Peptide ligands targeting FGF receptors promote recovery from dorsal root crush injury via AKT/mTOR signaling

Introduction

Neurological disorders are recognized as a leading cause of death and disability worldwide. The nervous system is vulnerable to various disorders and can be damaged by many factors, including trauma, infections, degeneration, structural defects, tumors, blood flow disruption, and autoimmune disorders. Findings from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) in 2015 and 2016 [1, 2] showed that neurological disorders are the largest cause of disability, and their contribution to the overall burden of all health conditions is increasing. Once injured, mature neurons in the mammalian central nervous system (CNS) fail to regenerate their axons due to poor intrinsic regenerative capacity coupled with the hostile CNS environment [3-6]. The failure of axon regeneration by damaged adult CNS neurons and to rebuild functional connections cause permanent disabilities in individuals with spinal cord injury or stroke [7]. In contrast, mammalian peripheral nervous system (PNS) neurons retain the ability to self-repair and reactivate intrinsic growth programs following injury and better regenerate than those in the CNS [3, 8]. However, severe damage to peripheral nerves can also cause permanent neurological deficits, including failure to reinnervate and chronic pain development, resulting in severe disability and decreased quality of life [9].

The current repair strategies for healing peripheral nerve injuries include end-to-end repair, nerve grafting, conduit implantation, and stem cell therapy [10, 11]. However, these methods are highly dependent on the repairability of the neurons themselves. Activating the repair mechanism of damaged neurons can promote the recovery of neuronal function with conventional treatment methods and improve patient prognosis. Growth factors (GFs) are a family of proteins that regulate biological development and neural function, including regulating the survival of neurons, enhancing synaptic function recovery, and boosting axon growth and remodeling [12, 13]. In multiple drug treatment methods, the administration of exogenous GFs is an emerging and versatile therapeutic strategy for enhancing peripheral nerve regeneration and functional recovery [14, 15]. Furthermore, GFs alone or in combination with other methods can lead to better neural circuit reconstruction and functional recovery from spinal cord injury (SCI) [16]. Some GFs have been well investigated and employed in preclinical trials [14], such as brain-derived neurotrophic factor (BDNF) [17], fibroblast GF 2 (FGF2) [18], and neurotrophin-3, (NT-3) [19, 20].

The generation of a...