Substituted amphetamines, namely metham-phetamine (MA) and methylen-dioxymeth-amphetamine, are widely used to induce selective nigrostriatal DA degeneration in mice. Both amphetamines induce the formation of multilamellar inclusion bodies ( ' ' whorls'') in nigral DA neurons (Figs. 1,2), which can be stained by antibodies against a-synuclein and ubiquitin (Fornai et al., 2004). These effects occur after few repeated, two h apart, neurotoxin administration, as opposed to what observed with bolus administration of another widely used neurotoxin, MPTP (see below). The neurotoxic effect of amphetamines has been related to an increased cytoplasmic release of DA from DA vesicles; excessive amounts of cytoplas-
mic DA induce the formation of toxic byproducts, free radicals, in a cascade of events culminating in significant oxidative stress for DA neurons. We speculated that in these experimental conditions the formation of multilamellar inclusions could represent a defense reaction of the DA neurons since: a) whorls can be observed only in DA nigros-triatal neurons and in GABAergic cells of the dorsal striatum, where DA terminals impinge, and where a massive, non-physiologic DA release is induced by amphetamines; b) they occur before the formation of nigrostria-tal degeneration; c) their onset can be occluded by antioxidant substances. Moreover, time-dependency of whorls formation and its DA-dependency is confirmed in a more controlled setting, such as cultured PC12 cells which possess the machinery for DA synthesis, and release DA. The close relationship between whorls and LB-like, multifibrillar inclusions could be observed when examining PC12 cells exposed to MA at different time points. And again, the close relationship between inclusion formation and DA availability was demonstrated by showing that inhibition of tyrosine-hydroxylase, before exposure to MA attenuates inclusion bodies formation, and that a similar effect is obtained by pre-treating these cells with a powerful antioxidant, such as S-apomorphine.
A relevant role of a-synuclein in the neurotoxic effects of substituted amphetamines has been suggested. We recently demonstrated that both amphetamines derivatives, at doses inducing selective nigrostriatal degeneration in mice, induce also an overexpression of a-synuclein in the spared DA nigrostriatal neurons (Fornai et al., 2004). This phenomenon is selective for this subclass of SNpc neurons, since it does not occur in pars reticulata GABAergic cells. This observation lends substance to the link between a-synuclein over-expression and DA degeneration (Fornai et al., 2005a), and it confirms the ''gain of function'' for the mechanism of PD due to a-synuclein. As already mentioned, this is in line with the observation of a form of PD associated with over-expression of a-synuclein (Singleton et al., 2003), and DA nigrostriatal degeneration in mice over-expressing the wild-type form of a-synuclein (Masliah et al., 2000).
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