The primary symptom of
diabetic encephalopathy (DE), a kind of central
diabetic neuropathy caused by
diabetes mellitus (DM), is
cognitive impairment. In addition, the tetracyclic
oxindole alkaloid isorhynchophylline (IRN) helps lessen
cognitive impairment. However, it is still unclear how IRN affects DM and DE and what mechanisms are involved. The effectiveness of IRN on brain
insulin resistance was carefully examined in this work, both in vitro and in vivo. We found that IRN accelerates spliced form of
X-box binding protein 1 (sXBP1) translocation into the nucleus under high
glucose conditions in vitro. IRN also facilitates the nuclear association of pCREB with sXBP1 and the binding of regulatory subunits of
phosphatidylinositol 3-kinase (PI3K) p85α or p85β with XBP1 to restore high
glucose impairment. Also, IRN treatment improves high
glucose-mediated impairment of
insulin signaling, endoplasmic reticulum stress, and pyroptosis/apoptosis by depending on sXBP1 in vitro. In vivo studies suggested that IRN attenuates
cognitive impairment, ameliorating peripheral
insulin resistance, activating
insulin signaling, inactivating
activating transcription factor 6 (ATF6) and C/EBP homology
protein (CHOP), and mitigating pyroptosis/apoptosis by stimulation of sXBP1 nuclear translocation in the brain. In summary, these data indicate that IRN contributes to maintaining
insulin homeostasis by activating sXBP1 in the brain. Thus, IRN is a potent
antidiabetic agent as well as an sXBP1 activator that has promising potential for the prevention or treatment of DE.