Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury

Abstract

In previous studies, we showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) protects neurons against ischemic brain injury. In the present study, we investigated the developmental changes of TIGAR level in mouse brain and the correlation of TIGAR expression with the vulnerability of neurons to ischemic injury. We found that the TIGAR level was high in the embryonic stage, dropped at birth, partially recovered in the early postnatal period, and then continued to decline to a lower level in early adult and aged mice. The TIGAR expression was higher after ischemia/reperfusion in mouse brain 8 and 12 weeks after birth. Four-week-old mice had smaller infarct volumes, lower neurological scores, and lower mortality rates after ischemia than 8- and 12-week-old mice. TIGAR expression also increased in response to oxygen glucose deprivation (OGD)/reoxygenation insult or H2O2 treatment in cultured primary neurons from different embryonic stages (E16 and E20). The neurons cultured from the early embryonic period had a greater resistance to OGD and oxidative insult. Higher TIGAR levels correlated with higher pentose phosphate pathway activity and less oxidative stress. Older mice and more mature neurons had more severe DNA and mitochondrial damage than younger mice and less mature neurons in response to ischemia/reperfusion or OGD/reoxygenation insult. Supplementation of cultured neurons with nicotinamide adenine dinuclectide phosphate (NADPH) significantly reduced ischemic injury. These results suggest that TIGAR expression changes during development and its expression level may be correlated with the vulnerability of neurons to ischemic injury.

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

“…G6PD is the rate-limiting enzyme of the oxPPP, which is upregulated in ischemia (Li et al, 2014), while TIGAR promotes the oxPPP at the expense of glycolysis. In line with our findings, inhibition of the oxPPP flux by silencing G6PD aggravated stroke outcome (Zhao et al, 2012), while TIGAR protects ischemic brain injury, though oxPPP flux measurements were not performed in this study (Cao et al, 2015; Li et al, 2014). Some evidence suggests a contextual role of the PPP, attributing opposing fates to NADPH.…”

TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis

“…TIGAR is a novel target protein involved in glucose metabolism and cerebral ischemic injury18192436. The previous study showed that TIGAR increases PPP flux and promotes the production of NADPH to remove reactive oxygen species (ROS) and to maintain cell survival24373839.…”

Protective Effect of Nicotinamide Adenine Dinucleotide Phosphate on Renal Ischemia-Reperfusion Injury

“…Additionally, NADPH provides the energy to shuttle isocitrate into the mitochondria to develop cellular energy homeostasis. It was previously demonstrated that exogenous NADPH could protect neurons from IRI [18]. Thus, we hypothesized that NADPH could also prevent IRI-induced kidney damage.…”