Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

Abstract

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

“…A recent study performed in the context of brain hemorrhage and neuronal death showed that the protective effects of iron chelators were due to the inhibition of the proapoptotic ATF4-CHOP signaling (18), a notion that is also in line with our current observations showing that in the absence of CHOP, CPX is practically ineffective, both in vivo and in vitro. The observation that DFO produced opposite results from CPX in CHOP expression may be related to their different pharmacological properties and specificity to CHOP.…”

Early Erythrolysis in the Hematoma After Experimental Intracerebral Hemorrhage

“…That the erythrolysis might occur first in the core of a hematoma is supported by recent data on iron distribution within the hematoma after an ICH using X-ray fluorescence microscopy in mice. Those data showed higher iron concentrations on the periphery of the hematoma than in the center (31). Our current study showed a relationship between erythrolysis in the clot and neuronal loss in the perihematomal zone.…”

Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain

“…The small amount of tissue damage and astrocyte proliferation observed in mesh electronics/tissue samples at 2 wk postimplantation, which recovers by 4 wk, can be attributed to acute damage during the initial implantation. Thus, it should be possible to reduce this acute damage by using smallerdiameter needles for mesh injection and possibly speed the recovery time by coinjection of drugs that reduce inflammation (34,35) and/or biochemical modification of the mesh electronics (36)(37)(38)(39). More importantly, interpenetration of axons and neuron somata into the interior of mesh electronics allows for the formation of a seamless interface between mesh electronics and neural tissue in a manner not previously achieved with more conventional probes.…”