Br J Pharmacol. 2019 Oct 24. doi: 10.1111/bph.14883. [Epub ahead of print]

Isoproterenol protects intestinal stem cells from chemotherapy-induced damage.

Zeng H¹, Li H¹, Yue M¹, Fan Y^1,2, Cheng J¹, Wu X¹, Xu R¹, Yang W¹, Li M³, Tang J¹, Chen H¹, Kuang B¹, Fan G^1,2, Zhu Q¹, Shao L^1,2.

Abstract

BACKGROUND AND PURPOSE:

Damage to intestinal epithelial cells and mucosa limits the effectiveness of chemotherapy because of unknown underlying mechanism. It is little known how enteric nervous system regulates proliferation, differentiation, impairment and regeneration of intestinal stem cells. We currently investigated the effects of isoproterenol on the damaged intestinal stem cells induced by chemotherapeutic treatment in mice.

EXPERIMENTAL APPROACH:

The effects of inhibiting sympathetic and parasympathetic nerves on intestinal stem cells were examined. Protection of isoproterenol on intestinal stem cells was assessed in the presence or absence of 5-Fluorouracil (5FU) or cisplatin (CP). Cellular apoptosis, cell cycle, PI3K-Akt signaling and NF-κB signaling in intestinal stem cells were mechanistically evaluated.

KEY RESULTS:

Sympathetic nerve inhibitor 6-OHDA had a detrimental effect on the number and function of intestinal stem cells. 5FU or CP treatment damaged both intestinal stem cells and sympathetic nerves. Notably, isoproterenol accelerated the recovery of intestinal stem cells under 5FU or CP treatment. The protection of isoproterenol on damaged intestinal stem cells is mediated by β2 adrenergic receptor. The beneficial role of isoproterenol was mainly mediated by decreasing cellular apoptosis induced by 5FU treatment, which might contribute to fine-tuning regulating NF-κB signaling pathway by isoproterenol administration.

CONCLUSION AND IMPLICATIONS:

Administration with isoproterenol is a new avenue to ameliorate the damage to intestinal stem cells under chemotherapeutic stress conditions.