Central Action of Botulinum Toxin Type A – is it Possible?
Botulinum toxin (BoTx) is a product of gram-positive anaerobic bacteria of the Clostridium genus. At present, seven serotypes (A to G) of BoTx have been identified. Each of them functions as a zinc-dependent endopeptidase that hydrolyzes peptide bonds within soluble N-ethylmaleimide-sensitive fac...
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Інститут фізіології ім. О.О. Богомольця НАН України
2015
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| Цитувати: | Central Action of Botulinum Toxin Type A – is it Possible? / M. Galazka, D. Soszynski, K. Dmitruk // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 380-390. — Бібліогр.: 90 назв. — англ. |
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irk-123456789-1482132019-02-18T01:23:44Z Central Action of Botulinum Toxin Type A – is it Possible? Galazka, M. Soszynski, D. Dmitruk, K. Обзоры Botulinum toxin (BoTx) is a product of gram-positive anaerobic bacteria of the Clostridium genus. At present, seven serotypes (A to G) of BoTx have been identified. Each of them functions as a zinc-dependent endopeptidase that hydrolyzes peptide bonds within soluble N-ethylmaleimide-sensitive factor attaching protein receptors. BoTx affects proteins required for neurotransmitter release through presynaptic membranes. As a result, muscle weakness develops, or complete paralysis of the muscles occurs. These effects are not only limited to striated muscles but also may have impact on smooth muscles and secretory glands. The observation that BoTx can diffuse from the site of administration may indicate the possibility of direct or indirect influence of the toxin on the CNS. Consequently, the question arises: What is the mechanism of the central action of BoTx? Several mechanisms of such action have been proposed. However, recent findings showed that the most probable mechanism responsible for the central effects of BoTx action is its anterograde transport. In this review, we describe and discuss the most important aspects related to BoTx action on the CNS. Ботуліновий токсин (BoTx) є продуктом життєдіяльності грампозитивних бактерій роду Clostridium. На теперішній час ідентифіковано сім серотипів BoTx (A–G). Всі вони функціонують як цинкзалежні ендопеотидази, що гідролізують пептидні зв’язки з розчинним N-етилмалеімідчутливим фактором, контактуючим з протеїновими рецепторами. BoTx впливає на протеїни, необхідні для вивільнення нейротрансмітерів через пресинаптичні мембрани. Як результат, розвиваються м’язова слабкість або повний параліч м’язів. Такі ефекти не обмежуються поперечносмугастими м’язами, вони виявляються також у гладеньких м’язах та секреторних залозах. Як спостерігалося, BoTx може дифундувати від місця свого введення; це може вказувати на принципову можливість прямих або непрямих впливів токсину на ЦНС. Відповідно, виникає питання: яким є механізм центральної дії BoTx. Було запропоновано декілька гіпотез про механізми такої дії. Результати нещодавніх досліджень, однак, свідчать про те, що найбільш вірогідним механізмом, відповідальним за центральні ефекти BoTx, є його дія на антероградний транспорт. У нашому огляді ми описуємо та обговорюємо найбільш важливі аспекти дії BoTx на ЦНС. 2015 Article Central Action of Botulinum Toxin Type A – is it Possible? / M. Galazka, D. Soszynski, K. Dmitruk // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 380-390. — Бібліогр.: 90 назв. — англ. 0028-2561 http://dspace.nbuv.gov.ua/handle/123456789/148213 615.331:591.18 en Нейрофизиология Інститут фізіології ім. О.О. Богомольця НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| language |
English |
| topic |
Обзоры Обзоры |
| spellingShingle |
Обзоры Обзоры Galazka, M. Soszynski, D. Dmitruk, K. Central Action of Botulinum Toxin Type A – is it Possible? Нейрофизиология |
| description |
Botulinum toxin (BoTx) is a product of gram-positive anaerobic bacteria of the Clostridium
genus. At present, seven serotypes (A to G) of BoTx have been identified. Each of them
functions as a zinc-dependent endopeptidase that hydrolyzes peptide bonds within soluble
N-ethylmaleimide-sensitive factor attaching protein receptors. BoTx affects proteins required
for neurotransmitter release through presynaptic membranes. As a result, muscle weakness
develops, or complete paralysis of the muscles occurs. These effects are not only limited
to striated muscles but also may have impact on smooth muscles and secretory glands. The
observation that BoTx can diffuse from the site of administration may indicate the possibility
of direct or indirect influence of the toxin on the CNS. Consequently, the question arises:
What is the mechanism of the central action of BoTx? Several mechanisms of such action
have been proposed. However, recent findings showed that the most probable mechanism
responsible for the central effects of BoTx action is its anterograde transport. In this review,
we describe and discuss the most important aspects related to BoTx action on the CNS. |
| format |
Article |
| author |
Galazka, M. Soszynski, D. Dmitruk, K. |
| author_facet |
Galazka, M. Soszynski, D. Dmitruk, K. |
| author_sort |
Galazka, M. |
| title |
Central Action of Botulinum Toxin Type A – is it Possible? |
| title_short |
Central Action of Botulinum Toxin Type A – is it Possible? |
| title_full |
Central Action of Botulinum Toxin Type A – is it Possible? |
| title_fullStr |
Central Action of Botulinum Toxin Type A – is it Possible? |
| title_full_unstemmed |
Central Action of Botulinum Toxin Type A – is it Possible? |
| title_sort |
central action of botulinum toxin type a – is it possible? |
| publisher |
Інститут фізіології ім. О.О. Богомольця НАН України |
| publishDate |
2015 |
| topic_facet |
Обзоры |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/148213 |
| citation_txt |
Central Action of Botulinum Toxin Type A – is it Possible? / M. Galazka, D. Soszynski, K. Dmitruk // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 380-390. — Бібліогр.: 90 назв. — англ. |
| series |
Нейрофизиология |
| work_keys_str_mv |
AT galazkam centralactionofbotulinumtoxintypeaisitpossible AT soszynskid centralactionofbotulinumtoxintypeaisitpossible AT dmitrukk centralactionofbotulinumtoxintypeaisitpossible |
| first_indexed |
2025-07-12T18:38:02Z |
| last_indexed |
2025-07-12T18:38:02Z |
| _version_ |
1837467421831593984 |
| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4380
UDC 615.331:591.18
M. GALAZKA,1 D. SOSZYNSKI,1 and K. DMITRUK2
CENTRAL ACTION OF BOTULINUM TOXIN TYPE A – IS IT POSSIBLE?
Received April 25, 2014
Botulinum toxin (BoTx) is a product of gram-positive anaerobic bacteria of the Clostridium
genus. At present, seven serotypes (A to G) of BoTx have been identified. Each of them
functions as a zinc-dependent endopeptidase that hydrolyzes peptide bonds within soluble
N-ethylmaleimide-sensitive factor attaching protein receptors. BoTx affects proteins required
for neurotransmitter release through presynaptic membranes. As a result, muscle weakness
develops, or complete paralysis of the muscles occurs. These effects are not only limited
to striated muscles but also may have impact on smooth muscles and secretory glands. The
observation that BoTx can diffuse from the site of administration may indicate the possibility
of direct or indirect influence of the toxin on the CNS. Consequently, the question arises:
What is the mechanism of the central action of BoTx? Several mechanisms of such action
have been proposed. However, recent findings showed that the most probable mechanism
responsible for the central effects of BoTx action is its anterograde transport. In this review,
we describe and discuss the most important aspects related to BoTx action on the CNS.
Keywords: botulinum toxin (BoTx), proteins of the SNARE complex, neurotransmitters,
effeects on the CNS, anterograde transport, antinociceptive effect.
1,2 Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum,
Bydgoszcz, Poland (Department of Physiology: 1Neuroimmunology Unit,
2Human Physiology Unit).
Correspondence should be addressed to M. Galazka
(e-mail: malgorzata.galazka@cm.umk.pl)
INTRODUCTION
Botulinum toxins (BoTxs) are produced by gram-
positive anaerobic bacteria of the Clostridium genus
(Clostridium botulinum, Clostridium butyricum, and
Clostridium baratii). These bacteria have been with
mankind since the beginning of time. The interest
of scientists in BoTx began at the end of the 18th
century, when sausage poisoning in the German state
of Wurttemberg was first described. A few years later,
a German poet and district medical officer, Justin
Kerner, published a complete description of food-
borne botulism symptoms. However, the work done
by Kerner was not enough to identify the deadly
pathogen, although it allowed researchers to conclude
that the disease was closely related to consumption of
processed meat. The first to identify and describe the
pathogen was the German Professor of bacteriology at
the University of Ghent, Emile Van Ermengem [1–3].
Later on, research on BoTxs led to the identification
of their seven serotypes (A to G). The structure
of these toxins and the mechanisms of their effects
were described, which allowed researchers to begin
the therapeutic use of BoTx. In 1989, the US Food
and Drug Administration approved the use of BoTx
type A in the treatment of strabismus, blepharospasm,
hemifacial spasm, and cervical dystonia [4]. Nowadays
BoTxs are widely used both by the pharmaceutical
industry and in cosmetic medicine/surgery. Also, many
off-label uses of BoTx A are being developed. The list
of medical conditions treated by BoTx administration
is shown in Table 1.
Structure of BoTx; the Mechanism and Effects.
Each serotype of BoTx is formed by a 150 kDa
single polypeptide chain that is posttranslationally
proteolysed by endogenous proteases to a dichain
structure. As a result, an active form of BoTx is
composed of two polypeptide chains, a heavy
chain (HC, 100 kDa) and a light chain (LC,
50 kDa), which are connected by covalent disulfide
and noncovalent bonds. The heavy chain of BoTx
consists of two domains [5]. A C-terminal domain
contributes to the binding of the BoTx molecule to
membrane gangliosides and specific receptors, such as
synaptotagmins I and II [6, 7]. An N-terminal domain,
ОГЛЯДИ
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4 381
CENTRAL ACTION OF BOTULINUM TOXIN TYPE A – IS IT POSSIBLE?
on the other hand, allows BoTx to enter nerve cells by
translocation [8, 9]. Once the light chain of BoTx is
translocated into the neuron, it impairs the release of
neurotransmitters affecting a multiple-step cascade of
protein-protein interactions, which is as follows. The
arrival of an action potential (AP) at the axon terminal
activates voltage-gated calcium channels, causing an
influx of localized calcium ions into the cell. This,
in turn, according to the SNARE hypothesis, triggers
interaction of synaptotagmins with SNARE proteins
(soluble N-ethylmaleimide attachment to the protein
receptor). These events lead to fusion of the synaptic
vesicles with the presynaptic membrane within an
active zone. Briefly, once calcium ions attach to
synaptotagmins, binding of synaptobrevin (VAMP,
vesicle-associated membrane protein) to SNAP-25
and syntaxin is facilitated. Then, Rab-mediated
n-Sec1 dissociation from synataxin is observed. As
a consequence, a core complex is formed. Calcium-
dependent oligomerization of the core complex leads
Medical conditions treated with botulinum toxin [34, 81-91]
Медичні показання для лікування з використанням ботулінового токсину [34, 81–90]
Conditions for which treatment with BoTx has been used
Movement disorders:
dystonia;
hemifacial spasm;
tremor;
tics;
bruxism;
re-innervation synkinesias;
myokymia;
neuromyotonia;
stiff person syndrome.
Hypersecretory disorders:
hyperhidrosis;
sialorrhea;
hyperlacrimation;
rhinorrhea.
Ophthalmic disorders:
strabismus, nystagmus;
exotropia, esotropia, entropium;
protective ptosis.
Pain:
neuropathic pain;
tension headache;
migraine;
myofacial pain;
musculoskeletal pain;
arthritis.
Pelvic floor and gastrointestinal disorders:
achalasia;
anal fissures;
detrusor-sphincter dyssynergia;
vesical sphincter spasms;
sphincter oddi spasms;
animus;
vaginismus.
Cosmetic applications: muscular facial lines;
facial asymmetries.
Others:
eye-lid opening apraxia;
tetanus;
stuttering;
multiple sclerosis;
idiopathic bladder syndrome;
perioperative fixations in orthopedic surgery.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4382
M. GALAZKA, D. SOSZYNSKI, and K. DMITRUK
to the formation of a fusion pore; the latter is stabilized
by oligomerization of synaptotagmin I. As the result,
the membrane collapses, and the vesicle content is
released into the synaptic gap [10–12].
After the released neurotransmitters reach the
postsynaptic membrane, they bind to postsynaptic
receptors, ionotropic (ligand-gated ion channels)
or metabotropic (receptors coupled to G proteins).
This causes changes in the postsynaptic membrane
permeability followed by a shift of the potential on
the postsynaptic membrane. As a result, excitatory or
inhibitory postsynaptic potentials (EPSPs and IPSPs,
respectively) develop. If the postsynaptic membrane
undergoes depolarization, an EPSP occurs, and this
may lead to generation of an action potential (AP).
A milestone in understanding the process described
above was the following interpretation. The BoTx light
chain functions as a zinc-dependent endopeptidase and
hydrolyzes the SNARE protein complex [5]. Toxins
of the B, D, F, and G types act on synaptobrevin [13–
16]. The serotypes A and E hydrolyze SNAP25, while
the serotype C is able to degrade both SNAP25 and
syntaxin [17, 18] (for review, see [5, 19–21]). As a
result, neurotransmitter exocytosis is blocked at
different levels. Due to SNAP25 hydrolysis, BoTx type
A blocks the post-docking priming step of exocytosis.
Serotypes D, E, and F, on the other hand, prevent the
formation of the fusion complex, while BoTxs B, C,
and G uncouple fusion particles from the vesicle or
plasma membrane [22].
Regardless of the hydrolyzed SNARE-type protein,
the effect of BoTx on the nerve cell is the dose-
dependent inhibition of neurotransmitter release
through the presynaptic membrane (mainly that of
acetylcholine). This causes inhibition of striated-
muscle neuromuscular junctions with consequent
muscle weakness and possible complete paralysis.
Further experiments have shown that the action of
BoTx is not limited to acetylcholine release and
striated muscle weakness, but also influences the
secretion of neurotransmitters, including glutamate,
GABA, aspartate, met-enkephalin, noradrenaline [23,
24], serotonin [25], and glycine [26]. These effects
cause the respective electrophysiological alterations
[27] and can influence smooth muscles and secretory
glands [28].
Initially, it was thought that the BoTx-specific
effects are local. However, it was shown that BoTxs
are able to diffuse and act on other remote tissues,
perhaps even on those of the CNS, causing long-lasting
structural and functional changes in the vicinity of the
site of BoTx administration [29–32].
As was mentioned, therapeutics containing BoTx A
(e.g., Botox ® and Dysport ®) or BoTx B (Myobloc®)
are widely used in the treatment of medical conditions
associated with excessive activity of the striated
muscles, smooth muscles, or secretory glands, and
also in cosmetic medicine for wrinkle reduction.
Additionally, there are attempts to use BoTxs of types
A or B in the treatment of off-label medical conditions.
With increase in the therapeutic use of BoTx A and
BoTx B, an increased number of reports concerning
side effects of BoTx administration is observed.
Among the most frequently mentioned, there are
markers of neurological impairment (impaired vision,
conjunctival irritation, reduced sweating, swallowing
difficulties, mouth dryness, and others) [33, 34]. This
may suggest that, in addition to the peripheral action
correlated with side effects of toxin administration,
BoTx is likely to directly affect the nervous system by
influencing peripheral or central pathways.
Central Effects of BoTx Administration. The
hypothesis of the central BoTx action is consistent
with the results of research conducted in the 1960–
1970s. In 1963, Tyler [35] observed changes in
the Hoffman reflex (H reflex) in a patient with
botulism; a few years later, Polley et al. [36] found
BoTx-related changes in cortical electrical activity
in monkeys. Although the above authors [35, 36]
showed that peripherally administered BoTx can
cause symptoms associated with the CNS, there was
no direct evidence for the possibility of the presence
of BoTx in the CNS structures. The lack of this direct
evidence made it impossible to link neurological
effects of peripheral administration of BoTx with
the appearance of the toxin in the CNS. One of the
first research groups to prove that the peripherally
administered BoTx can be transported to the brain
or spinal structures was that of Wiegand et al. [31].
In their experiments, radioactively labeled BoTx was
injected into the cat m. gastrocnemius. As a result, a
distal-proximal gradient of radioactivity in the sciatic
nerve developed. In addition, ipsilateral ventral roots
innervating the injected muscle exhibited significantly
higher levels of radioactivity than ventral roots of the
contralateral (control) side. Direct stimulation of the
muscle injected with BoTx type A caused an increase
in the radioactivity level in the spinal half-segments
ipsilateral to the injected muscle [31]. Unfortunately,
the experiments using radioactively labeled BoTx
type A demonstrated only that the peripherally
administered BoTx A is, in principle, able to reach the
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4 383
CENTRAL ACTION OF BOTULINUM TOXIN TYPE A – IS IT POSSIBLE?
CNS. In addition, as in the case of all animal studies, it
was impossible to rule out the influence of anatomical
(e .g. , muscle innervat ion) and physiological
(e.g., metabolic rate) differences on the results
obtained. Similarly, the administered BoTx dose
was significantly higher than the doses used in the
treatment of humans. Taking this into consideration,
we doubt that BoTx type A found by Wiegand et al.
in the CNS [31] possessed significant enzymatic
activity, and that the observed results reflect changes
occurring after peripheral administration of the toxin
in humans. To resolve this, a few experimental and
clinical studies were conducted. As a result, the main
CNS structures, whose functions can be modulated by
peripherally administered BoTx, have been identified.
Among them, are the spinal cord, brainstem structures,
and motor cortex [37-40].
The influence of peripherally injected BoTx
on the spinal cord was confirmed by a series of
electrophysiological experiments carried out by
Hamjian and Walker [41]. Recording from the extensor
digitorum brevis (EDB) muscle before and after
administration of 10 U BoTx A in ten human subjects
demonstrated that i.m. injection of the toxin caused a
transient increase in the F-wave amplitude and a long-
term increase in the F/M amplitude ratio. The authors
suggested that the observed changes may result from
a tetanus-like inhibition of acetylcholine release from
Renshaw cells and reduced inhibition of ventral horn
cells. Moreover, since the peripheral silent period
remained unchanged, this could indicate that BoTx
type A did not influence afferent inputs from muscle
spindle receptors [41].
Moreno-Lopez et al. [42] tried to estimate the
impact of BoTx type A on the brainstem functions.
The authors recorded dose-dependent changes in
impulsation in cranial nerves after administration of
BoTx A to the lateral rectus muscle of the cat’s eye.
A single administration of the type A toxin in a dose
of 3 ng/kg changed the discharge pattern of abducens
motoneurons for three months. Based on these results,
it was hypothesized that the effect of a high dose of
BoTx A may be associated with the toxin transport
from early endosomes via the trans-Golgi network and
intra-Golgi transport to the endoplasmic reticulum
by retrograde transport [43] or due to transneuronal
changes [42]. Slawek and Reclawowicz [44] attempted
to assess the possible central action of BoTx type A
by recording auditory and somatosensory EPs in
patients with cervical dystonia. The patients taking
part in the experiment received BoTx A injections into
the mm. sternocleidomastoideus (splenius capitis),
trapezius, and lavator scapulae. In 4 to 6 weeks post-
injection, examination of the brainstem auditory
evoked responses (BAERs) and somatosensory evoked
potentials (SSEPs) induced by stimulation of upper
limbs was conducted. The results were compared
with those obtained before BoTx A injections, and
no statistically significant differences were observed.
This may suggest that a direct central action of BoTx
type A does not exist, and the neurological effect
observed after BoTx administration may result
from the impact of toxin on somatic elements of the
peripheral nervous system [44].
In order to determine the impact of the toxin on the
motor cortex, long-latency reflexes (LLRs) induced
by electrical nerve stimulation were examined. After
electrical stimulation of the median nerve, two types
of EMG responses could be recorded, LLR1 and
LRR2. The LLR1 is analogous to the stretch reflex,
while the LLR2 is considered to reflect the activity of
a cortical generator including the supplementary motor
area. Naumann and Reiners [45] noted that patients
with idiopathic focal dystonia manifested after BoTx A
injections a significant reduction of the LLR2
amplitude on the clinically affected side, suggesting
that BoTx A is capabile of modifying afferent outputs
coming from the injected muscle and of modulating
the central motor pattern in focal dystonia [45].
An another way to determine the cortical aspects
of BoTx peripheral administration was to use
transcranial magnetic stimulation (TMS) and analysis
of motor evoked potentials (MEPs). Byrnes et al.
[46] used this approach to plot an electrical activity
map of primary motor cortex projections to the hand
and forearm muscles in patients with writer’s cramp
during isometric contractions. It was found that i.m.
BoTx type A injections did not cause any long-term
improvement of the electrical activity map. However,
BoTx A treatment was accompanied by transient
reversal changes of abnormalities in the cortical
electrical activity map, and the duration of such shifts
depended on the clinical improvement associated
with administration of the toxin. After the BoTx A
effect declined, the cortical electrical activity map
returned to the state observed before the treatment.
These results suggest that changes within the primary
motor cortex occurring in patients with dystonia may
be due to abnormalities in afferent inputs, which can
be temporarily modulated by i.m. administration of
BoTx type A [46]. Experiments carried out on animals
also supported a possibility of motor reorganization
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4384
M. GALAZKA, D. SOSZYNSKI, and K. DMITRUK
following BoTx A injections. Using intracortical
microstimulations of the vibrissa motor cortex area,
Franchi [47] showed that BoTx A administration into a
rat vibrissal pad caused a decrease in the dimensions of
ipsilateral vibrissa representations in both hemispheres
with simultaneous expansion of the forelimb and
eye representations. This resulted in modulation of
the forelimb, eye, and neck movements induced by
electrical stimulation inside the former vibrissa region
[47].
Other CNS elements that may be affected by the
toxin are the structures involved in higher functions of
the CNS, in particular the unimodal and heteromodal
cortices, as well as structures of the paralimbic and
limbic systems [48]. Although Haaland and Davis
[50] did not succeed in proving the influence of BoTx
on memory in patients with botulism [50], there are
a few reports confirming such action. Experiments
with positron emission tomography (PET) conducted
on a group of patients diagnosed with adductor
spasmodic dysphonia (ADSD) showed that speech-
related responses of the CNS regions, involved in
pathophysiology of the disorder, were significantly
affected after administration of BoTx A [50]. In these
experiments, Ali et al. [50] compared the results of
PET examination in the course of the narrative speech
test, narrative whispering test, and during a rest period.
This was performed in a group of patients before and
after treatment with unilateral injection of BoTx type A
into the left thyroarytenoid muscle (16 ± 2.2 U, five
patients) or injection of the toxin into both left and
right thyroarytenoid muscles (2.9 ± 0.3 U, four
patients). Additionally, to determine CNS markers of
spasmodic dysphonia, the PET scan results of ADSD
patients were compared with the results of healthy
volunteers. Analysis of results of the narrative and
whispering speech tasks revealed that BoTx treatment
decreased the activity in the regions where responses
demonstrated hyperactivity in the ADSD patients,
including the right dorsal precentral gyrus, cerebellar
hemispheres, vermis, primary auditory cortex, anterior
cingulate cortex, and right anterior insula. The toxin
administered also augmented the activity in the regions
hypoactive in dysphonic patients. Among these regions
were the dorsal postcentral gyrus, right anterior
audidtory association cortex, posterior supramarginal
gyrus, and posterior middle temporal gyrus, i.e.,
the parts of the unimodal and heteromodal sensory
association areas. Moreover, the authors noticed a
correlation between most regions where the BoTx
treatment exerted its effects (increased or decreased
activity) and clinical improvement. Although the toxin
influenced a wide range of the CNS regions, it did not
affect the activity in other regions, which were hypo-
or hyperactive in ADSD. Among these regions, the
supplementary motor area, anterior middle temporal
gyrus, periaqueductal gray matter, posterior auditory
association cortex, and right ventral precentral gyrus
should be mentioned. According to the authors, these
findings suggest that peripherally adminstered BoTx
may, in fact, influence CNS activity. Unfortunately, the
validity of these results can be brought into question.
The obtained differences between healthy volunteers
and patients may not be determined by the illness
itself but reflect compensatory events or secondary
responses to a primary pathophysiological process.
This would explain the decrease of hyperactivity in
the motor areas of people with ADSD, which are not
typically associated with direct control of the oral
and laryngeal muscles. Another troubleshooting issue,
besides differentiation of the real impact of the toxin
on spasmodic dysphonia pathophysiology related to the
influence on compensatory mechanisms, is the dose and
the side of toxin administration [52]. As was mentioned,
five of nine patients received single unilateral injections
of BoTx into the left thyroarytenoid muscle, while
the remaining four patients were bilaterally injected
with the toxin into both left and right thyroarytenoid
muscles. Since it has been proven that the toxin’s action
is dose-dependent [51], it seems to be unlikely that
the dose and side of administration did not affect the
observed clinical improvement and PET scans in the
above-mentioned experiments.
Besides human studies, the influence of BoTx on
higher functions of the CNS seems to be confirmed by
animal studies. Ando et al. [52] used administration
of BoTx B to the entorhinal cortex to develop the
rat model of dementia. Tests in the Hebb–Williams
maze, AKON-1 maze, and a continuous alternation
task in the T maze revealed the cognitive impairment
in old rats and changes in learning and memory in
adult rats. In addition, the analysis of induction of
long-term potentiation (LTP) indicated significant
suppression of this process in old rats [52]. Similar
changes of the cognitive functions in CD1 mice after
intracerebroventricular (i.c.v.) injection of the toxin
types A and B were observed. During conditioning
of active avoidance and of object recognition in the
respective tests, BoTx-treated mice showed a reduced
capacity to discriminate a novel object within a
familiar environment [53]. In other experimental
model with i.c.v. injections of the toxin type A
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CENTRAL ACTION OF BOTULINUM TOXIN TYPE A – IS IT POSSIBLE?
in rats, the Rotarod and Morris water maze tests
were used to evaluate motor activity and spatial
memory, respectively. The temporal characteristics
of spatial memory impairment obtained during the
experiment suggested a slower onset (during up to
3 months after i.c.v. BoTx A injections) and a long-
term spatial memory disorder [54]. These results
contradict the existing knowledge on the temporal
characteristics of BoTx action. In most clinical cases,
a measurable effect of BoTx action appears 3 to
30 days after administration [55]. In an animal model,
products of BoTx A proteolysis were confirmed in the
hippocampus 3 days after intrahippocampal injections
[56].
Taken together, the results of experimental and
clinical observations suggest that, in principle, the
peripherally administered toxin can affect the CNS
functions. Due to these results, a question arises: What
is the mechanism of BoTx’s central action?
Possible Mechanisms of the Central Action of
BoTx. Currently, several possible major mechanisms
of BoTx central action have been hypothesized. One
of the most probable mechanisms of central action
is related to blocking of acetylcholine release from
γ-motoneurons connected with intrafusal muscle fibre
endings. This leads to reduction of the input from
Ia afferents with possible changes in presynaptic
inhibitory effects of Ia afferents of antagonistic
muscles or to reorganization of the cortical motor
maps. The second mechanism involves the blockade
of neuromuscular connections between α-motoneurons
and extrafusal muscle fibers inducing plastic changes
in motoneurons. Another possibility is transportation
of the toxin from the cell body to axon terminals by
anterograde transport followed by BoTx conveyance
from one cell to another by membrane-bound carriers
(a process called transcitosis) [38, 57]. Antonucci et
al. [56] conducted an experiment in which BoTx type
A was introduced in the hippocampus of C57BL/6N
mice and Sprague–Dawley rats. To establish the
central effect of such intrahippocampal injections,
the emergence of SNAP25 breakdown products was
recorded by immunohistochemical staining. The
staining procedure was preceded by Western blot
experiments; the latter demonstrated that polyclonal
antibodies used in the experiment were recognized
to be specifically cleaved by BoTx A or BoTx E
SNAP- 25 and not by the whole protein. Interestingly,
the SNAP25 hydrolysis product was found in a
contralateral hemisphere. The staining spots were
observed in the neuropil of superficial layers II-III.
Since the II/III-layer neurons of the entorhinal cortex
project to the hippocampus, retrograde transport can be
assumed to be realized. In the same study, injections
of BoTx toxin type A into a rat whisker muscle were
performed. As a result, the SNAP25 proteolysis
products appeared in the facial nucleus [56]. These
results are strongly supported by the work by Restani
et al. [58], who performed a multistep experiment on
the rat visual pathways. Using an immunostaining
technique and Western blotting, the authors managed
to confirm the presence of BoTx A-truncated SNAP25
in the retinorecipient layer of the colliculus superior,
as well as to rule out the possibility of the systemic
spread of the toxin. Furthermore, the intraocular
injection of colchicine revealed lack of BoTx A-
truncated SNAP25 in the tectum after blockade of
the anterograde transport. This fact, together with
the lack of immunorectivity in retinal terminals after
double immunostaining by markers of excitatory and
inhibitory synapses, strongly suggests transcitosis and
anterograde transport of the toxin. Since it could be
argued that the conducted experiments showed the
anterograde transport of cleaved SNAP25 rather than
that of BoTx A itself, Restani et al. [58] combined
intravitreal administration of toxin type A followed
by section of the optic nerve with BoTx E intratectal
injection. Similarly to BoTx A, the type-E toxin
cleaves SNAP25. As a result, a 26-residue fragment
is removed, while the BoTx type A removes only nine
residues from the same region. Additionally, the action
of BoTx E is short-lasting [59]. As was expected, the
amount of BoTx A-truncated SNAP25 in the superior
colliculus initially decreased. After the completion
of BoTx type E effects, the catalytic activity of
BoTx A, however, reappeared by means of increased
BoTx A-truncated SNAP25, undeniably showing that
toxin type A is transported anterogradely to the CNS
structures [58]. Results presented by Bogucki [60], on
the other hand, undermine the possibility of BoTx A
retrograde transport to the CNS elements. To eliminate
the possibility of BoTx A retrograde transport,
peripheral nerve dissection was performed in an
animal model. Single muscle fiber-EMG confirmed the
presence of neuromuscular transmission disturbance
in distant muscles, suggesting that hematogenic
spreading of toxin type A occurs [60].
The third proposed mechanism seems to be the
least likely since it implies toxin transport through the
blood-brain barrier (BBB). Although Boroff and Chen
[61] showed the presence of BoTx A in parenchyma
and brain blood vessels after peripheral administration
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M. GALAZKA, D. SOSZYNSKI, and K. DMITRUK
in mice [62], the molecular size of botulinum toxin
(150 kDa) makes the diffusion of BoTx through the
BBB poorly probable.
Despite obtained evidence confirming the central
action of BoTx and a few proposed mechanisms
of such action, it seems that new experimental
approaches in this respect are needed.
Antinociceptive Action of BoTx – New Insight into
its Central Action. Unexpectedly, a new insight into
the central effect of BoTx type A was provided due to
explanation of an antinociceptive effect of the toxin. It is
well known that pain transmission depends on the release
of certain neurotransmitters and neuropeptides, including
glutamate, substance P (SP), and calcitonin gene-related
peptide (CGRP) [62]. Since it was shown that BoTx A
inhibits the release all these agents (glutamate [63],
substance P [64] and calcitonin gene-related peptide
[65]), it seems reasonable to conclude that BoTx type
A is capable of inducing the antinonciceptive effect
by blocking the release of the above neurotransmitters
and neuropeptides. This “pain relief” action does not
always correlate with muscle weakness (if such occurs)
and strongly suggests that the antinonciceptive BoTx
A action depends on a mechanism differing from that
responsible for muscle weakness. In subjects diagnosed
with a muscle-centered temporomandibular disorder, i.m.
injection of BoTx type A caused weakness in chewing
muscles and reduction in subjective pain sensation.
Eight weeks after toxin administration, the muscle power
returned to baseline, while pain relief was maintained
[67]. Similarly, Tarsy and First [68] found that the
treatment of cervical dystonia with BoTx type A induced
pain relief without improvement in the head positioning
[67]. Further evidence for the antinonciceptive action
of BoTx A has been provided using experimental
inflammatory pain models. Pretreatment with BoTx type
A reduced the formalin-induced grooming response [69]
and licking/lifting behavior within the second phase of
inflammatory pain [69] independently of the dose and
route of administration [70, 71]. Also, pretreatment
with BoTx A in carrageenan- and capsaicin-induced
inflammatory pain models induced suppression
of thermal and mechanical hyperalgesia [72, 73].
Neuropathic pain animal models confirmed the analgesic
effect of BoTx type A. In the neuropathy model induced
by sciatic nerve transection, single subcutaneous (s.c.)
administration of BoTx A reduced or even completely
abolished thermal and mechanical hyperalgesia [74].
In the chronic constriction-injury model of neuropathic
pain, single intraplantar injection of the toxin reduced
mechanical allodynia in mice [75] and rats [76], as
well as thermal hyperalgesia [76] and allodynia [77]
in rats. The peripheral polyneuropathic rat model also
provided information on the analgesic effect of BoTx
type A administration. In this model, paclitaxel-induced
mechanical hyperalgesia was inhibited in both paws after
BoTx A administration ipsilaterally to the paclitaxel
injection side. The threshold for paw withdrawal pressure
3 days after the toxin injection was comparable with that
observed in rats injected with saline [72].
It is well known that i.p. injection of streptozotocin
induces diabetic neuropathy, which results in increased
sensitivity to mechanical and thermal stimuli three
weeks after injection. Administration of BoTx type A not
only reduced mechanical hypersensitivity ipsilaterally
to the injection side, but contralaterally as well. The
antinonciceptive effect of the toxin towards thermal
stimuli was observed only on the ipsilateral side [71].
It is worth mentioning that the antinonciceptive effect
of BoTx type A administration in all described pain
models was observed without any changes in the muscle
power, once again suggesting the existence of a different,
than muscle weakness-inducing, mechanism of BoTx
A action. If so, the question of the nervous system
structures involved in BoTx type A action rearises. As
was proposed by Pavone and Luvisetto [78], BoTx A
can exert its action by inhibiting the neurotransmitter
and/or neuropeptide release from nonciceptive
endings. This, in turn, reduces peripheral and/or central
sensization, as well as blocks neurotransmission
from central terminals of nonciceptive afferents. The
possibility of retrograde transport also should be taken
into consideration [79]. To establish the BoTx A side
of action, a series of experiments on the toxin-related
antinonciceptive effect was conducted. Bach-Rojecky
and Lackovic [79] employed acidic saline-induced pain,
colchicine administration, and sciatic nerve transection
to demonstrate the central analgesic action of BoTx A. In
these experiments, unilateral intramuscular injection of
an acidic saline into the rat’s hindpaw induced bilateral
mechanical hyperalgesia, which was latter reduced in
both hindpaws by s.c. toxin administration. When BoTx
type A was injected contralaterally to the pain induction
side, the antinonciceptive effect was observed only on
the above side. To eliminate the possibility of peripheral
desensitization, the toxin was ipsilaterally injected
after acidic saline administration into the sciatic nerve.
Then, this nerve was cut distally to the side of injection,
preventing BoTx A appearance in peripheral nerve
endings. Surprisingly, a significant antinonciceptive
effect on the contralateral side was induced after such
BoTx type A injection. The authors hypothesized that
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CENTRAL ACTION OF BOTULINUM TOXIN TYPE A – IS IT POSSIBLE?
the decrease in mechanical hyperalgesia might reflect
the central action of the toxin after its retrograde
transport. To confirm this possibility, BoTx A injection
was followed by colchicine administration. Both
substances were injected ipsilaterally to the acidic
saline administration side. Due to colchicine-induced
blockade of the axonal transport, the toxin effect was
abolished both ipsilaterally and contralaterally. The
final evidence for the central BoTx type A action was
the effect of intrathecal toxin injection, which resulted
in the abolishment of mechanical hypersensitivity on
both sides [80]. In another study, colchicine injection
into the trigeminal ganglion decreased the analgesic
effect of BoTx A in the formalin-induced pain model.
Additionally, immunostaining revealed the presence of
cleaved SNAP25 in the dorsal horn of the ipsilateral
trigeminal nucleus caudalis after BoTx type A application
into the rat whisker pad [68].
Taken together, these data strongly suggest a
possibility ot the central action of BoTx A based on
retrograde transport of the latter. However, additional
work should be done to clarify possible BoTx-induced
modifications of the CNS functions.
This publication is a review paper; it was not associated
with any experiments on animals or tests involving human
subjects; therefore, it does not require confirmation of compli-
ance with existing ethical standards from this aspect.
The authors of this communication, M. Galazka,
D. Soszynski, and K. Dmitruk, confirm the absense of
any conflict related to comercial or financial interests, to
interrelations with organizations or persons in any way involved
in the research, and to interrelations of the co-authors.
М. Галазка1, Д. Сожинський1, К. Дмітрук1
ЦЕНТРАЛЬНА ДІЯ БОТУЛІНОВОГО ТОКСИНУ
ТИПУ А – ЧИ ВОНА МОЖЛИВА?
1 Університет ім. Миколая Коперніка, Колегіум Медікум
ім. Людвіга Ридигера, Бидгощ (Польща).
Р е з ю м е
Ботуліновий токсин (BoTx) є продуктом життєдіяльно-
сті грампозитивних бактерій роду Clostridium. На теперіш-
ній час ідентифіковано сім серотипів BoTx (A–G). Всі вони
функціонують як цинкзалежні ендопеотидази, що гідролізу-
ють пептидні зв’язки з розчинним N-етилмалеімідчутливим
фактором, контактуючим з протеїновими рецепторами.
BoTx впливає на протеїни, необхідні для вивільнення ней-
ротрансмітерів через пресинаптичні мембрани. Як резуль-
тат, розвиваються м’язова слабкість або повний параліч
м’язів. Такі ефекти не обмежуються поперечносмугастими
м’язами, вони виявляються також у гладеньких м’язах та се-
креторних залозах. Як спостерігалося, BoTx може дифунду-
вати від місця свого введення; це може вказувати на прин-
ципову можливість прямих або непрямих впливів токсину
на ЦНС. Відповідно, виникає питання: яким є механізм цен-
тральної дії BoTx. Було запропоновано декілька гіпотез про
механізми такої дії. Результати нещодавніх досліджень, од-
нак, свідчать про те, що найбільш вірогідним механізмом,
відповідальним за центральні ефекти BoTx, є його дія на
антероградний транспорт. У нашому огляді ми описуємо та
обговорюємо найбільш важливі аспекти дії BoTx на ЦНС.
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