The Mechanism of Taurine Protection Against Endoplasmic Reticulum Stress in an Animal Stroke Model of Cerebral Artery Occlusion and Stroke-Related Conditions in Primary Neuronal Cell Culture - Advances in Experimental Medicine and Biology - page 238

under physiological conditions but is strongly induced in ER stress under hypoxic
conditions (Nemetski and Gardner 2007 ; Oyadomari and Mori 2004 ; Paschen et al.
1998 ). We showed that an increase in CHOP was prevented by administration of
taurine both in primary neuronal cultures and in the MCAO stroke model. Taurine
can upregulate Akt phosphorylation to prevent ischemia-induced apoptosis
(Taranukhin et al. 2008 ) and to attenuate ER stress (Yung et al. 2007 ) . Taurine has
also been shown to affect the pathways related to ER stress (Pan et al. 2010, 2011 ) .
Our current study demonstrated that taurine has beneficial effects on the protection
against ER stress in the core of the MCAO infarct and on cortical neurons under
hypoxia/reoxygenation. It has been shown that caspase-12, the first ER-associated
member of the caspase family, is activated by ER stress (Yoneda et al. 2001 ;
Nakagawa et al. 2000 ). We analyzed the expression of caspase-12 in the presence or
in the absence of taurine in both in vivo and in vitro models. Our data demonstrated
that the caspase-12 or cleaved caspase-12 expression was clearly reduced by taurine
following hypoxia/reoxygenation in primary neuronal culture, but no change was
seen in the MCAO stroke model. PERK, ATF6, and IRE1, three ER-resident trans-
membrane proteins, serve as the main proximal sensors of the ER stress response.
In this chapter, we tried to identify which particular ER stress-induced pathway can
be affected by taurine treatment in the brain of MCAO model and also in the cortical
neuronal culture model under hypoxia/reoxygenation. Under ER stress conditions,
PERK has proved to be responsible for repressing global protein synthesis via
phosphorylation of a subunit of eIF2a (Kumar et al. 2001 ; Harding et al. 2000b ) .
Phosphorylation of eIF2a, on the other hand, can also indirectly control gene
transcription by positively regulating the translation of transcription factors as has
been shown for mammalian ATF4 (Szegezdi et al. 2006 ). Since p-eIF2a and ATF4
are two downstream proteins in the PERK pathway of ER stress, it is appropriate to
measure expression levels of these two proteins in order to determine the extent of
PERK pathway response in the presence or in the absence of taurine treatment.
We found that in the MCAO model of stroke and after hypoxia/reoxygenation in
primary cell culture, there was a strong increase in ATF4 expression, indicating that
the PERK pathway is activated in both models. However, there were no significant
alterations of ATF4 protein levels in taurine-treated groups both in vitro and in vivo.
These results suggest that taurine may have neither suppressed nor facilitated the
activation of the PERK pathway, which plays an important role in attenuating pro-
tein translation to restore neuronal homeostasis during ER stress. After dissociation
of GRP78, ATF6 translocates from the ER to the Golgi apparatus where it is cleaved
to its active form (cleaved ATF6) (Chen et al. 2002 ). The ratio of cleaved ATF6 to
full-length ATF6 demonstrates that taurine clearly inhibits ATF6 cleavage in both
MCAO stroke model and in primary neuronal cultures under hypoxia/reoxygen-
ation. The levels of p-IRE1 in both the MCAO stroke model and in the hypoxia/
reoxygenation model of primary neuronal cultures were measured to test whether
taurine has an effect on the IRE1 pathway. The results indicate that the elevation of
p-IRE1 is strongly suppressed by taurine treatment, either using in vivo or in vitro
experiments. These findings provide strong evidence that activation of the IRE1
pathway can be inhibited by taurine. Furthermore, the results indicating suppression