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MECHANISM OF ACTIONBotulinum Neurotoxin Mechanism of ActionAdvisory Editor
IntroductionConsiderable insights into the mechanism of action of botulinum neurotoxin (BoNT) have been gained over the past decade. The inhibitory effects of BoNT on acetylcholine-mediated neurotransmission at the neuromuscular junction, smooth muscle varicosities, and in the central nervous system are reviewed, as are the toxin’s reduction of the release of glutamate, substance P, and calcitonin gene-related peptide, which are involved in neurogenic inflammation and nociception. The therapeutic implications of new information will be discussed for all major clinical applications of BoNT therapy. Botulinum Neurotoxin
BoNT is produced by Clostridium botulinum as a complex of proteins containing the neurotoxic moiety associated with non-toxic components. BoNT is synthesized as a relatively inactive single-chain polypeptide with a molecular weight of ~150 kDa and becomes activated by selective proteolytic cleavage to yield the heavy and light chains that are linked by a single disulphide bond and non-covalent interactions. There are seven BoNT serotypes (A, B, C1, D, E, F, and G), all of which inhibit acetylcholine release, although their intracellular target proteins, the characteristics of their actions, and their potencies vary substantially (Aoki and Guyer, 2001; Dolly et al, 2002). Type A toxin has been the most widely studied and has been found to be very successful for therapeutic purposes. Recently, type B became commercially available (Callaway, 2004), but its effects are less prolonged (O’Sullivan et al, 1999; Dolly et al, 2002) and much higher doses are required (Jankovic, 2004). Mechanisms of ActionAction at the Neuromuscular Cholinergic SynapseSkeletal muscles are innervated by motoneurons that have their cell bodies in the brain stem or spinal cord. Motoneuron axons pass out of the central nervous system in the anterior spinal roots to form peripheral nerves that branch within the skeletal muscle into terminals and contact several striated muscle fibers, forming neuromuscular synapses. A group of striated muscle fibers innervated by a single motoneuron forms a motor unit. The signal to a muscle to contract originates in the central nervous system and travels as an action potential down the motoneuron to the skeletal muscle fibers. The action potential depolarizes the motoneuron terminal to stimulate the release of acetylcholine into the neuromuscular synaptic cleft via elevating the Ca 2+ concentration. Acetylcholine is released from the cytosol by Ca 2+-regulated exocytosis, a multi-stage process that involves the participation of several proteins collectively called SNAREs ( soluble N-ethylmaleimide–sensitive factor attachment protein receptors). When acetylcholine reaches the postsynaptic muscle membrane, its binding to nicotinic cholinergic receptors opens a transmembrane channel, resulting in an influx of sodium ions (Na +) into the muscle fiber and subsequent efflux of potassium (K +); this initial reduction in the membrane potential of the muscle fiber generates an endplate potential. When the endplate potential reaches a threshold, an action potential is created in the muscle, causing it to contract.
A multi-step mechanism of action of BoNT at the motor nerve terminal was first proposed by Simpson in 1979, and the provision of experimental evidence established this process (Dolly et al, 1984; Black and Dolly, 1986a; Black and Dolly, 1986b; Dolly et al, 1994). These steps comprise 1) binding to ecto-acceptors on the cholinergic nerve terminal, 2) acceptor-mediated internalization, 3) translocation to the cytosol, and 4) inhibition of Ca 2+-dependent neurotransmitter release (Thakker and Rubin, 2004)(Figure 1). Binding to the presynaptic acceptor requires the C-terminal half of the heavy chain (molecular weight = 100 kDa), which can be maintained in the correct confirmation by its association with the light chain (molecular weight = 50 kDa). The toxin is then internalized by receptor-mediated endocytosis until it is completely circumscribed in a vesicle. At that point, as shown in Figure 1, the active moiety passes through the vesicle wall and the protease of the light chain cleaves one of the proteins responsible for vesicle fusion and release of acetylcholine (Dolly, 1997; Aoki, 2004). Table 1 lists the different SNARE or site within these targets each of the BoNT serotypes selectively cleaves (Aoki and Guyer, 2001).
Figure 1. Acetylcholine in nerve terminals is packaged in vesicles. On nerve stimulation, which raised the intra-neuronal Ca 2+ concentrations, the vesicle membrane fuses with the plasmalemma of the nerve terminal, releasing the transmitter into the synaptic cleft. The process is mediated by a series of proteins collectively called the SNARE proteins. BoNT, taken up into the nerve terminals, cleaves the SNARE proteins, preventing creation of the functional fusion complex and, thus, blocking the release of acetylcholine. Reprinted with permission from Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med. 2002;347:382-383.
Reprinted with permission from Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. Eur J Neurol. 2001;8(suppl 5):21-29. BoNT types A, C1, and E cleave synaptosomal-associated proteins of 25 kDa (SNAP-25) (Foran et al, 2003). BoNT types B, D, F, and G cleave vesicle-associated membrane protein (VAMP), also known as synaptobrevin (Schiavo et al, 2000). Proteolytic cleavage of the SNAREs disables the exocytotic machinery, and thus exocytosis of acetylcholine is inhibited. When the target tissue is a muscle, this chemical denervation results in paresis. Type A toxin causes an amazingly extended neuroparalysis that lasts for months in humans (O’Sullivan et al, 1999). Such a prolonged therapeutic effect has been attributed to 1) a long lifetime of the toxin’s protease activity (O’Sullivan et al, 1999), 2) anchoring of the light chain to the presynaptic membrane (Fernandez-Salas et al, 2004), 3) persistence of the toxin-truncated SNAP-25 (Meunier et al, 2003), and 4) endplate remodeling. In vivo imaging of individual nerve terminals in mouse muscle revealed that blockade of acetylcholine release results in nerve sprouting, with the creation of functional synapses extra-junctionally (de Paiva et al, 1999). On the eventual recovery of endocytotic/exocytotic activity at the parent terminals, retraction of the sprouts occurs with a return to the exact compact shape of the original endplate. Muscle Spindle OrganControl of body posture and movements in response to a changing environment is provided by the proprioceptive system that communicates information to the motor system, in return initiating compensatory movements. The regulation of posture and movement is mediated primarily via afferent input from two receptors located in skeletal muscles, the muscle spindle and the Golgi tendon organs. The muscle spindle organs are localized within the belly of the skeletal muscle. As shown in Figure 2, they consist of the intrafusal muscle fibers and their efferent and afferent nerve fibers. Intrafusal muscle fibers are activated by gamma motoneurons and can be separated into nuclear bag and nuclear chain fibers. Afferent nerve fibers consist of Ia fibers innervating primary endings and II fibers innervating secondary endings. They record muscle length and the velocity of muscle length changes. Golgi tendon organs are localized in the tendon of skeletal muscle and measure tendon tension. When muscle stretch occurs, afferent signals from muscle spindle organs excite the alpha motoneurons of the stretched muscle as well as interneurons, inhibiting the alpha motoneurons of its antagonistic muscles. Signals from muscle spindle afferents are also relayed to supraspinal structures involved in long latency responses to the stretch reflex and in the generation of a body image in space. Information from tendon organs is primarily used to limit forces on the tendons.
Figure 2. Muscle spindle organ. This consists of the intrafusal muscle fibers and their efferent and afferent nerve fibers. Intrafusal muscle fibers can be separated into nuclear bag and nuclear chain fibers. Afferent nerve fibers consist of Ia fibers innervating primary endings and II fibers innervating secondary endings. Reprinted with permission from Kings College, London, www.kcl.ac.uk/teares/gktvc/vc/lt/mspindle/spin1.htm. The effects of BoNT on the muscle spindle organs were described over a decade ago (Filippi et al, 1993; Rosales et al, 1996). Injection of BoNT into a muscle reduces alpha motoneuron activity on the extrafusal muscle fibers (Aoki and Guyer, 2001). Muscle spindles are simultaneously inhibited by the toxin’s blockade of the gamma motoneuron control of intrafusal fibers and by its subsequent reduction of Ia afferent signaling, thereby reducing feedback to the alpha motoneurons and other pathways to reduce muscle contraction (Aoki and Guyer, 2001; Aoki, 2004). Action at Noncholinergic Synapses and on NeuropeptidesAcetylcholine is not the only neurotransmitter affected by BoNT. The release of substance P, a neuropeptide involved in neurogenic inflammation and the genesis of pain disorders, also requires the SNARE protein activity that is inhibited by BoNT (Aoki, 2004). Inhibition of substance P release by BoNT was demonstrated in the iris muscles of rabbits as well as in cultured dorsal root ganglion neurons (Ishikawa et al, 2000; Purkiss et al, 2000). Association of this inhibition with a decrease of SNAP 25 levels suggests a direct effect of BoNT. In demonstrating the neurotoxin-induced suppression of substance P in embryonic rat dorsal root ganglia neurons, it was noted that the highest potency was associated with BoNT type A and a substantially lower potency with other serotypes (Welch et al, 2000). BoNT has also been shown to suppress the release of glutamate, another neurotransmitter involved in nociception in the periphery and in the dorsal horn of the spinal cord (Cui et al, 2000; Cui et al, 2002). This confirmed earlier findings of BoNT-induced inhibition of glutamate release from cerebrocortical synaptosomes (McMahon et al, 1992). Moreover, BoNT can reduce the release of other neurotransmitters (Ashton and Dolly, 1988) and neuromediators including epinephrine, norepinephrine, and calcitonin gene-related peptide (Aoki, 2004). Lack of Direct Action of Botulinum Neurotoxin on the Central Nervous SystemDespite reports of the systemic distribution of injected BoNT, direct effects on the central nervous system have not been clearly demonstrated. With its size of 150 kDa, BoNT cannot penetrate the blood-brain barrier (Dressler et al, 2005). The possibility of retrograde neuronal transport of radioactively labeled BoNT from the muscle into the dorsal root and the spinal cord was first suggested by the work of Wiegand et al in 1976. However, no trans-synaptic transport was observed, and the time lag associated with the retrograde transport was so long that BoNT was apparently inactivated before it reached the central nervous system (Wiegand et al, 1976; Dressler et al, 2005). An action of BoNT on Renshaw cells was only demonstrated after intraspinal injection (Hagenah et al, 1977; Dressler et al, 2005). Demonstration of BoNT binding to brain synaptosomes (Williams et al, 1983; Evans et al, 1986) suggest that the central nervous system is receptive to the neurotoxin, although uptake appeared to be minimal and penetration into intact brain slices was restricted (Black and Dolly, 1987). More recently, Aoki and Guyer confirmed the retrograde axonal transport of radioactively labeled BoNT type A in rats but noted that the transported toxin became inactivated (Aoki and Guyer, 2001). Indirect Effects of BoNT on the Central Nervous SystemThe effects of BoNT on the neuromuscular junction and muscle spindle organs can have indirect effects in the central nervous system. At the spinal level, BoNT produces reflex inhibition of alpha motoneurons by gamma motoneuron blockade and subsequent Ia/II afferent input suppression (Dressler et al, 2005). BoNT also normalizes altered reciprocal inhibition between flexor and extensor muscles in patients with upper limb dystonia (Priori et al, 1995; Dressler et al, 2005). A similar effect was demonstrated in patients with essential tremor (Modugno et al, 1998; Dressler et al, 2005). Changes in the electromyographic signals of the contralateral ocular muscles and the abducens motoneuron discharge after injection of BoNT into the lateral rectus muscle also suggest central effects (Moreno-Lopez et al, 1997; Dressler et al, 2005). On the supraspinal level, BoNT normalizes altered intra-cortical inhibition and somatosensory evoked potentials (Dressler et al, 1995; Gilio et al, 2000, Dressler et al, 2005). BoNT can enhance some aspects of cortical activation but fails to improve the impaired activation of the primary motor cortex seen in writer’s cramp (Ceballos-Baumann et al, 1997; Dressler et al, 2005). Therapeutic Implications of the Mechanisms of Action of Botulinum NeurotoxinMuscle Hyperactivity DisordersMuscle hyperactivity disorders including dystonia, spasticity, dyskinesias, synkinesias, and spasms have been successfully treated with BoNT for many years. BoNT’s therapeutic effects include reduction of muscle hyperactivity, functional improvement, and pain reduction (Bakheit et al, 2001; Boyd and Hays, 2001; Reichel, 2001; Brashear et al, 2002; Ade-Hall et al, 2002; Moore, 2002) and can be explained by toxin-induced normalization of the muscle hyperactivity, reducing irritation of muscles, tendons, joints, nerves, and vessels. Furthermore, BoNT produces changes in muscle spindles that alter sensory input and could affect nociceptive transmission (Wohlfarth et al, 2001). BoNT’s therapeutic effects in muscle hyperactivity disorders may be related to several mechanisms of action. BoNT produces direct effects on the alpha motoneuron by blockade of its neuromuscular synapse, thus producing localized and well-controlled muscle relaxation (Dressler et al, 2005). It also indirectly affects the motoneuron by inhibition of the monosynaptic stretch reflex through gamma motoneuron blockade and subsequent reduction of Ia/II afferent motoneuron drive. Additional indirect effects on the central nervous system, including normalization of altered reciprocal inhibition and altered somatosensory evoked potentials, may also contribute to this mechanism. Other central nervous system dysfunctions seen in dystonia should be studied for possible normalization by BoNT. These include impairment of the inhibitory integration of afferent, mainly proprioceptive inputs, probably as a result of altered surrounding inhibition (Tinazzi et al, 2000); impairment of cortical processing of proprioceptive input (Siggelkow et al, 2002); and impairment of the tonic vibration reflex (Yoneda et al, 2000). Because pain reduction in dystonia seems to precede and to outlast muscle relaxation and seems to occur in uninjected muscle groups, anti-nociceptive mechanisms may include mechanisms other than muscle relaxation. Those anti-nociceptive mechanisms are discussed in a subsequent section. Autonomic Nervous SystemBoNT blocks acetylcholine release not only in motoneurons but also in autonomic neurons (MacKenzie et al, 1982). Those autonomic neurons include efferent neurons innervating exocrine glands, such as sweat glands, salivary glands, lacrimal glands, and smooth muscles, including gastrointestinal and urogenital sphincters. This provides the rationale for the therapeutic use of BoNT for focal hyperhidrosis, hypersalivation, hyperlacrimation (Dressler et al, 2005), achalasia (Annese et al, 2000), sphincter of Oddi dysfunction, detrusor-sphincter dyssynergia, anal fissures (Dressler et al, 2005), and spastic constipation (Ron et al, 2001). Action of BoNT does not seem to be restricted to efferent autonomic neurons but may also affect afferent autonomic neurons and ganglionic neurons (Kim et al, 2002). Pain DisordersPathophysiology of Pain Transmission of pain signals from the periphery to the cortex involves signal processing within the spinal cord, brain stem, and forebrain (Burstein, 2001). Unmyelinated C- and thinly myelinated A-delta-nociceptors perceive cutaneous and visceral noxious stimuli and relay them to the spinal cord or brain stem through C-fibers or A-delta-fibers of spinal or cranial nerves. From there they reach higher central nervous system levels in specific wide-dynamic-range neurons. Nociceptive afferent fibers release glutamate and several neuropeptides to activate dorsal horn neurons. In general, C-fibers release neuropeptides, whereas A-delta-fibers release glutamate. The functions of these peptides are incompletely understood, but they presumably mediate slow, modulatory synaptic activity in the dorsal horn neurons. Neuropeptides are always colocalized with “classical” neurotransmitters such as acetylcholine. Sensitization, a component of chronic pain, may develop either through peripheral mechanisms or as a consequence of alterations in nociceptive pathways in the spinal cord or forebrain. Peripheral sensitization can occur in nociceptor nerve terminals when repeated stimulation lowers the depolarization threshold. The peripheral sensitization model of pain proposes that peripheral silent afferents become activated after injury by the release of peripheral nociceptive mediators (Michaelis et al, 1996). In response to muscle inflammation, substance P, calcitonin gene-related peptide, and glutamate are released from primary sensory nerve terminals in the injured area (Graven-Nielsen and Mense, 2001). These neuropeptides sensitize pain receptors, providing a feedback circuit sustaining inflammation, muscle pain, and allodynia (Graven-Nielsen and Arendt-Nielsen, 2002). The central sensitization model proposes that repetitive nociceptive stimulation involving substance P, glutamate, aspartate, calcitonin gene-related peptide, and nitric oxide induces neuroplastic changes in the dorsal horn (Mense, 1996). Peripheral and central sensitization is likely to occur simultaneously in chronic pain disorders (Burstein, 2001; Graven-Nielsen and Arendt-Nielsen, 2002; Malick and Burstein, 2000). One hypothesis on the pathophysiology of chronic back and neck pain is that group III and IV afferents, mediators of muscular pain, stimulate muscle spindle efferents in the spinal cord, leading to increased muscle spindle sensitivity, thus further increasing muscle hyperactivity. The further increase in muscle hyperactivity leads to an increased release of inflammatory and nociceptive mediators. However, there is a lack of sufficient data on human subjects, and further research is needed (Knutson, 2000). In animal models, muscle pain induced by intramuscular injection of hypertonic saline increased the sensitivity of muscle spindles to stretch (Thunberg et al, 2002). Reduction of the afferent input from the muscle spindle organs could therefore reduce pain sensation (Sheean, 2002). Anti-nociceptive Mechanisms of Botulinum Neurotoxin Cui et al investigated the underlying mechanisms of the anti-nociceptive effects of BoNT using the rat formalin inflammation pain model. Subcutaneous injection of BoNT produced a significant, long-lasting, and dose-related inhibition of the sensitized pain response without apparent muscle weakness (Cui et al, 2000). The observed inhibition was attributed to a reduction of glutamate release in the periphery and expression of c-fos in the dorsal horn with an associated reduction in the nociceptive activity of wide-dynamic-range neurons in the dorsal horn (Cui et al, 2000; Cui et al, 2002). The investigators proposed that BoNT directly inhibits the peripheral sensitization produced by local glutamate release from primary sensory neurons, which then leads to an indirect reduction in central sensitization (Cui et al, 2002). Therapeutic Efficacy of Botulinum Neurotoxin in Headache Disorders Evidence for the efficacy of BoNT in tension-type headache is inconsistent because of the varying quality of the studies and methodological differences in treatment protocols. The contribution of muscle relaxation to the anti-nociceptive effect in tension-type headache is controversial. It has been argued that contraction of craniofacial muscles or central sensitization processes following continuous nociceptive input of craniofacial muscles contributes to the pathogenesis of tension-type headache and explains the observed therapeutic effect of BoNT (Schmitt et al, 2001). Other arguments maintain that there is little evidence that muscle hyperactivity plays a role in the etiology of tension-type headache or its response to BoNT (Rollnik et al, 2000). It has been proposed that tension-type headaches are related to central sensitization at the level of the spinal dorsal horn or the trigeminal nucleus because of prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to these structures may result in supraspinal sensitization (Bendtsen, 2000). Some studies suggest that BoNT-A can improve the symptoms of migraine (Silberstein et al, 2000; Binder et al, 2000). An open-label study of patients with migraine treated with BoNT injections showed complete elimination of symptoms in over 50% of patients, with a mean duration of complete response of 2.6 months (Binder et al, 2000). The first prospective, randomized, double-blind, placebo-controlled study of BoNT in migraine showed that BoNT significantly reduced the frequency and severity of migraine based on consumption of migraine medication and the occurrence of migraine-related symptoms (Silberstein et al, 2000). In another double-blind, placebo-controlled study, BoNT reduced the intensity, but not the frequency or duration, of migraine attacks (Brin et al, 2000). One theory of migraine pathophysiology suggests a role for activation of peripheral sensory fibers innervating intracranial blood vessels and the dura. Activation of meningeal nociceptors could stimulate release of calcitonin gene-related peptide, thus initiating neurogenic dura inflammation (Burstein, 2001; Williamson and Hargreaves, 2001). The anti-nociceptive effects of BoNT in migraine might therefore be explained by the toxin-induced reduction of the release of calcitonin gene-related peptide, substance P, and glutamate. The effectiveness of BoNT in migraine might also be explained by its muscle-relaxing effect, as shown by a recent study demonstrating an association between migraine and musculoskeletal symptoms such as neck pain, back pain, and leg muscle pains (Hagen et al, 2002). This hypothesis is supported by the observation that surgical resection of the corrugator supercilii muscles can improve or eliminate migraine (Guyuron et al, 2002). The investigators proposed that terminal branches of the trigeminal nerve are stimulated by contraction of the corrugator supercilii and the temporalis muscles, and this irritation results in the inflammation and release of neuropeptides such as substance P, calcitonin gene-related peptide, and neurokinin A. Suppression of the impingement of these trigeminal nerve branches by surgical removal of the corrugator and temporalis muscles, or by chemical relaxation of these muscles with BoNT, may therefore contribute to the improvement or elimination of migraine. Future DirectionsA rapidly expanding application of BoNT is in the treatment of conditions involving painful muscle spasms. A double-blind, placebo-controlled study (Foster et al, 2001) showed significant improvement in patients with low back pain. Other conditions involving painful muscle spasms reported to benefit from BoNT include myofascial pain and temporomandibular joint and orofacial pain, as well as other musculoskeletal pain and spasm syndromes (Jankovic, 2004). The use of BoNT in the treatment of headache appears promising, and the variable results from studies of BoNT in tension headache are becoming more consistent, as the selection of appropriate patient groups is improved. Current data suggest that BoNT may have greater efficacy in migraine headache than in tension headache. Well-designed, controlled studies are emerging that continue to establish the safety and efficacy of BoNT for both muscle contraction and migraine headaches. For example, a subgroup analysis of a recent randomized, double-blind, placebo-controlled trial on the effectiveness of botulinum toxin for treating chronic daily headaches (CDH) concluded that type A toxin “is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other prophylactic medications” (Dodick et al, 2005). Other promising applications for future BoNT use include nystagmus and other muscle hypercontractility disorders, including muscle spasticity from upper motor lesions, particularly those secondary to multiple sclerosis, spinal cord injuries, or stroke; tremors secondary to Parkinson’s disease; and tics associated with Tourette syndrome (Thakker and Rubin, 2004). ReferencesAde-Hall RA, Moore AP. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy. Cochrane Database Syst Rev. 2000;(2):CD001408. Annese V, Bassotti G, Coccia G, et al. 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Dr. Dolly discusses the composition of 
