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 227

crucial role in hypoxia/ischemia-induced cell dysfunction (Azfer et al. 2006 ;
DeGracia and Montie 2004 ). Cerebral hypoxia or ischemia leads to a decrease of
oxygen and glucose availability which in turn induces the release of glutamate at
the presynaptic level. The high levels of glutamate and the subsequent excessive
activation of glutamatergic postsynaptic receptors are the main cause of the death
of neurons (Choi and Rothman 1990 ; Nicholls and Attwell 1990 ) . Overstimulation
of glutamate receptors in neuronal injury has been observed in several neurode-
generative disorders and in acute insults, and this leads to massive brain cell
death related to excitatory imbalance, which occurs in stroke and epilepsy (Lipton
and Paul 1994 ; Mattson 2003 ). Hypoxia triggers the accumulation of unfolded pro-
teins in the ER, leading to the unfolded protein response (UPR) (Kaufman 1999 ) .
Pathways that are initiated in response to the UPR include activation of PKR-like
endoplasmic reticulum kinase (PERK), transcription factor 6 (ATF6), and inosi-
tol-requiring enzyme 1 (IRE1), which in turn activate distinct signaling cascades
mediating the ER stress response (Wang et al. 1998 ; Harding et al. 2000a ) . In
normal neuronal homeostasis, PERK, ATF6, and IRE1 activities are inhibited by
binding to glucose-regulated protein 78 (GRP78), an ER chaperone. In ER dys-
function, GRP78 dissociates from PERK, ATF6, and IRE1, inducing the dimeriza-
tion and phosphorylation of PERK and IRE1, and cleavage of ATF6 (P90) to
ATF6 (P50). Finally these components cause more apoptosis through the action
of the CHOP protein. Taurine, 2-aminoethanesulfonic acid, is a free amino acid
and the most abundant amino acid present in mammalian nervous system (Wu
and Prentice 2010 ). It has been shown that taurine can provide protection against
neurological diseases, including Huntington's disease, Alzheimer's disease, and
stroke (Lousada 2004 ; Tadros et al. 2005 ; Takahashi et al. 2003 ) . It has been
proposed not only that taurine can protect neurons against glutamate-induced
neurotoxicity by preventing glutamate-induced membrane depolarization and
calpain activation due to elevation of intracellular [Ca 2+ ] but also that it can
upregulate Bcl-2 and prevent apoptosis (Wu et al. 2009 ) . Membrane integrity,
intracellular calcium homeostasis, osmoregulation, and antioxidant actions are
also important functions of taurine in the brain (Balkan et al. 2002 ; Chen et al.
2001 ; Moran et al. 1987 ; Wade et al. 1988 ). It has been shown that not only does
taurine have its own specific receptors on the cell membrane, but also it can elicit
hyperpolarization by the inward movement of chloride through GABA and gly-
cine receptors to reduce neuronal excitability (Hussy et al. 1997 ; Wang et al.
2007 ; Wu et al. 1992 ). Recently, it has been shown that taurine can reduce rat
neurological deficits, brain infarct volume, and also caspase-3 activities in the isch-
emic penumbra 24 h after middle cerebral occlusion (MCAO) (Sun and Xu 2008 ) .
Stroke and especially the ischemic stroke is one of the leading causes of serious
disability and death; there has been little progress toward the development of
treatments to improve its prognosis (Weant and Baker 2012 ) . Therefore, novel
therapeutic strategies may be beneficial for improving clinical outcomes. In this
study, we showed that taurine can exert a protective function against hypoxia by
increasing the cell viability, decreasing infarct volume, and reducing ER stress
both in vitro and in vivo.