Neurotherapeutic effects of novel <scp>HO</scp>‐1 inhibitors <i>in vitro</i> and in a transgenic mouse model of Alzheimer's disease
Bibliographic record
Abstract
Heme oxygenase-1 (HO-1) encoded by the HMOX1 gene is a 32-kDa stress protein that catabolizes heme to biliverdin, free iron, and carbon monoxide (CO). Glial HO-1 is over-expressed in the CNS of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The HMOX1 gene is exquisitely sensitive to oxidative stress and is induced in brain and other tissues in various models of disease and trauma. Induction of the glial HMOX1 gene may lead to pathological brain iron deposition, intracellular oxidative damage, and bioenergetic failure in AD and other human CNS disorders such as PD and MS. Therefore, targeted suppression of glial HO-1 hyperactivity may prove to be a rational and effective therapeutic intervention in AD and related neurodegenerative disorders. In this study, we report the effects of QC-47, QC-56, and OB-28, novel azole-based competitive and reversible inhibitors of HO-1, on oxidative damage to whole-cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. We also report the effect of OB-28 on the behavior and neuropathology of APP(swe)/PS1(∆E9) mice. OB-28 was found to reduce oxidative damage to whole-cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. Moreover, OB-28 was found to significantly counter behavioral deficits and neuropathological alterations in APP(swe)/PS1(∆E9) mice. Attenuation of AD-associated behavioral deficits and neuropathological changes suggests that HO-1 may be a promising target for neuroprotective intervention in AD and other neurodegenerative diseases. We propose that the targeted suppression of glial heme oxygenase-1 (HO-1) hyperactivity may prove to be a rational and effective therapeutic intervention in Alzheimer's disease (AD) and related neurodegenerative disorders. We report attenuation by a selective HO-1 inhibitor of oxidative damage to whole-cell and mitochondrial compartments in astrocytes in vitro and amelioration of behavioral anomalies in a transgenic mouse model of AD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".