Systemic treatment with a novel basic fibroblast growth factor mimic small-molecule compound boosts functional recovery after spinal cord injury.

Shiro Imagama,Yoshiari Shimmyo,Ryoko Ogino,Naoki Ishiguro,Shigeki Tamura,Yukihiro Matsuyama,Norihito Murayama,Mariko Kuroda,Teruyoshi Inoue,Yasuhiro Morita,Shinya Ueno,Naohiro Takemoto,Kenji Kadomatsu,Taisuke Kadoshima,Michal Hetman

doi:10.1371/journal.pone.0236050

Abstract

Neurotrophic factors have been regarded having promising potentials for neuronal protection and regeneration, and thus promoting beneficial effects of kinesiological functions. They can be suspected to play important roles in cell/tissue grafting for various neural diseases. The clinical applications of such trophic factors to the central nervous system (CNS), however, have caused problematic side effects on account of the distinctive bioactive properties. In the course of developing synthetic compounds reflecting beneficial properties of basic fibroblast growth factor (bFGF), we conducted screening candidates that stimulate to trigger the intracellular tyrosine phosphorylation of FGF receptor and lead to the subsequent intracellular signaling in neurons. A small synthetic molecule SUN13837 was characterized by mimicking the beneficial properties of bFGF, which have been known as its specific activities when applied to CNS. What is more remarkable is that SUN13837 is eliminated the bioactivity to induce cell proliferation of non-neuronal somatic cells. On the bases of studies of pharmacology, behavior, physiology and histology, the present study reports that SUN13837 is characterized as a promising synthetic compound for treatment of devastating damages onto the rat spinal cord.

Highlights

Spinal cord injury (SCI) is a life threatening medical condition that often leads to substantial, permanent neurological impairment
Accumulating research has revealed that endogenous expression of both basic fibroblast growth factor and FGF receptors (FGFR) are upregulated at the injury site shortly after spinal cord damage; acting to prevent cell necrosis/apoptosis and axonal growth inhibition associated with SCI pathogenesis [5]
Other undesired side effects such as carcinogenesis [14] have been reported. basic fibroblast growth factor (bFGF) treatment, did show some advantageous outcomes in the long-term recovery phase following cerebral stroke [15]. These data suggest that a selective activator of FGF receptors lacking cell proliferating activity would be a preferable therapeutic agent for the treatment of SCI, with the ideal candidate compound profile exhibiting all of the beneficial activities of bFGF but no proliferative effect and better pharmacokinetic properties compared with bFGF

Summary

Introduction

Spinal cord injury (SCI) is a life threatening medical condition that often leads to substantial, permanent neurological impairment. BFGF exhibits potent neuroprotective activity and promotes axonal outgrowth [6, 7, 8, 9], it has the potential to stimulate proliferation of cells responsible for either inflammation or glial scar formation at the injury site [10, 11, 12], and these opposing actions of bFGF reduce its value as a therapeutic agent for SCI This is underscored by the fact that bFGF treatment in an animal model of SCI led only to ambiguous results and administration of bFGF to patients with brain infarction exhibited serious adverse effects, such as decreased blood pressure and increased numbers of leukocytes due to enhanced proliferation of inflammatory cells [13]. These data suggest that a selective activator of FGF receptors lacking cell proliferating activity would be a preferable therapeutic agent for the treatment of SCI, with the ideal candidate compound profile exhibiting all of the beneficial activities of bFGF but no proliferative effect and better pharmacokinetic properties compared with bFGF

Methods

Results

Conclusion