BHF177 Suppresses Diabetic Neuropathic Pain by Blocking PKC/CaMKII/ERK1/2/CREB Signaling Pathway through Activating GABAB Receptor

Author:

Liu Boyu1ORCID,Guan Fengxi2,Zhao Jiapeng3,Niu Yao1,Jiang Hongbo4

Affiliation:

1. Department of Endocrine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China

2. Department of Ultrasonography, Yanggu People’s Hospital, Yanggu 252300, China

3. Department of Neurosurgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China

4. Department of Nutrition, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China

Abstract

The gamma-aminobutyric acid type B (GABAB) receptor may participate in the development of diabetic neuropathic pain (DNP). BHF177 serves as a positive allosteric modulator of the GABAB receptor. In the current study, we sought to study the role of the BHF177-GABAB receptor in DNP and its underlying mechanism. Streptozotocin was adopted to induce a rat model of DNP, followed by determination of the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and glucose level. The effect of BHF177 on DNP by regulating the GABAB receptor in vivo was determined by the injection of BHF177 and/or CGP46381 (a GABAB receptor antagonist) into rat models of DNP. Hippocampal neuronal cells were isolated and cultured, and the neurons and DNP model rats were treated with activators of PKC (PMA), CaMKII (CaCl2), or ERK1/2 (EGF) to study the role of GABAB receptors in DNP via regulation of the NR2B-PKC-CaMKII-ERK-CREB pathway. BHF177 suppressed DNP symptoms by activating the GABAB receptors, as evidenced by increased PWT and PWL of DNP rats and the increased number of neurons expressing the GABAB receptor, but this effect was reversed by CGP46381 treatment. BHF177 treatment markedly repressed PKC, CaMKII, p-ERK1/2, and p-CREB expressions in the rat DNP model, but these suppressive effects were abrogated by treatments with PMA, CaCl2, or EGF treatment, respectively. To sum up, BHF177 suppresses DNP symptoms by blocking the PKC/CaMKII/ERK1/2/CREB signaling pathway to activate the GABAB receptors.

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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