Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury, sclerosis, and diabetic neuropathy. Protein misfolding and accumulation in the ER lumen initiate unfolded protein response in energy-starved neurons which are relevant to toxic effects. In neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, ER dysfunction is well recognized, but the mechanisms remain unclear. In stroke and ischemia, spinal cord injury, and amyotrophic lateral sclerosis, chronic activation of ER stress is considered as main pathogeny which causes neuronal disorders. By targeting components of these ER signaling responses, to explore clinical treatment strategies or new drugs in CNS neurological diseases might become possible and valuable in the future.
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.
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