Isoproterenol Induced Stressful Reactions in the Brain Are Characterized by Inflammation due to Activation of NADPH Oxidase and ER Stress: Attenuated by Apocynin, Rehmannia Complex and Triterpene Acids

Abstract

Inflammatory changes in the cerebral network are present in early mechanisms involved in neurodegenerative disease, Alzheimer disease (AD), and aging brain. We intended to verify that these are likely due to an activation of NADPH oxidase (NOX) and endoplasmic reticulum (ER) stress. Apocynin (APO) an inhibitor of NOX is potential to ameliorate these changes. Rehmannia complex (Reh) a famous prescription in China and the triterpene acids (TTA) isolated from Reh may relieve the isoproterenol (ISO) induced chronic inflammation in the brain, compared with APO. Rats were administered with ISO for 10days and astrocytes were incubated with ISO for 24h. Changes in neural MMP(matrix metalloproteinase), Cx43, AQP4 (aquaporin 4), NFκB, IκBβ, and p-PERK (PKB like kinase) were conducted and intervened with APO, Reh and TTA, in vivo and in vitro, respectively. An increased MDA and upregulated NOX subunit p47phox, ETA, PERK in association with abnormal MMP-2/9 and Cx40/43 were found in cerebral tissue of ISO-injected rats. Astrocytes incubated with ISO exhibited upregulated APQ4, IκBβ, NFκB and p-PERK/PERK and downregulated Cx43. These were significantly abrogated by APO and Reh, in vivo, and APO and TTA in vitro. In conclusion, neural damages induced by ISO were characterized by inflammatory changes in cerebral tissue and astrocytes, which were blunted significantly by APO, Reh and TTA, respectively. Reh and TTA are potential in alleviating the early pathogenesis in neurodegenerative changes in AD in the clinical settings through suppressing NOX and ER stress in the brain.