Involvement of Bradykinin Receptor 2 in Nerve Growth Factor Neuroprotective Activity.

Carla Petrella,Sebastiano Cavallaro,Sonia Piccinin,Delio Mercanti,Robert Nisticò,Maria Teresa Ciotti,Simona Capsoni,Roberta Possenti,Pietro Calissano,Cinzia Severini

doi:10.3390/cells9122651

Abstract

Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer’s disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells.

Highlights

Neurotrophin nerve growth factor (NGF) is characterized by the ability to improve the growth and differentiation of sensory and sympathetic nerve cells [1]
Expression of Bradykinin (BK) and BK Receptors in cortical neurons (CNs) Following NGF Treatment and Deprivation encoding for BK (Kng1), B1R (Bdkrb1), and B2R (Bdkrb2)
It has been reported that NGF deprivation of sympathetic neurons leads to their degeneration and massive death due to the activation of programmed cell death [44]

Summary

Introduction

Neurotrophin nerve growth factor (NGF) is characterized by the ability to improve the growth and differentiation of sensory and sympathetic nerve cells [1]. The clinical application of NGF in AD is limited by its poor bio-distribution to the brain after systemic delivery [9] and its potent pain sensitizing activity after systemic exposure [10,11]. NGF plays an important role in inflammatory pain by driving peripheral sensitization, directly acting on the peripheral terminal to produce heat hyperalgesia [12,13,14]. As demonstrated in dorsal root ganglion sensory neurons (DRGs), long-term exposure to NGF profoundly regulates the gene expression of several functionally important proteins, including neurotransmitters, receptors, and voltage-regulated ion channels involved in pain transduction [11,15]. Among nociceptive-related peptides released by the activation of nociceptive neurons, bradykinin (BK) is the most potent endogenous pain-producing substance known [16,17,18] Numerous papers have proposed NGF as a possible therapeutic option in the treatment of Alzheimer’s disease (AD) due to its ability to sustain cholinergic activity [2,3,4] and its neuroprotective function [5,6], together with its ability to directly inhibit amyloidogenesis [7,8].

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