0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
tolerability and a tendency to slow down the decline of ALSFRS score
[Traynor et al. 2006 Neurology 67: 20-27].
Oxidative stress is also one of the earliest mechanisms in the cascade
leading to motoneuron death in mouse models and likely in the patients, too.
In fact, alterations of mitochondria, that are the major cellular source of free
radicals, were observed in the motor neurons long before their degeneration
[Bendotti, Carrì (2004) Trends Mol Med 10(8): 393-400]. We have recently
demonstrated that alteration of the ratio between reduced glutathione and
oxidized glutathione (GSH/GSSG) inside mitochondria is critical in mutant
SOD1-mediated death of motoneurons in vitro [Ferri et al. (2006) Proc Natl
Acad Sci USA 103: 13860-13865]. Use of GSH in man is generally safe and its
administration has already been tried in ALS patients, although with poor
success because of its limited accessibility to the CNS. On the contrary, N-
acetyl-cysteine (NAC, the acetylated variant of the amino acid L-cysteine) is
able to restore viability and ATP production in human neuroblastoma cells
expressing mutSOD1 G93A [Beretta et al. (2003) Neurobiol Dis 13: 213-221]
and to prolong survival of G93A transgenic mice [Andreassen et al. (2000)
Neuroreport 11: 2491-2493]. NAC use in humans is safe and its efficacy is
probably related not only to the well-known anti-oxidant activity of NAC, but
also to the fact that this drug is an excellent source of sulfhydryl groups and
in vivo is converted into metabolites capable of stimulating glutathione synthesis.
Therefore, NAC treatment may show beneficial effects in combination
with other drugs.
Finally, we propose the combined use of minocycline, a second generation
tetracycline, which was reported to inhibit significantly caspases and
microglia activation, two late events in the process of motoneuron degeneration.
Different studies on SOD1 mutant transgenic mice showed an increased
median survival after treatment with minocycline either alone or in combination
with creatine or riluzole [see Carrì et al. (2006) Trends in Pharmac Sci 27:
267-273 for review]. Moreover, minocycline has already been tested in small
phase II clinical studies that demonstrated good tolerability and safety in
patient with ALS [Gordon et al. (2004) Neurology 62: 1845-1847]. Two phase
III efficacy clinical trials are currently ongoing in Europe and in USA, respectively.
If such combination of drugs will not provide positive results, we will
test another cocktail including a neuroprotective drug, such as arimoclomol
together with a compound showing protective effect on mitochondria as well
as the ability to maintain and restore neuromuscular innervation, like acetyl-
L-carnitine.
Arimoclomol (Biorex R&D, Hungary) is a heat shock inducer, which
resulted in a major effect in prolonging the survival of SOD1G93A mice even
when administered at the onset of symptoms. Its mechanism of action is
based on the capability to favour the degradation of abnormal misfolded proteins,
thus protecting the cell.
Acetyl-L carnitine (LAC; Sigma-Tau SPA) is a donor of acetyl groups and
increases the intracellular levels of carnitine, which serves as a major transporter
of fatty acids across the mitochondrial membranes. This drug has been
used for the treatment of peripheral neuropathies in humans and was shown
574 2009