Dual Delivery of NGF and bFGF Coacervater Ameliorates Diabetic Peripheral Neuropathy via Inhibiting Schwann Cells Apoptosis

Abstract

Diabetic neuropathy is a kind of insidious complications that impairs neural and vascular function and ultimately leads to somatic and visceral denervation. Basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) are important neurotrophic factors for stimulating angiogenesis and improving peripheral nerve function. Administrating a single factor has good therapeutic effect on diabetic peripheral neuropathy (DPN). However, the short half-life and rapid diffusion of growth factors under physiological conditions limits its clinical applications. Here, we used a biodegradable coacervate, composed of heparin and polycation, to dominate the combined release of bFGF and NGF in a steady fashion. We found this combined growth factors (GFs) coacervate, administered as a single injection, improved motor and sensory functions, restored morphometric structure and decreased apoptosis of Schwann cells in a rat model of prolonged DPN. Similarly the GFs coacervate, as compared with free bFGF and NGF combination, markedly reduced the apoptosis level of a rat Schwann cell line, RSC 96 cells in vitro. We also demonstrated that neuroprotective effects of the GFs coacervate in both rat DPN model and hyperglycemia-induced RSC 96 cell model is likely due to suppression of endocytoplasmic reticulum stress (ERS).

Dual Delivery of bFGF- and NGF-Binding Coacervate Confers Neuroprotection by Promoting Neuronal Proliferation

“…Additionally, with the different dissociation constant (kd) of bFGF (2 nM) and NGF (600 nM), the release efficiency of NGF(60%) was higher than that of bFGF(30%) in coacervate (Fig. 1C), consistent with our previous study [8].…”

“…We found that bFGF and NGF together in free-form and each GF alone incorporated in coacervate significantly increased the growth and proliferation of PC12 cells and SH-SY5Y cells compared to each GF alone. This study in conjunction with previous studies have demonstrated that combined treatment with NGF and bFGF has a greater potential to promote the proliferation and differentiation of neural stem cells and nerve regeneration [8,31] . Thus, dual delivery of bFGF and NGF using coacervate greatly increased the growth and proliferation of neuronal cells when compared to all the other groups, suggesting that controlled dual-delivery of bFGF and NGF using [PEAD:heparin] coacervate does not hinder the beneficial effects of bFGF and NGF, but rather improves it when compared to free application of both factors or coacervate delivery of each GF separately.…”

“…PEAD is a biodegradable polycation with high biocompatibility and high charge density, which strongly binds to heparin and consequently is capable of incorporating growth factors with high efficiency [11].Previous studies have demonstrated that [PEAD:heparin] coacervate controls the release of growth factors for over 30 days in a nearly linear fashion, can maintain the bioactivity of bFGF, and can increase the bioactivity of NGF [8], indicating that [PEAD:heparin] coacervate may be an optimal delivery system for growth factors for the treatment of neurodegenerative diseases.…”

“…Within the family of neurotrophic factors, nerve growth factor (NGF) stimulates the survival and maturation of developing neurons in the peripheral nervous system and protects neurons in the degenerating mammalian brain [5][6][7][8]. It has been used as a therapeutic agent for the restoration and maintenance of neuronal function in both basic and clinical studies.…”

“…It has been used as a therapeutic agent for the restoration and maintenance of neuronal function in both basic and clinical studies. Basic fibroblast growth factor (bFGF) is highly expressed in the nervous system and exerts multiple roles supporting the survival and growth of cultured neurons and neural stem cells [8][9][10]. Although bFGF and NGF have distinctive neuroprotective properties, their short half-life and rapid diffusion rate seriously hinders their clinical applicability.…”