The drug adaptaquin blocks ATF4/CHOP-dependent pro-death Trib3 induction and protects in cellular and mouse models of Parkinson's disease

Abstract

Identifying disease-causing pathways and drugs that target them in Parkinson’s disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.

Hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibition after contusive spinal cord injury does not improve locomotor recovery

“…Adaptaquin (AQ), a hydroxyquinoline-based inhibitor of PHDs, abrogates ATF4-CHOP-dependent neuronal death and improves functional outcomes in mouse models of ICH and Parkinson’s disease [ 15 , 19 ]. While these studies implicate PHDs in ATF4-CHOP-mediated neuronal death, their involvement in OL death and white matter damage after SCI remains unknown.…”

HIF Prolyl Hydroxylase Inhibitors for COVID-19 Treatment: Pros and Cons

“…The first inhibitor of this group, adaptaquin, was identified 10 years ago in high throughput screening using a cell-based luciferase fusion reporter (HIF1 ODD-luc (Smirnova et al, 2010) (Warshakoon et al, 2006)). Adaptaquin was shown to be neuroprotective in in vivo hemorrhagic stroke models, likely working by suppressing the pro-death functions of ATF4 (Aimé et al, 2020), a plausible substrate of HIF PHD isoform 3 (Köditz et al, 2007;Wottawa et al, 2010;Hiwatashi et al, 2011). 8-Oxyquinoline inhibitors of HIF PHD contain a "branched tail" at the 7th position mimicking the fold of HIF peptide at the entry to the active site cavity.…”

“…Recent studies link the severity of COVID to the so called hyperferritinemia (Vargas-Vargas and Cortés-Rojo, 2020) and thus, to ferroptosis (Hirschhorn and Stockwell, 2019b;Edeas et al, 2020). Interestingly, adaptaquin and its improved variants are potent inhibitors of ferroptosis working via the inhibition of HIF PHD1 (Aimé et al, 2020). Therefore, HIF PHD inhibitors may have additional benefits in comparison to the treatment with Epo alone.…”

Ways into Understanding HIF Inhibition

“…HDAC inhibitors seem to be further qualified as a treatment option for neurological diseases characterized by oxidative stress-related cell loss [68], including multiple sclerosis [69], Parkinson's disease [70], and stroke [71]. HDAC inhibitors act by acetylation of histones and, moreover, via modulation of numerous proteins, such as transcription factors.…”