Research articleIntrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats
Introduction
Multiple sclerosis (MS) is a disease with multifactorial etiology and both genetic and environmental factors contribute to the risk of the disease [10]. Pathological hallmarks of this neuro-inflammatory disease are immune cell infiltration into the central nervous system (CNS) parenchyma, demyelination, and neurodegeneration [28]. Some treatment options are currently available for the early relapsing-remitting disease stage of MS which act mostly through modulation of the immune system. However, only a small number of therapies exist for the chronic progressive disease stage in which demyelination and neurodegeneration are pathological hallmarks [25]. Therefore, finding therapies that potentially restore the myelin sheath, re-establish efficient axonal conduction, and protect axons from secondary neurodegeneration has high priority in neurological research [8].
A recent study has re-invigorated interest in insulin-like growth factor 1 (IGF-1) as a potential therapy for neuro-inflammation [1]. Whereas IGF-1 was shown to be a potent promotor of developmental myelin formation [33], its potential to enhance remyelination remained controversial [6], [27], [32]. The functionally and structurally related hormone insulin could yet be another approach to boost remyelination. It shows some crossreactivity at the level of receptors, shares some signaling pathways with IGF-1 [21], [30] and has been shown to enhance remyelination in vitro [16], [29].
Here, we used lysolecithin injections into the spinal cord dorsal funiculi as a model of local demyelination, and compared the effects of chronic intrathecal infusion of IGF-1 or insulin on myelin repair in young and aged rats. Aged rats show weak innate remyelination and are therefore a good model for chronic demyelination, similar to the situation in progressive MS [24].
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Animals
Young (12–14 weeks, 200–300 g) and aged (12 months, 300–400 g) female Long Evans rats were used for all experiments (LE, strain code 006, Charles River, Italy). Rats were housed in a specific-pathogen-free (SPF) animal facility in groups of 3–4 rats under a constant 12 h light/dark cycle (light from 06:00 a.m. to 06:00 p.m.) with standard rodent chow and water ad libitum. All animal procedures and protocols were approved by the Veterinary Office of the Canton of Zurich, Switzerland.
Lysolecithin injections
Lysolecithin
Intrathecal IGF-1 or insulin did not alter food intake in rats
The lesions induced by our stereotaxic injections of lysolecithin were entirely located within the dorsal funiculi of the spinal cord. It has been shown before that low doses (7.5–10 mU/day) of intraventricular applied insulin reduce food intake and weight of rats [4], [12], [13]. Therefore, we monitored food intake of rats during the experiment. Neither IGF-1 at 100 μg/day nor insulin at 3U/day altered the amount of chow eaten (Fig. 2A, B), water intake (data not shown), or body weight (data not
Discussion
We investigated the role of the hormonal growth factors IGF-1 and insulin as potential remyelinating agents. Continuous intrathecal infusion of IGF-1 but not insulin promoted remyelination in both young and aged rats after induction of focal demyelination in the spinal cord.
It has been shown earlier that chronic intraventricular infusion of insulin at 7.5–10 mU/day causes a reduction in food intake and body weight [4]. We therefore monitored food intake and weight in rats chronically infused
Conflicts of interest
All authors declare that they have no conflict of interest. Role of the sponsor: neither the Swiss National Science Foundation, the Christopher and Dana Reeve Foundation the Swiss MS Society, nor the Hartmann-Müller Foundation had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The contents of this paper do not represent the
Author contributions
BVI and MH conceived the project; BVI, MH, AD, PSP, AG, NG, and MSS carried out the experiments and analyzed the data; DFL and MES provided critical input on the project design and data interpretation, as well as editing of the manuscript; BVI and MH wrote the manuscript.
Compliance with ethical standards
For all studies including animals, all applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal procedures and protocols were approved by the Veterinary Office of the Canton of Zurich, Switzerland. This article is written in accordance with the ARRIVE Guidelines [20].
Acknowledgements
This work was supported by the Swiss MS Society, the Hartmann-Müller Foundation, Zurich, the Desirée-and-Niels-Yde Foundation (to BVI) and an MD-PhD fellowship of the Swiss National Science Foundation (No. 323530_151488, to BVI). Dianne Figlewicz Lattemann is supported by a Senior Research Career Scientist award of the Dept. of Veterans Affairs.
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These authors contributed equally and share the first authorship.