Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress

Abstract

Reduction in ER stress-induced spinal cord injury was achieved by the administration of 4-PBA. 4-PBA may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.

Activation of the Unfolded Protein Response Enhances Motor Recovery after Spinal Cord Injury

“…In this context, oligodendrocytes and neuropeptide-secretory neurons are of particular relevance for future studies in order to uncover the mechanisms underlying the impact of the UPR in SCI. In fact, correlative studies suggest that the protection of valproate 11,36 or sodium 4-phenylbutyrate 14 against SCI models is associated with attenuated levels of ER stress markers. The partial improvement obtained after XBP1s gene transfer over a wild-type condition where the UPR is already activated suggests that locomotor improvements can be achieved with treatments of days after damage (considering the delay of 41 week for gene expression after AAV gene transfer).…”

“…Similarly, damage to the spinal cord by transient ischemia correlates with increased ER stress levels. 12,14 A recent study indicated that deletion of chop enhances motor recovery after moderate levels of SCI induced by contusion, 13 whereas CHOP deficiency did not have any effect under conditions of severe SCI. 15 As CHOP expression is one of dozens downstream targets of the UPR, 5 and the ATF4/CHOP pathway is activated by a variety on non-ER stress-related stimuli including DNA damage, 16 oxidative stress, 17 metabolic changes, 18 inflammation, among other effects, 19 direct manipulation of proximal UPR components is required to directly define the contribution of ER stress to SCI.…”

Targeting the unfolded protein response for disease intervention

“…The administration of 4-PBA and TUDCA improves insulin sensitivity and glucose homeostasis in liver of mouse models of diabetes and obesity [88], reducing of leptin resistance in mouse obesity model [89]. These compounds have neuroprotective effects in models of brain ischemia-reperfusion [90], HD [91], as well as spinal cord ischemia model [92], among other diseases.…”

Modulation pharmacologique de la réponse au stress du réticulum endoplasmique

“…L'administration de chaperons chimiques dans un modèle expérimental d'ischémie-reperfusion cérébrale atténue le stress du RE, en corrélation avec les effets neuroprotecteurs. Des résultats similaires ont également été publiés dans des modèles expérimentaux de lésions de la moelle épinière et d'altérations des photorécepteurs [32]. Les chaperons chimiques protègent égale-ment le foie de la stéatose et de l'ischémie associée au stress du RE [33].…”