Modulation of the autophagy ‐lysosomal pathway and endoplasmic reticulum stress by ketone bodies in experimental models of stroke

We report for the first time that the protective effect of β-hydroxybutyrate (BHB) against stroke and glucose deprivation is enantiomer selective. We discovered that D-BHB treatment prevented the cleavage of the lysosomal membrane protein LAMP2, maintained lysosome integrity and stimulated the autophagic flux. Also, D-BHB notably reduced the activation of the PERK and IRE1α branches of the unfolded protein response (UPR), attenuating protein synthesis inhibition and preventing endoplasmic reticulum stress. Together our results support the therapeutic use of D-BHB treatment post-ischemia, by preventing the loss of proteostasis through maintaining lys osome integrity, allowing functional autophagy, and attenuating UPR activation. AbstractIschemic stroke is a leading cause of disability worldwide. There is no simple treatment to alleviate ischemic brain injury, as thrombolytic therapy is applicable within a narrow time window. During the last years, the ketogenic diet (KD) and the exogenous administration of the ketone body β-hydroxybutyrate (BHB) have been proposed as therapeutic tools for acute neurological disorders and both can reduce ischemic brain injury. However, the mechanisms involved are not completely clear. We have previously shown that the D enantiomer of BHB stimulates the autophagic flux in cultured neu rons exposed to glucose deprivation (GD) and in the brain of hypoglycemic rats. Here, we have investigated the effect of the systemic administration of D-BHB, f...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research