Scavenging acrolein with 2-HDP preserves neurovascular integrity in a rat model of diabetic retinal disease
Notice bibliographique
Résumé
AIMS/HYPOTHESIS: Diabetic retinal disease (DRD) is characterised by progressive neurovascular unit (NVU) dysfunction, often occurring before visible microvascular damage. Our previous studies suggested that the accumulation of acrolein (ACR)-derived protein adducts on retinal Müller cells and neuronal proteins may contribute to NVU dysfunction in diabetes, although this has yet to be directly tested. In this study, we evaluated the effects of the novel ACR-scavenging drug 2-hydrazino-4,6-dimethylpyrimidine (2-HDP) on retinal NVU dysfunction in experimental diabetes and explored its potential for systemic delivery in humans. METHODS: Sprague Dawley rats were divided into three groups: non-diabetic rats; streptozocin (STZ)-induced diabetic rats; and STZ-induced diabetic rats treated with 2-HDP in their drinking water throughout the duration of diabetes. Endpoint measures were taken at varying time points, ranging from 1 to 6 months post-diabetes induction. Retinal function and structure were evaluated using electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT). Retinal vessel calibre, BP and vasopermeability (assessed by Evans Blue leakage) were also monitored. Immunohistochemistry was employed to assess retinal neurodegenerative and vasodegenerative changes, while cytokine arrays were used to investigate the effect of 2-HDP on diabetes-induced retinal inflammation. The accumulation of the ACR-protein adduct Nε-(3-formyl-3,4-dehydropiperidino)lysine (FDP-Lys) in human diabetic retinas was analysed. Computational chemistry simulations were performed to predict 2-HDP's passive permeability properties and its potential for systemic delivery. RESULTS: levels or BP in diabetic rats (p>0.05). However, it protected against retinal FDP-Lys accumulation (p<0.05) and neurophysiological dysfunction, preserving ERG waveforms at 3 and 6 months post-diabetes induction (p<0.05 to p<0.001 for scotopic for a-wave, b-wave and summed oscillatory potentials). SD-OCT imaging revealed that 2-HDP prevented retinal thinning at 3 months (p<0.01) and protected against synaptic dysfunction, as evidenced by preserved synaptophysin expression (p<0.01 and p<0.001 for inner and outer plexiform layers, respectively). It also prevented neurodegeneration by maintaining retinal ganglion cells, amacrine cells, bipolar cells, and photoreceptors (p<0.05 to p<0.01). In addition, 2-HDP prevented retinal arteriolar dilation (p<0.01), reduced microvascular permeability (p<0.05) and attenuated microvascular damage, as indicated by preserved pericyte numbers and reduced acellular capillary formation (p<0.05). Mechanistically, 2-HDP inhibited microglial activation (p<0.05), suppressed the upregulation of proinflammatory molecules associated with NVU dysfunction in the diabetic retina (p<0.05 to p<0.001) and preserved the expression of the Müller cell glutamate-handling proteins, glutamate aspartate transporter 1 and glutamine synthetase (p<0.05 to p<0.01). FDP-Lys accumulation was observed in post-mortem human retinas from individuals with type 2 diabetes (p<0.05), in a pattern that was similar to that in the rat model of diabetes. Molecular dynamics simulations showed that the neutral form of 2-HDP readily crosses cell membranes, with enhanced permeation in the presence of ACR, highlighting its potential for systemic delivery. CONCLUSIONS/INTERPRETATION: 2-HDP protects against retinal NVU dysfunction in diabetic rats by reducing FDP-Lys accumulation, preserving neuroretinal function and preventing microvascular damage, independent of glycaemic control. These results, combined with evidence from human diabetic retinas and molecular dynamics simulations, support 2-HDP's potential as a promising therapeutic agent for DRD, warranting further preclinical and clinical investigation.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».