Inhibition of protein tyrosine phosphatase 1B protects against sevoflurane-induced neurotoxicity mediated by ER stress in developing brain

Background: ER stress is involved in sevoflurane-induced neurotoxicity. Protein tyrosine Phosphatase 1B (PTP1B) resided in the ER membrane is known to regulate ER stress. However, the role of PTP1B in sevoflurane-induced neurotoxicity is unknown.

Method: Seven-day-old mice treated with 2.3% sevoflurane for 6 h as animal model. The hippocampal tissues were harvested following sevoflurane exposure for evaluation of ER stress markers with Western blot, ER morphology with transmission electron microscopy and density of dendrite spine with Golgi staining. In another subset of mice, neurocognitive function was assessed 4 weeks after anesthesia using Morris water maze test. We also examined the effects of PTP1B or PERK Inhibitor on sevoflurane-induced neurodegeneration in the hippocampus.

Result: The results showed inhibition of PTP1B significantly ameliorated sevoflurane-induced (1) ultrastructural ER alternations and ER stress activation as indicated by upregulation of PERK and eIF2α phosphorylation; (2) increase in cleaved Caspase-3 expression; (3) elevated expressions of proinflammatory NF-κB and TNFα;(4) decreases in expression of synaptophysin, Arc and BDNF-TrkB proteins as well as loss of dendrite spine in the hippocampus; and (5) impairment in neurobehavioural performance at adolescence. Similarly, ER stress inhibitor is also found to downregulate eIF2α phosphorylation and neuroinflammation, and increase expressions of synaptic proteins and BDNF-TrkB signaling proteins.

Conclusions: Our study shows PTP1B inhibition mitigates sevoflurane-induced neurodegeneration maybe mediated by ER stress in developing brain, and eventually improves cognitive function. This suggests PTP1B inhibition could represent a promising strategy to prevent sevoflurane-induced neurotoxicity.