Reduced Fragmentation of IGFBP-2 and IGFBP-3 as a Potential Mechanism for Decreased Ratio of IGF-II to IGFBPs in Cerebrospinal Fluid in Response to Repeated Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis.

Andreas Hoeflich,Armin Tuchscherer,Julia Brenmoehl,Brit Fitzner,Christina Walz,Michael Hecker,Uwe Klaus Zettl

doi:10.3389/fendo.2020.565557

Andreas Hoeflich, Armin Tuchscherer + Show 5 more

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https://doi.org/10.3389/fendo.2020.565557

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the brain and spinal cord causing a wide range of symptoms such as impaired walking capability, spasticity, fatigue, and pain. The insulin-like growth factor (IGF) system has regulatory functions for the induction of inflammatory pathways in experimental encephalomyelitis. We have therefore assessed expression and regulation of the IGF system on the level of IGFs and IGFBPs in serum and cerebrospinal fluid (CSF) in the course of four repeated triamcinolone acetonide (TCA) administrations in two female and four male MS patients. Sample series of 20 treatment cycles were analyzed. IGF-I and IGF-II were quantified by ELISAs, and IGFBPs were analyzed by quantitative Western ligand (qWLB) and Western immunoblotting (WIB) in order to differentiate intact and fragmented IGFBPs. The ratios of fragmented to intact IGFBP-2 and -3 were calculated in serum and CSF. Finally, the ratios of IGF-I and IGF-II to the total IGF-binding activity, quantified by qWLB, were determined as an indicator of IGF-related bioactivity. After the fourth TCA administration, the average level of IGF-I was increased in serum (p < 0.001). The increase of IGF-I concentrations in serum resulted in an increased ratio of IGF-I to IGFBPs in the circulation. By contrast in CSF, fragmentation of IGFBP-2 and IGFBP-3 and the ratio of IGF-II to intact IGFBPs were decreased at the fourth TCA administration (p < 0.01). Furthermore, reduced fragmentation of IGFBP-3 in CSF was accompanied by increased concentrations of intact IGFBP-3 (p < 0.001). We conclude that reduced fragmentation of IGFBPs and concomitant reduction of IGF-II to IGFBP ratios indicate regulation of bioactivity of IGF-II in CSF during repeated intrathecal TCA administration in MS patients.

Highlights

Multiple SclerosisMultiple sclerosis (MS) is a chronic progressive disease of the central nervous system that often manifests in young adulthood and in women
If gender was included in the statistical model, the male groups was characterized by higher concentrations of insulin-like growth factor (IGF)-I in all serum samples (p < 0.01; data not shown)
IGF-I is required for brain growth and development, and the lack of IGF-I in knockout mice resulted in reduced brain growth and hypomyelination [6]

Summary

Introduction

Multiple SclerosisMultiple sclerosis (MS) is a chronic progressive disease of the central nervous system that often manifests in young adulthood and in women. In the course of the disease, MS patients develop a variety of neurological symptoms such as depression, fatigue, paresis, and spasticity, the latter leading to severe impairment of the patients’ abilities, pain, and contractures [2]. Therapeutic options for MS-related spasticity include oral applications of gamma-aminobutyric acid agonists, centrally acting a2 adrenergic agonists, postsynaptic muscle relaxants, and hydrochloride salts [2, 3]. Another option for MS patients with predominantly spinal cord symptoms such as spasticity is the intrathecal injection of sustained-release steroids such as triamcinolone acetonide (TCA) [4]. Due to its invasive application form, repeated TCA administration is restricted to highly selected patients and applied only at experienced MS centers

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