Downregulation of BDNF-TrkB signaling may contribute to the colonic motility disorders in mice with streptozocin-induced diabetes.

Abstract

Brain-derived neurotrophic factor (BDNF) acts as a neuromodulator to regulate gut motility, but the role of BDNF in diabetes-related dysmotility is uncertain. The aim of this study was to investigate the possible involvement of BDNF and its receptor TrkB in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. A single intraperitoneal injection of STZ was used to establish a type 1 diabetes model. An organ bath system was applied to observe the contractile activities of colonic muscle strips. Immunofluorescence and western blotting were performed to evaluate the expression of BDNF and TrkB in the colon. ELISA was used to detect BDNF and SP levels in the serum and colon. The patch-clamp technique was applied to record the currents of L-type calcium channels and large conductance Ca2+ -activated K+ channels on smooth muscle cells. Compared with healthy controls, diabetic mice showed attenuated colonic muscle contraction (p < 0.001), which was partly reversed by BDNF supplementation. TrkB protein expression was significantly reduced in diabetic mice (p < 0.05). In addition, both BDNF and substance P (SP) levels were decreased, and exogenous administration of BDNF increased SP levels in diabetic mice (p < 0.05). Both the TrkB antagonist and the TrkB antibody inhibited the spontaneous contraction of colonic muscle strips (p < 0.01). Moreover, the BDNF-TrkB signaling system enhanced SP-induced muscle contraction. Downregulation of BDNF/TrkB signaling and reduced SP release from the colon may contribute to the colonic hypomotility associated with type 1 diabetes. Brain-derived neurotrophic factor supplementation may have therapeutic potential for diabetes-related constipation.