Botulinum toxins (BoNTs) are a true wonder of nature. Like Dr. Jekyll and Mr. Hyde,
they have a double “personality”, making them unique among the toxins of bacterial
origin. As Dr. Jekyll, BoNTs are drugs approved for a variety of clinical conditions
while, as Mr. Hyde, they are one of the most dangerous toxins, causing botulism. In
the past, many studies have extensively investigated the mechanism of action of BoNTs,
showing a variety of apparently different mechanisms which have in common the block
of the cholinergic transmission, mainly at the neuromuscular junction. These discoveries
gave an extraordinary consensus to therapeutical use of BoNTs in human pathologies
characterized by excessive muscle contractions, i.e., hypercholinergic dysfunctions
including torticollis, blepharospasms, dystonia, and so on. Recently, the list of
human disorders in which treatments with BoNTs have produced, or are expected to produce,
beneficial effects is long and continuously growing. The ambitious goal of this Special
Issue of Toxins was to provide an up-to-date picture on the state of studies for the
development of new therapeutic treatments with BoNTs, mainly with serotypes A (BoNT/A)
or B (BoNT/B). This Editorial is an introduction to the 25 contributions (14 research
and 11 review papers) collected in this Special Issue of Toxins, which I strongly
invite you to read in their original versions.
The first three papers focus on the treatment with BoNT/A of limb essential tremors
(ETs), a neurology condition characterized by persistent postural, or kinetic, tremor
due to involuntary rhythmic muscle activity of the upper or lower limbs, neck, and
trunk. In detail, Zakin and Simpson [1] contributed with an overview on the techniques
for BoNT/A injection, together with muscle targeting techniques, in the treatment
of ETs. Niemann and Jankovic [2] reported the results of a retrospective study performed
on a large database of patients treated with BoNT/A for hand tremor of different origins,
mainly ETs but also dystonic, Parkinsonian, and cerebellar. Finally, Samotu et al.
[3] analyzed the efficacy of BoNT/A in one open-label trial, with participants affected
by Parkinson’s disease (PD) and ETs.
Three clinical studies investigated the effects of BoNT/A in post-stroke spasticity
(PSS), a common impairment arising from involuntary activation of muscles that often
appears after stroke. Rosales et al. [4] performed a clinical trial (ONTIME) in post-stroke
patients with spastic paresis, and analyzed the impact of BoNT/A on symptomatic spasticity
progression. ONTIME provided evidence that an early BoNT/A injection improved muscle
tone, delayed time to appearance of PSS symptoms, and significantly increased time
until re-injection. Shin et al. [5] reported results from an open-label pilot study
demonstrating that BoNT/A injection into finger and wrist flexors, followed by electrical
stimulation of the finger extensor, improved active hand function in chronic stroke
patients. Ianieri et al. [6] recalled the importance of performing an accurate evaluation
of spasticity to determine how invalidating the symptoms are in order to personalize,
for each patient, the optimal doses of BoNT/A, muscles, and injection time.
Another series of papers focuses on new dermatological uses of BoNTs. Kim et al. [7]
contributed with a review for the use of BoNT/A in several off-label dermatological
indications, including regenerative treatments of hypertrophic scarring and keloids,
postoperative scar prevention, rosacea and facial flushing, and post-herpetic neuralgia,
all conditions associated with hyperhidrosis, oily skin, psoriasis, and itching. Itching
constitutes another dermatological condition where application of BoNT/A may exert
beneficial effects, especially in the treatment of neuropathic itching, a debilitating
symptom appearing secondary to several skin, systemic, metabolic, and psychiatric
disorders. The action of BoNT/A as an antipruritic agent is exhaustively reviewed
by Gazerani [8] who summarizes all the evidence in favor both in animal models and
in healthy human volunteers, and in many clinical conditions. The mechanism originating
the antipruritic effects of BoNTs is discussed by Gazerani and also by Ramachandran
et al. [9], who also give a possible explanation. The authors, analyzing the antipruritic
effects of both BoNT/A and B in murine models, showed that both BoNT/A and B exert
antipruritic effects in a mast cell/histamine-dependent and -independent manner.
Pain is another condition where the use of BoNTs is very promising. Different approaches
have been adopted to treat chronic pain and, among others, the use of BOTOX® (commercial
preparation of BoNT/A from Allergan, Inc., Irvine, CA, USA) has been recently authorized
as a novel pharmacological indication for the prophylaxis of chronic migraine. In
this context, Ion et al. [10] reported the results from a prospective study on the
effect of a new BoNT/A formulation, namely XEOMIN® (commercial preparation of BoNT/A
from Merz Pharmaceuticals, Inc., Frankfurt am Main, Germany), injected in patients
with refractory chronic migraine. Unlike the other commercial preparationd of BoNT/A,
XEOMIN® benefits from the absence of binding albumin protein, minimizing allergic
reactions. The authors proved that XEOMIN® can be a prophylactic treatment in chronic
migraine, effectively reducing the number of attack days, the number of migraine episodes
per day, and the drug intake. Expanding the therapeutic uses of BoNTs, not only in
pain, but also for overactive bladder, neurogenic detrusor overactivity, osteoarthritis,
and wound healing, is exhaustively reviewed by Fonfria et al. [11]. The authors not
only reviewed the effects of BoNTs, remote from injection sites, but also the effects
of novel formulations, including modified and recombinant toxins, and of novel delivery
methods, including transdermal, transurothelial, and transepithelial methods. Another
potential analgesic effect of BoNTs is reviewed by Sandahl Michelsen et al. [12],
who analyzed the results from a series of studies examining the effect of BoNT/A in
alleviating pain in children with cerebral palsy (CP). The authors emphasize the difficulty
concerning the treatment of pain in children with cerebral palsy (CP), a physical
disability that affects the development of movement and posture in children and a
neurological disorder in childhood caused by damage to either the fetal or the infant
brain.
Continuing on the topic dedicated to the pain, Lee et al. [13] tested the efficacy
of a lumbar sympathetic block with BoNT/A and B as pain therapy for complex regional
pain syndrome (CRPS), a neuropathic pain syndrome causing spontaneous pain and allodynia.
They found that the lumbar sympathetic block, with both BoNTs serotypes, constitutes
a safe method to treat CRPS and, more surprisingly, BoNT/B is more effective and longer
lasting than BoNT/A. The effects of BoNTs on CRPS as well as other neuropathic pain
are also reviewed by Park et al. [14]. In addition to CRPS, this review also reports
a complete overview of clinical studies of BoNT effects for central neuropathic pain,
such as neuropathic pain after spinal cord injury, post-stroke shoulder pain, and
central pain associated with multiple sclerosis.
In a basic science study, Finocchiaro et al. [15] compared the effect of BoNT/A and
B in counteracting neuropathic pain in a murine model of sciatic nerve injury. The
results confirmed that BoNT/A reduces neuropathic pain over a long period of time
and, in parallel, it induces an acceleration of the regenerative processes of injured
nerves, improving the functional recovery of the injured limb. BoNT/B can also reduce
neuropathic pain over a long period of time, but, compared to BoNT/A, this reduction
is not accompanied by an improvement in functional recovery. Finally, in an interesting
review, Rojewska et al. [16] discussed whether and how BoNT/A reduces the development
of neuropathic pain, with particular emphasis on spinal neuron–glia interactions and
on the role of glial cells in BoNT/A-induced analgesia.
Another experimental study presented by Wang et al. [17] reported the nerve regeneration
effects of BoNT/A on injured spinal cords in rats. What renders this paper unusual
is the use of the BoNT/A heavy chain (BoNT/A-HC) as a catalytic subunit. This is completely
in disagreement with the canonical view that BoNT/A-HC is the subunit necessary to
bind to the vesicle presynaptic membrane and to translocate, inside the vesicle, the
BoNT/A light chain (BoNT/A-LC), which constitutes the catalytic subunit which, by
cleaving the SNARE proteins, blocks the neuronal transmission. The authors found that
local application of BoNT/A-HC to the site of spinal cord injury significantly induced
an increased expression of growth-associated protein, together with a stimulation
of neurite outgrowths. The mechanism by which BoNT/A-HC favors the relief of spinal
motor dysfunction after nervous injury remains unknown.
As for novel indications of BoNTs, we should not forget that BoNTs have been considered
as agents for inducing controlled paralysis in different muscles of the oral, maxillofacial,
and temporomandibular joint region, with the aim to treat dysfunction and dislocation
in clinical orthodontics and maxillofacial surgery. Clinical applications of BoNTs
in treatment for the correction of severe malocclusion-associated problems, including
occlusion after orthognathic surgery and mandible fracture, are reviewed by Seok and
Kim [18]. This particular application of BoNTs is based on the principle that the
induction of controlled paralysis of masticatory muscles reduces the tensional force
to the mandible and prevents relapse, and affects maxillofacial bone growth and dental
occlusion. Yoshida [19] performed a study comparing the treatment outcome after intramuscular
injection of BoNTs in patients with recurrent temporomandibular joint dislocation
(TMD). Restivo et al. [20] reported an interesting effect of BoNT/A in reducing hypersalivation
in patients with neurological diseases of different etiologies, including Parkinson’s,
amyotrophic lateral sclerosis, brain injury, and cerebral palsy.
Two reviews focus on new therapeutic approaches of BoNTs in gynecology and urinary
tract dysfunctions. In the first, Moga et al. [21] made a literature review regarding
the efficiency of BoNT/A in the treatment of chronic pelvic pain, vaginismus, vulvodynia,
and overactive bladder or urinary incontinence. In the second, Jhang and Kuo [22]
did a literature review regarding treatment of neurogenic lower urinary tract dysfunction,
such as overactive bladder, neurogenic detrusor overactivity, interstitial cystitis,
urethral sphincter dyssynergia, dysfunctional voiding, benign prostate hyperplasia,
and chronic prostatitis.
Moving on to completely different topics, Caleo and Restani [23] contributed with
a review describing the experimental use of BoNTs as a tool to block synaptic function
in specific brain areas, with central delivery of BoNTs used to treat pathological
brain conditions such as epilepsy, cerebral ischemia, Parkinson’s, and prion disease.
For obvious reasons, primarily toxicity and toxin diffusion, these studies are still
limited to animals. An example of this unusual utilization of BoNT/A is also reported
by Antipova et al. [24], who injected toxin directly into the striatum of mice and
compared the motor behavior. The authors speculate that locally applied BoNTs could
be useful for treating brain dysfunctions that require the deactivation of local brain
circuitry.
The last paper was contributed by Bano et al. [25]. This paper reports a relevant
observation on the fact that a tetanus neurotoxin (TeNT), a relative of BoNT/B produced
by a Clostridia tetani strain, is neutralized by antisera raised against BoNT/B. This
finding implicates that, although TeNT is not considered a food-borne pathogen, it
can be present in foodstuffs and interfere with the detection of Clostridia botulinum
by the mouse test, giving rise to misleading results. It is interesting to recall
that humans are not usually vaccinated against type B botulism but citizens in many
countries are regularly vaccinated for tetanus. It might be interesting to investigate
whether the human vaccine for type B botulism also protects from certain isoforms
of TeNTs.
In conclusion, the papers included in this Special Issue of Toxins contributed to
the advancement of the state of the art in the novel therapeutic uses of BoNTs. Furthermore,
many of the published studies focused on emerging or less investigated applications
of BoNTs, in particular for pathologies, thus providing the scientific community with
new data supporting better knowledge of the contributions given by BoNTs to improve
the health of humanity.