Therapeutic Uses

The demonstration that the inhibition of the nerve-muscle impulse is followed by a functional recovery of the NMJ provides the scientific basis of the rapidly growing use of BoNTs in the therapy of a variety of human diseases caused by hyperfunc-tion of cholinergic terminals and other neurodiseases (Jankovic 2006; Montecucco et al. 1996; Scott et al. 1989; Truong and Jost 2006). Injections of minute amounts of BoNT into the muscle(s) to be paralyzed lead to a depression of the symptoms lasting months. Owing to the long lasting duration of its effect, BoNT/A has almost invariably been used. Since the NMJ paralysis is reversible, the injection has to be repeated, and the possibility of an immune response with production of BoNT/A-neutralizing antibodies can occur (Brin 1997; Hanna et al. 1999; Jankovic and Schwartz 1995; Sankhla et al. 1998; Zuber et al. 1993). The injection of a different BoNT serotype could overcome this drawback. BoNT/E and BoNT/F were tested in humans and were found to have beneficial effects of short duration (Aoki 2001; Billante et al. 2002; Chen et al. 1998b; Eleopra et al. 1998b, 2006; Mezaki et al. 1995). Also BoNT/B has a rather short duration of action, and longer paralysis can only be achieved with very high doses, thus increasing the possibility of an immune response (Brin et al. 1999; Dressler and Bigalke 2005; Dressler and Eleopra

2006; Lew et al. 1997; Sloop et al. 1997). Studies performed in humans (reviewed in Eleopra et al. 2006) and in mice (Morbiato et al. 2007), show that BoNT/C has a general profile of action similar to that of BoNT/A.

Injection of BoNT is currently recognized as the best available treatment for dystonias and for certain types of strabismus, and new uses are continuously found (Bhidayasiri and Truong 2005; Montecucco and Molgo 2005). In addition, BoNT/A inhibit ACh release at autonomic nerve terminals which innervate the glands and smooth muscle, and it is currently used to treat diseases such as hypersalivation and hypersudoration (Brisinda et al. 2004; Naumann and Jost 2004).

The use of BoNT/A has been increasingly reported in many conditions of pathological pain, including migraine and other headache disorders (Aoki 2003; Binder and Blitzer 2003), musculoskeletal pain, such as myofascial pain, low back pain, and other chronic pain syndromes (Luvisetto et al. 2007; Reilich et al. 2004; Sycha et al. 2004).

BoNTs are not known to be retrotransported to the CNS, but they are highly toxic when injected directly in the brain (Luvisetto et al. 2003). Both the intraventricular and the hind paw injection of minute amounts of BoNT/A in mice strongly depress the perception of inflammatory pain induced by formalin (Luvisetto et al. 2006). On the basis of the differential effect of BoNT on glutamatergic and GABAergic nerve terminals in hippocampal neurons (Verderio et al. 2004), BoNT/E was tested as a potential therapeutic of epilepsy, and it was found to effectively lower the symptoms induced in mice by the epileptogenic kaininic acid (Costantin et al. 2005).

TeNT has not yet been used as a therapeutic but it has a series of interesting biological properties. When injected in the hippocampus of rats it induces an epilepticlike syndrome (Bagetta and Nistico 1994). The carboxy-terminal third of TeNT, which retains most, but not all, of the neuronal binding and uptake properties of the entire toxin, has been used as a carrier of lysosomal hydrolase (Dobrenis et al. 1992; Jiang et al. 2005), superoxide dismutase inside cells in culture (Figueiredo et al. 1997; Francis et al. 1995), or p-galactosidase in mouse embryos (Coen et al. 1997). These studies open the possibility of using TeNT as carrier of various bio-logicals from peripheral sites of injections to selected areas of the CNS.

Acknowledgements This work is supported by by research grants from Telethon-Italia GP0272Y01, the University of Padova, and FIRBRBNE01RHZM.

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