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ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS. [ABSTRACT FROM AUTHOR]

Abstract: 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropiridine (MPTP) is a neurotoxin, widely used to produce experimental models of Parkinson Disease in rodents and primates. Although dopaminergic neurons are the most sensitive to MPTP neurotoxicity, different neuronal subtypes are affected. Among these, recent studies indicate that MPTP may produce pathological effects on spinal neurons. In fact, MPTP activates apoptotic proteins within the spinal cord and in particular within the motor neurons, suggesting commonalities between Parkinson Disease and Amyotrophic Lateral Sclerosis. In order to assess this point, in the present study we measured whether MPTP produces motor neurons loss. We chose a dose of MPTP (20mg/kg×3, 2h apart), which in C57BL/6N mice was able to induce a massive nigrostriatal damage. Since both Parkinson Disease and Amyotrophic Lateral Sclerosis are characterized by altered alpha-synuclein immunostaining, this protein was also evaluated within spinal motor neurons, following MPTP administration. Three different monoclonal antibodies, recognizing distinct epitopes in the sequence of alpha-synuclein were used. Severe dopaminergic cell loss was quantified by stereology within the substantia nigra pars compacta, along with marked decrease of striatal tyrosine hydroxylase densitometry. The same doses of MPTP also caused a significant motor neuron loss in the spinal cord (roughly 30%). Spared motor neurons appeared often dysmorphic and vacuolated and possessed altered alpha-synuclein immunostaining. This latter finding extended to other cell types of the spinal cord. These data indicate that MPTP, apart from being a dopaminergic neurotoxin, produces also motor neuron death, thus bridging experimental Parkinsonism and motor neuron disease. [Copyright &y& Elsevier]