Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
mobilization of Ca 2+ with the consequent activation of multiple signals, whereas
diacylglycerol activates enzymes such as protein kinase C (PKC). Aluminium leads to a
decrease in the hydrolysis of phosphatidylinositol biphosphate (PIP2) both in vivo and in
vitro (McDonald and Mamrack 1988, Shafer et al. 1993, McDonald and Mamrack 1995,
Shafer and Mundy 1995, Nostrandt et al. 1996). As we have seen before, aluminium
preferential binding to negative charges of polyphosphoinositides causes partial
neutralization of negative charge, clustering, and increased local concentration of these
lipids. All these together result in a limited accessibility of PI-PLC to its substrates and
the subsequent decreased in the enzyme activity (Figure 23) (Verstraeten and Oteiza
2002, Verstraeten et al. 2003). Signaling cascades involving either binding of regulatory
proteins to polyphosphoinositides in the membranes or involving phosphatidylinositol
(PI)-derived second messengers may be negatively altered by aluminium.
Figure 23: PIP2 hydrolysis altered by aluminium (Oteiza et al. 2004)
Inflammation generally accompanies neurodegenerative diseases. One of the
initial events in the cascade leading to inflammatory responses is the activation of
transcription factors. The cytokine TNF-α activates transcription factor NF-κB which
consecutively accelerates the transcription of specific genes involved in inflammation,
such as other cytokines, iNOS, and complement factors by translocating to the nucleus
and binding to their promoter regions. Aluminium was reported to cause an
inflammatory response in the brain both in vivo and in vitro (Yokel and O‟Callaghan
1998, Ghribi et al. 2001a, Platt et al. 2001, Campbell et al. 2002, Becaria et al. 2003,
Johnson and Sharma 2003). The metal activates NF-κB and TNF-α expression leading
to cell death and proliferation of reactive glial cells rising tissue damage (Campbell et
al. 2002, 2004).
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