Effects of 4‐phenylbutyric acid on the process and development of cerebrum injury in diabetic rats: regulation of endoplasmic reticulum stress inflammatory response

Abstract

BackgroundInflammation may contribute to the pathogenesis of diabetic nephropathy (DN) and inflammatory response plays an important role in diabetic cerebrum injury, although the precise regulatory mechanism is still unclear. Recent reports have shown that 4‐phenylbutyric acid (4‐PBA) can suppress endoplasmic reticulum (ER) stress. We therefore hypothesized that 4‐PBA could provide neuroprotection through the suppression of ER stress inflammatory response in DN rats.Methods and ResultsMale SD rats were randomly divided into three groups: a normal control group, a streptozotocin and high fat diet‐induced DN model group, and a DN plus 4‐PBA (1g/kg) treatment group. In diabetic animals, elevated ER stress markers, GRP78, ATF‐4, XBP‐1, CHOP and the expression of p‐eIF, p‐JNK in the cerebral cortex were increased; TNF‐¦Á and IL‐6 levels were increased and NF‐kappaB signal pathway was activated; In cultured hippocampus neurons, high glucose induced a time‐dependent increase of ER stress and inflammatory factor production. In contrast, alleviation of ER stress by 4‐PBA or blockade of JNK activity attenuated inflammatory gene expression induced by high glucose, 4‐PBA also inhibit neuron cell apoptosis in vitro and in vivo.Conclusion4‐PBA exerts a marked neuroprotective effect possibly due to modulating ER stress and related inflammatory response.