BDNF-TrkB and proBDNF-p75NTR/Sortilin Signaling Pathways are Involved in Mitochondria-Mediated Neuronal Apoptosis in Dorsal Root Ganglia after Sciatic Nerve Transection

Abstract

Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear. Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

“…Kim et al 151 Inhibiting mPTP opening in PNI with cyclosporin A attenuates allodynia and spinal cord cytochrome c release. Wang et al 150 Pro-BDNF induces mitochondria-mediated apoptosis of neurons and satellite glia in vitro Diabetic neuropathy…”

“…149 Mitochondrial dysfunctions can trigger apoptosis and axonal degeneration in the periphery and spinal cord, leading to pain. [149][150][151][152] However, neuropathic pain in PNI is not exclusively caused by degeneration. Both peripheral and central sensitization contribute to pain maintenance.…”

proBDNF expression induces apoptosis and inhibits synaptic regeneration by regulating the RhoA-JNK pathway in an in vitro post-stroke depression model

“…Under physiological conditions, proBDNF induces neuronal apoptosis in vitro and in vivo after nerve injury [ 33 , 34 ]. In the present study, our data indicated that the survival rate of prefrontal cortical or hippocampal neurons treated with recombinant p75NTR and siJNK was significantly higher than that in the PSD group.…”

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases

“…Peng et al (2018) found that GOLPH3 regulation sensitizes glioma cells to apoptotic stimuli induced by the chemotherapy drug temozolomide. The p75 neurotrophin receptor (p75NTR) is a glycoprotein belonging to the TNFR/nerve growth factor receptor family that is traditionally detected at the cell membrane (Wang et al, 2020). Recently, Giraud et al (2011) found, using immunofluorescence microscopy, that a part of p75NTR is located in the GA of glioma cells.…”