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Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

Menzie J, Prentice H, Wu JY - Brain Sci (2013)

Bottom Line: Taurine, an endogenous amino acid, exhibits a plethora of physiological functions.It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect.Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA. jmenzie@fau.edu.

ABSTRACT
Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke.

No MeSH data available.


Related in: MedlinePlus

Schematic depiction of the ER-stress pathways and taurine’s neuroprotective effect on these pathways. During ER stress ATF6 (90 kDa) is cleaved to its active form, cleaved ATF6. Both PERK and IRE1 are also activated; by phosphorylation. Of the downstream players in the PERK pathway, phosphorylated eif2α activates the transcription factor ATF4 which translocates to the nucleus and transcribes CHOP. Cleaved ATF6 another transcription factor, also transcribes CHOP. Phosphorylated IRE1 along with its downstream players potentiates the expression of CHOP. CHOP, a transcription factor, transcribes pro-apoptotic proteins. Caspase-12, also localized at the ER membrane, is cleaved into its active form, cleaved caspase-12. Cleaved caspase-12 facilitates the caspase cascade apoptosis. Taurine inhibits the IRE1 and ATF6 pathways thereby attenuating cell death via ER stress [73,190].
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brainsci-03-00877-f002: Schematic depiction of the ER-stress pathways and taurine’s neuroprotective effect on these pathways. During ER stress ATF6 (90 kDa) is cleaved to its active form, cleaved ATF6. Both PERK and IRE1 are also activated; by phosphorylation. Of the downstream players in the PERK pathway, phosphorylated eif2α activates the transcription factor ATF4 which translocates to the nucleus and transcribes CHOP. Cleaved ATF6 another transcription factor, also transcribes CHOP. Phosphorylated IRE1 along with its downstream players potentiates the expression of CHOP. CHOP, a transcription factor, transcribes pro-apoptotic proteins. Caspase-12, also localized at the ER membrane, is cleaved into its active form, cleaved caspase-12. Cleaved caspase-12 facilitates the caspase cascade apoptosis. Taurine inhibits the IRE1 and ATF6 pathways thereby attenuating cell death via ER stress [73,190].

Mentions: In addition to the cell death mediated by the mitochondrion, increasing evidence points to ER stress as a critical player in hypoxic-ischemic cell death [109,180,181]. The ER is an essential sub-cellular organelle responsible for calcium storage and signaling, calcium-dependent processes such as the folding and processing of synthesized proteins and lipid biosynthesis [182,183,184]. Ischemic stroke induced ER stress, resulting in the impairment of ER protein folding [185]. An accumulation of unfolded/misfolded proteins activates the unfolded protein response (UPR) [186] mediated by ER transmembrane stress sensors, inositol-requiring kinase 1 (IRE1), double-stranded RNA-activated protein kinase 1 (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF 6) [187]. Each stress sensor activates corresponding intracellular pathways (the IRE1-, PERK- and ATF6-pathways; Figure 2) that in turn mediate the up-regulation of the transcription factor C/EBP homologous protein (CHOP) also known as growth arrest and DNA damage inducible protein 153 (GADD 153) [188]. The UPR also activates caspase-12, an essential player in ER stress-mediated apoptosis [189]. In an in vitro model of hypoxia/reoxygenation, (0.3%, oxygen for 24 h, followed by reoxygenation at 21% oxygen for 24–48 h) we observed the neuroprotective effect of taurine against ER stress-mediated apoptosis [73]. In this study, taurine significantly increased the cell viability of the primary neuronal culture. The neuroprotective effect of taurine was dose-dependent, inhibiting the expression of CHOP and of caspase-12. The ratio of cleaved ATF6 to ATF6 declined by 50% in neurons treated with taurine relative to neurons exposed to hypoxia/reoxygenation alone, thereby inhibiting the ATF6-pathway. We also observed that taurine dramatically reduced the expression of p-IRE1 (the activated form of IRE1) in the IRE1 pathway but had no effect on the PERK pathway [73]. In a later study, using experimental stroke model of middle cerebral artery occlusion, (2 h ischemia followed by 4 days reperfusion) we observed that taurine attenuated infarct volume in 2 mm brain slices 6 mm from the frontal pole. Taurine’s neuroprotective effect on ER stress molecules was similar to our in vitro study; a reduction in the expression of CHOP, caspase-12, p-IRE1 and ATF6 [190]. We also observed that GRP78, another ER stress marker was reduced by taurine in this later study [190]. These studies provide convincing evidence that taurine is able to protect the ischemic brain against ER stress and subsequently ER stress mediated apoptosis, since CHOP; a transcription factor that upregulates the transcription of pro-apoptotic Bim (Bcl2 interacting mediator of cell death), and PUMA (p53 upregulated modulator of apoptosis) [191], while downregulating the transcription of anti-apoptotic Bcl2 [192], was downregulated by taurine.


Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

Menzie J, Prentice H, Wu JY - Brain Sci (2013)

Schematic depiction of the ER-stress pathways and taurine’s neuroprotective effect on these pathways. During ER stress ATF6 (90 kDa) is cleaved to its active form, cleaved ATF6. Both PERK and IRE1 are also activated; by phosphorylation. Of the downstream players in the PERK pathway, phosphorylated eif2α activates the transcription factor ATF4 which translocates to the nucleus and transcribes CHOP. Cleaved ATF6 another transcription factor, also transcribes CHOP. Phosphorylated IRE1 along with its downstream players potentiates the expression of CHOP. CHOP, a transcription factor, transcribes pro-apoptotic proteins. Caspase-12, also localized at the ER membrane, is cleaved into its active form, cleaved caspase-12. Cleaved caspase-12 facilitates the caspase cascade apoptosis. Taurine inhibits the IRE1 and ATF6 pathways thereby attenuating cell death via ER stress [73,190].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061860&req=5

brainsci-03-00877-f002: Schematic depiction of the ER-stress pathways and taurine’s neuroprotective effect on these pathways. During ER stress ATF6 (90 kDa) is cleaved to its active form, cleaved ATF6. Both PERK and IRE1 are also activated; by phosphorylation. Of the downstream players in the PERK pathway, phosphorylated eif2α activates the transcription factor ATF4 which translocates to the nucleus and transcribes CHOP. Cleaved ATF6 another transcription factor, also transcribes CHOP. Phosphorylated IRE1 along with its downstream players potentiates the expression of CHOP. CHOP, a transcription factor, transcribes pro-apoptotic proteins. Caspase-12, also localized at the ER membrane, is cleaved into its active form, cleaved caspase-12. Cleaved caspase-12 facilitates the caspase cascade apoptosis. Taurine inhibits the IRE1 and ATF6 pathways thereby attenuating cell death via ER stress [73,190].
Mentions: In addition to the cell death mediated by the mitochondrion, increasing evidence points to ER stress as a critical player in hypoxic-ischemic cell death [109,180,181]. The ER is an essential sub-cellular organelle responsible for calcium storage and signaling, calcium-dependent processes such as the folding and processing of synthesized proteins and lipid biosynthesis [182,183,184]. Ischemic stroke induced ER stress, resulting in the impairment of ER protein folding [185]. An accumulation of unfolded/misfolded proteins activates the unfolded protein response (UPR) [186] mediated by ER transmembrane stress sensors, inositol-requiring kinase 1 (IRE1), double-stranded RNA-activated protein kinase 1 (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF 6) [187]. Each stress sensor activates corresponding intracellular pathways (the IRE1-, PERK- and ATF6-pathways; Figure 2) that in turn mediate the up-regulation of the transcription factor C/EBP homologous protein (CHOP) also known as growth arrest and DNA damage inducible protein 153 (GADD 153) [188]. The UPR also activates caspase-12, an essential player in ER stress-mediated apoptosis [189]. In an in vitro model of hypoxia/reoxygenation, (0.3%, oxygen for 24 h, followed by reoxygenation at 21% oxygen for 24–48 h) we observed the neuroprotective effect of taurine against ER stress-mediated apoptosis [73]. In this study, taurine significantly increased the cell viability of the primary neuronal culture. The neuroprotective effect of taurine was dose-dependent, inhibiting the expression of CHOP and of caspase-12. The ratio of cleaved ATF6 to ATF6 declined by 50% in neurons treated with taurine relative to neurons exposed to hypoxia/reoxygenation alone, thereby inhibiting the ATF6-pathway. We also observed that taurine dramatically reduced the expression of p-IRE1 (the activated form of IRE1) in the IRE1 pathway but had no effect on the PERK pathway [73]. In a later study, using experimental stroke model of middle cerebral artery occlusion, (2 h ischemia followed by 4 days reperfusion) we observed that taurine attenuated infarct volume in 2 mm brain slices 6 mm from the frontal pole. Taurine’s neuroprotective effect on ER stress molecules was similar to our in vitro study; a reduction in the expression of CHOP, caspase-12, p-IRE1 and ATF6 [190]. We also observed that GRP78, another ER stress marker was reduced by taurine in this later study [190]. These studies provide convincing evidence that taurine is able to protect the ischemic brain against ER stress and subsequently ER stress mediated apoptosis, since CHOP; a transcription factor that upregulates the transcription of pro-apoptotic Bim (Bcl2 interacting mediator of cell death), and PUMA (p53 upregulated modulator of apoptosis) [191], while downregulating the transcription of anti-apoptotic Bcl2 [192], was downregulated by taurine.

Bottom Line: Taurine, an endogenous amino acid, exhibits a plethora of physiological functions.It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect.Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL 33431, USA. jmenzie@fau.edu.

ABSTRACT
Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke.

No MeSH data available.


Related in: MedlinePlus