The Protective Effects of IGF-1 on Different Subpopulations of DRG Neurons with Neurotoxicity Induced by gp120 and Dideoxycytidine In Vitro

Abstract

Peripheral neuropathy induced by human immunodeficiency virus (HIV) infection and antiretroviral therapy is not only difficult to distinguish in clinical practice, but also difficult to relieve the pain symptoms by analgesics because of the severity of the disease at the later stage. Hence, to explore the mechanisms of HIV-related neuropathy and find new therapeutic options are particularly important for relieving neuropathic pain symptoms of the patients. In the present study, primary cultured embryonic rat dorsal root ganglion (DRG) neurons were used to determine the neurotoxic effects of HIV-gp120 protein and/or antiretroviral drug dideoxycytidine (ddC) and the therapeutic actions of insulin-like growth factor-1 (IGF-1) on gp120- or ddC-induced neurotoxicity. DRG neurons were exposed to gp120 (500 pmol/L), ddC (50 μmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L), gp120 (500 pmol/L) plus IGF-1 (20 nmol/L), ddC (50 μmol/L) plus IGF-1 (20 nmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L) plus IGF-1 (20 nmol/L), respectively, for 72 hours. The results showed that gp120 and/or ddC caused neurotoxicity of primary cultured DRG neurons. Interestingly, the severity of neurotoxicity induced by gp120 and ddC was different in different subpopulation of DRG neurons. gp120 mainly affected large diameter DRG neurons (>25 μm), whereas ddC mainly affected small diameter DRG neurons (≤25 μm). IGF-1 could reverse the neurotoxicity induced by gp120 and/or ddC on small, but not large, DRG neurons. These data provide new insights in elucidating the pathogenesis of HIV infection- or antiretroviral therapy-related peripheral neuropathy and facilitating the development of novel treatment strategies.

Progress in Pathological and Therapeutic research of HIV-related Neuropathic Pain

“…The reversible nature of polarization suggests that infected macrophages can continuously switch between latent and active infection.In addition, gp120 induces macrophages to produce a variety of inflammatory mediators that may contribute to cellular activation and recruitment of potential neurotoxic substances (Kedzierska et al , 2003). P2X receptors can assist gp120 in entering macrophages, while the interaction of gp120 with macrophages can in turn stimulate increased ATP release, and increased ATP can activate P2X receptors, leading to increased release of various noxious substances, such as inflammatory cytokines; thus, gp120 causes NP through indirect damage to neurons (Lu et al , 2014;Retamal et al , 2017).…”

The delicate balance between neurotoxicity and neuroprotection in the context of HIV‐1 infection

“…In fact, IGF rescues DRG neurons from undergoing apoptosis and the loss of neuronal processes via the PI3K/AKT signaling pathway. Whereas it could be appealing to assign a therapeutic effect to this factor in HIV‐1‐induced neurotoxicity, it might not be sufficient by itself to reach clinical expectations since it only improves the growth of some subpopulations of DRG neurons (H. Li et al, 2016; Lu et al, 2014). Hence, IGF could be combined with erythropoietin to further prevent neuronal loss in a synergistic fashion as demonstrated in a mouse model of HIV‐1 through increased AKT and GSK‐3β phosphorylation/activation and inhibition, respectively.…”

Dor neuropática em pacientes com HIV/AIDS em uso de terapia antirretroviral

“…Essa sensibilidade exacerbada foi referida principalmente no uso da TARV, que afeta neurônios de pequeno diâmetro do gânglio da raiz dorsal da medula 49 . Além disso, a severidade da neuropatia foi correlacionada a um menor volume de massa cinzenta cortical 50 .…”