Thiamine deficiency activates hypoxia inducible factor-1α to facilitate pro-apoptotic responses in mouse primary astrocytes

Abstract

Thiamine is an essential enzyme cofactor required for proper metabolic function and maintenance of metabolism and energy production in the brain. In developed countries, thiamine deficiency (TD) is most often manifested following chronic alcohol consumption leading to impaired mitochondrial function, oxidative stress, inflammation and excitotoxicity. These biochemical lesions result in apoptotic cell death in both neurons and astrocytes. Comparable histological injuries in patients with hypoxia/ischemia and TD have been described in the thalamus and mammillary bodies, suggesting a congruency between the cellular responses to these stresses. Consistent with hypoxia/ischemia, TD stabilizes and activates Hypoxia Inducible Factor-1α (HIF-1α) under physiological oxygen levels. However, the role of TD-induced HIF-1α in neurological injury is currently unknown. Using Western blot analysis and RT-PCR, we have demonstrated that TD induces HIF-1α expression and activity in primary mouse astrocytes. We observed a time-dependent increase in mRNA and protein expression of the pro-apoptotic and pro-inflammatory HIF-1α target genes MCP1, BNIP3, Nix and Noxa during TD. We also observed apoptotic cell death in TD as demonstrated by PI/Annexin V staining, TUNEL assay, and Cell Death ELISA. Pharmacological inhibition of HIF-1α activity using YC1 and thiamine repletion both reduced expression of pro-apoptotic HIF-1α target genes and apoptotic cell death in TD. These results demonstrate that induction of HIF-1α mediated transcriptional up-regulation of pro-apoptotic/inflammatory signaling contributes to astrocyte cell death during thiamine deficiency.

Thiamine as a Possible Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Encephalopathy

“…Together, these findings are congruent with recent observations that TD per se is able to modulate the activity of the Hypoxia Inducible Factor-1α (HIF-1α) [ 22 , 29 ], as likewise it occurs after brain hypoxia-ischemia in full-term human neonates [ 74 , 75 ]. HIF-1α is the main transcription factor involved in hypoxic stress, which regulates the expression of genes involved in pro-inflammatory, pro-apoptotic and pro-survival responses [ 76 ].…”

“…The precise mechanisms underlying HIF-1α mediated neuroprotection or injury remain unclear and they may be partly related to the maturation stage of the brain at the time of the hypoxic-ischemic insult [ 74 ]. Most in vitro and in vivo findings suggest that the stabilization and activation of specific HIF-1α signaling may play an important role in promoting neuronal survival in both HIE and thiamine deficiency either by up-regulation of protective or repair genes, such as vascular-endothelial growth factor and erythropoietin, or by reduced expression of pro-apoptotic HIF-1α target genes and hence apoptotic cell death [ 22 , 29 , 31 , 74 ]. Of note, in TD in particular, thiamine replenishment in astrocytes is able to inhibit this specific pro-apoptotic mechanism [ 22 , 29 ].…”

“…Indeed, no preclinical or clinical studies are available in literature on the effect of thiamine and its derivatives in neonatal HIE. Importantly, in animals resuscitated from cardiac arrest, a kind of preclinical model of HIE, administration of thiamine improved survival and neurological outcome; moreover, investigations on pathological histology documented less ischemic brain injury, compared with vehicle-treated controls [ 26 ] Considering these findings, and on the basis that similar biochemical and histological sequence of events occur in the brain during thiamine deficiency (TD) and hypoxia/ischemia related brain damage, both at synaptic and intracellular level, [ 27 , 28 , 29 , 30 , 31 ], in this review we suggest a probable therapeutic role of high doses parenteral thiamine, defined as dosage greater than 100 mg intravenous daily, in the clinical management of neonatal HIE. Moreover, we will discuss the physiological and biochemical bases of the action of thiamine and its biologically active phosphorylated derivatives in the main phases of this encephalopathy.…”

HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

“…Thus, further studies are needed to conclude the contribution of HIF in the degenerative retina. HIF may be related to the neurodegeneration in a cell autonomous manner such as apoptosis (Greijer & Van der Wall, 2004); besides, non-cell autonomous mechanisms including recruitment of cytotoxic inflammatory cells or activation of supporting cells can be considered to induce RGC damages (Zera & Zastre, 2017). HIF inhibition may suppress these negative reactions against the RGC survival in the process of the degeneration.…”

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

“…2 C). To confirm that increased Jagged1 was HIF-1 α -dependent, the HIF-1 α inhibitor YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl-indazole] was used to block HIF-1 α activity 30 , 31 , 32 . As expected, YC-1 significantly attenuated hypoxia-induced changes in Jagged1 mRNA levels ( Fig.…”