of action of the short-acting BoNT/E and long-acting BoNT/A, and reinforce their overall safety profiles.

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Section: Spread and Neuronal Transportmentioning

confidence: 46%

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat

Martin,

Carre,

Bilbault

et al. 2024

Toxins

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Tirbanibulin (KX2‐391) analog KX2‐361 inhibits botulinum neurotoxin serotype A mediated SNAP‐25 cleavage in pre‐ and post‐intoxication models in cells

Koc,

Ibis,

Besarat

et al. 2024

Drug Development Research

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Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA‐approved, orally bioavailable compound, KX2‐391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2‐391, KX2‐361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2‐361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)‐derived motor neurons, with imaging‐based assays. Following, we tested KX2‐361 in mESC‐derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre‐ and post‐intoxication conditions. Excitingly, KX2‐361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2‐361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2‐361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication.

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Experimental parkinsonism induced by tetanus toxin injected into basal ganglia

Meglić,

Šoštarić,

Habek

et al. 2024

Preprint

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Background and Objectives: Local inhibitory circuits and long-range inhibitory projections within the interconnected basal ganglia nuclei are critical for control of voluntary movement and pathophysiology of different extrapyramidal movement disorders. Herein, we examined the major motor effects of tetanus neurotoxin (TeNT), a presynaptic neurotoxin that selectively targets the GABA-ergic synaptic transmission, when injected into individual basal ganglia nuclei. Methods: The rats were injected with low-dose TeNT (0.4-0.8 ng) unilaterally into globus pallidus internus (GPi), substantia nigra (SN), or caudate putamen (CPu). The effects of TeNT-induced disinhibition were characterized by repeated assessments of motor coordination, gait, and rotational behavior, followed by measurement of regional protein content of major neuronal monoaminergic, GABA-ergic and glutamatergic population markers. Results: In the beamwalk test, the CPu injection of TeNT induced contralateral plantar misplacement. TeNT injections into GPi and CPu were associated with decreased stride length and increased duration of step cycle and induced a slight ipsiversive circling during open field observation, and more intensive rotational behavior during swimming, differentially affected by D-amphetamine. Unlike rotational behavior, the gait and motor control deficits during beamwalk recovered promptly by day 14 post TeNT, which, along with the lack of reduced neuronal marker protein contents, suggested the reversibility and lack of neuronal degeneration. Conclusion and Implications: Tetanus toxin injected into basal ganglia evokes transient hypokinetic motor dysfunctions consistent with experimental parkinsonism, with differential occurrence of individual motor symptoms depending on the region targeted. These results suggest that TeNT might be a useful non-neurodegenerative pharmacological agent for investigating the motor control abnormalities involving GABA-ergic basal ganglia circuits.

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Beyond neuromuscular activity: botulinum toxin type A exerts direct central action on spinal control of movement

Cited by 3 publications

References 60 publications

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat

Intramuscular Botulinum Neurotoxin Serotypes E and A Elicit Distinct Effects on SNAP25 Protein Fragments, Muscular Histology, Spread and Neuronal Transport: An Integrated Histology-Based Study in the Rat

Tirbanibulin (KX2‐391) analog KX2‐361 inhibits botulinum neurotoxin serotype A mediated SNAP‐25 cleavage in pre‐ and post‐intoxication models in cells

Experimental parkinsonism induced by tetanus toxin injected into basal ganglia

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