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

INTRODUCTION
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Another pathway has been linked to excitotoxicity. In PD there is evidence for
abnormal activation of cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase
which needs activating partners, p35 and p39 (Cheung et al. 2004, Cheung 2006). Over-
activation of NMDAR was shown to provoke cleavage of p35 to p25, a protein that
cause a more robust and prolonged activation of Cdk5. Excessive Cdk5 activity has
been linked to PD pathogenesis (O‟Hare et al. 2005, Smith et al. 2006, Wang et al.
2007, Qu et al. 2007) and is known to contribute to neuronal death by phosphorylating
the transcription factor myocyte enhancer factor 2 (MEF2) and the antioxidative stress
enzyme peroxiredoxin 2 (Prx2), leading to attenuation of their normal prosurvival
functions. Actually, Prx2 breaks down H2O2 to H2O and O2 protecting the cells against
oxidative stress (Abou-Sleiman et al. 2006), whereas MEF2 is an important
transcription factor of prosurvival genes (Potthoff and Olson 2007).
Neuroinflammation and glial cells
It is well known that the brain can initiate injury responses, such as
neuroinflammation, as a way to clean up injured brain tissues. The main cellular
responders are microglia, specialized macrophages capable of producing cytokines and
other protective factors to regulate the injury response. Although neuroinflammation
may have initial protective effects, it has been hypothesized to be a potential contributor
to PD pathogenesis (Hartmann et al. 2003). Its exact role is unclear: it may act as an
initial event of PD pathogenesis or be a downstream result of another triggering
pathogenic factor.
Immunohistochemical studies have demonstrated the presence of activated
microglia, increased expression of iNOS, cytokines like tumour necrosis factor-α (TNF-
α) and interleukin (IL)-1β, and pro-inflammatory signalling cascades such as
cyclooxygenase-2 (COX-2) and NF-κB in striatum, SN and cerebrospinal fluid (CSF) of
PD patients (Boka et al. 1994, Mogi et al. 1994, Blum-Degen et al. 1995, Hunot et al.
1996, Hirsh et al. 1998, Muller et al. 1998, Hunot et al. 1999, Knott et al. 2000, Nagatsu
et al. 2000, Nagatsu 2002). Animal models of PD using rotenone, MPTP, and 6-OHDA
showed levels of microglial activation similar to what is found in PD (Czlonkowska et