Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Abstract

Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.

Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome

“…Recently, mounting evidence indicates autophagy activation is associated with neuroprotection in brain ischemia and crosstalk between the UPR and autophagy plays a critical role in stroke outcome. 30,[38][39][40] For example, in a rat model of ischemic preconditioning, blocking autophagy with 3-methyladenine (3-MA) inhibits GRP78 upregulation, exacerbates ER stress, increases apoptosis, and worsens stroke outcome. 39 Using a rat stroke mode, a significant decrease of p62, indication of autophagy activation, was not observed until 6 h reperfusion.…”

Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis

“…Moreover, it was reported that autophagy is decreased by treatment with 4-PBA in acute lung injury [39]. Furthermore, 4-PBA also attenuates transit ischemic brain injury [40]and right ventricular dysfunction during monocrotaline-induced rat Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry pulmonary arterial hypertension [41]. The molecular mechanisms by which ER stress regulates autophagy have been wellcharacterized.…”

Pre-stroke Metformin Treatment is Neuroprotective Involving AMPK Reduction

“…Western blots were done as described previously [14]. The right brain cortex tissues were collected before occlusion or at 12 h after occlusion or reperfusion and were homogenized using RIPA buffer.…”