Treatment with hypoxia‐mimetics protects cultured rat Schwann cells against oxidative stress‐induced cell death

Abstract

Schwann cell (SC) grafts promote axon regeneration in the injured spinal cord, but transplant efficacy is diminished by a high death rate in the first 2–3 days postimplantation. Both hypoxic preconditioning and pharmacological induction of the cellular hypoxic response can drive cellular adaptations and improve transplant survival in a number of disease/injury models. Hypoxia‐inducible factor 1 alpha (HIF‐1α), a regulator of the cellular response to hypoxia, is implicated in preconditioning‐associated protection. HIF‐1α cellular levels are regulated by the HIF‐prolyl hydroxylases (HIF‐PHDs). Pharmacological inhibition of the HIF‐PHDs mimics hypoxic preconditioning and provides a method to induce adaptive hypoxic responses without direct exposure to hypoxia. In this study, we show that hypoxia‐mimetics, deferoxamine (DFO) and adaptaquin (AQ), enhance HIF‐1α stability and HIF‐1α target gene expression. Expression profiling of hypoxia‐related genes demonstrates that HIF‐dependent and HIF‐independent expression changes occur. Analyses of transcription factor binding sites identify several candidate transcriptional co‐regulators that vary in SCs along with HIF‐1α. Using an in vitro model system, we show that hypoxia‐mimetics are potent blockers of oxidative stress‐induced death in SCs. In contrast, traditional hypoxic preconditioning was not protective. The robust protection induced by pharmacological preconditioning, particularly with DFO, indicates that pharmacological induction of hypoxic adaptations could be useful for promoting transplanted SC survival. These agents may also be more broadly useful for protecting SCs, as oxidative stress is a major pathway that drives cellular damage in the context of neurological injury and disease, including demyelinating diseases and peripheral neuropathies.

Enhanced sciatic nerve regeneration by relieving iron-overloading and organelle stress with the nanofibrous P(MMD-co-LA)/DFO conduits

“…1 F exhibited cell viability of RSCs on the membrane at 24 ​h. The viability of RSCs on PDPLA/DFO electrospun films was significantly improved, which may be attributed to the pharmacological induction of hypoxia adaptation to promote the survival of transplanted RSCs [ 36 ]. The results showed that both PDPLA and PDPLA/DFO were suitable for adhesion and growth of Schwann cell and possessed good cyto-compatibility.…”

Structure–Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

“…The oxygen deprivation model (OGD) was performed using the human neuroblastoma SH-SY5Y cell line. We chose adaptaquin as a control compound for the group of branched oxyquinolines since it showed neuroprotection in the post-treatment of hemorrhagic stroke in vivo model [ 20 ] and oxidative stress in vitro model at 1 μM concentration [ 21 , 22 ]. The experimental design was the same as we used before for the drugs targeting HIF PHD, Nrf2, and HDAC6, which showed almost complete neuroprotection at 24 h pretreatment in the range of concentrations matching the IC 50 in the HIF1 ODD-luc and Neh2-luc reporter assays [ 11 ].…”

“…Neuradapt was shown to be neuroprotective in a hypoxia model in the hippocampal neuronal network [ 10 ]. Adaptaquin, a branched-tail oxyquinoline inhibitor discovered earlier [ 8 ], is neuroprotective in in vivo models of hemorrhagic stroke [ 20 ] and Parkinson’s disease [ 32 ], and against oxidative stress in vitro models [ 21 , 22 ]. There are studies demonstrating that neuroprotection exerted by adaptaquin in vivo is not HIF dependent [ 33 ].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications

“…Recent evidence has indicated that the atorvastatin-induced upregulation of miR-221-3p in MSC-EVs results in the recovery of endothelial cell function, thus alleviating diabetic skin defects [ 138 ]. As a hypoxia-mimic compound, deferoxamine can activate a HIF-1α signaling pathway [ 139 ]. Compared with natural MSC-EVs, diabetic rats treated with EVs secreted by deferoxamine-stimulated MSC exhibit enhanced angiogenic activity [ 140 ].…”