Alterations in IGF-I, BDNF and NT-3 levels following experimental brain trauma and the effect of IGF-I administration

https://doi.org/10.1016/j.expneurol.2003.12.004Get rights and content

Abstract

The effects of a unilateral, penetrating brain trauma on IGF-I, BDNF and NT-3 were studied immunocytochemicaly in the rat. BDNF and NT-3 were decreased in the peritraumatic area, but increased in the adjacent region, 4 and 12 h post-injury. One week following the trauma, BDNF remained low in the peritraumatic area, but was restored to normal levels in the adjacent, while no effect of injury on NT-3 levels was detected in either area. Injury resulted in an increase in IGF-I levels in the peritraumatic area, which was most pronounced 1 week following the trauma, indicating that IGF-I could participate in endogenous repair processes. We thus administered IGF-I immediately following the trauma and investigated its effects on injury-induced changes in neurotrophin levels. Administration of IGF-I partially reversed the injury-induced decrease in BDNF and NT-3 in the peritraumatic area observed 4 and 12 h post-injury, while at the same time-points, it completely cancelled the effects of injury in the adjacent region. One week after the trauma, BDNF levels were dramatically increased in both the peritraumatic and adjacent area, reaching levels even higher than those of the sham-operated animals, following IGF-I administration. Our results showing that IGF-I not only counteracts injury-induced changes in neurotrophins, but can also further increase their levels, indicate that this growth factor could mediate repair and/or protective processes, following brain trauma.

Introduction

Traumatic brain injury (TBI) as a result of automobile or work accidents, or the use of guns, remains a major public health problem worldwide. According to recent estimations, approximately 500,000 new cases of TBI occur each year in the US alone. Among them, the incidence of penetrating head injuries is 12 per 100,000 and it increases considerably during war conflicts (Narayan et al., 2002). An increasing number of experimental results suggest that most of the long-term consequences of TBI are due to molecular and cellular changes that occur during the acute phase of the injury and which persist, or even progress, subsequently Bramlett et al., 1997, Dixon et al., 1999, McIntosh et al., 1998. The exact cellular mechanisms involved in the initiation and propagation of such secondary processes are not yet fully understood. In this context, the study of the injury-induced changes of molecules that act to regulate cell survival, such as neurotrophins and other growth factors, is essential.

The neurotrophin family consists of six highly homologous peptides: nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) as well as NT-4/5, NT-6 and NT-7 Barbacid, 1995, Lipton and Kalil, 1995. The differentiation, mitogenic and growth effects of neurotrophins are mediated by their interaction with a class of high affinity tyrosine kinase (trk) receptors and the low affinity p75 receptor Chao and Hempstead, 1995, Ebadi et al., 1997, Kaplan and Miller, 2000. BDNF was the second neurotrophin to be isolated and characterised (Leibrock et al., 1989) and acts mainly through the trkB receptor (Klein et al., 1991). NT-3 was cloned subsequently (Maisonpierre et al., 1990) and acts mainly through its high-affinity binding to the trkC receptor (Lamballe et al., 1991) and with low affinity to trkB (Klein et al., 1991). BDNF mRNA levels are low in the embryonic brain and increase rapidly during the early postnatal period, while NT-3 mRNA levels show the opposite developmental pattern of expression Ernfors et al., 1992, Maisonpierre et al., 1990. In the adult rat brain, BDNF mRNA is more abundant than that of NT-3 Conner et al., 1997, Ernfors et al., 1990, Guthrie and Gall, 1991, Hofer et al., 1990, Philips et al., 1990. BDNF has been shown to affect the survival and differentiation of cultured dopaminergic, cholinergic and cerebellar neurons Hyman et al., 1991, Knusel et al., 1991, Lindholm et al., 1993, while NT-3 supports the survival of adult sensory and motor neurons (Munson et al., 1997) and the differentiation of glial cells Cohen et al., 1996, Kumar et al., 1998. Interestingly, in addition to their “classical” neurotrophic role, BDNF and to a lesser extent NT-3, have been shown to play a role in activity-dependent changes in synaptic function in the adult brain Altar and DiStefano, 1998, Lessman, 1998, Lohof et al., 1993, Song et al., 1998.

A number of studies have focused on the post-traumatic changes in BDNF and NT-3 mRNA, in various models of brain as well as spinal cord injury Dougherty et al., 2000, Griesbach et al., 2002, Hicks et al., 1997, Hicks et al., 1999a, Hicks et al., 1999b, Hughes et al., 1999, Kokaia et al., 1995, Matzilevich et al., 2002, Nakamura and Bregman, 2001, Oyesiku et al., 1999, Scarisbrick et al., 1999, Skoglosa et al., 1999, Truettner et al., 1999, Wong et al., 1997, Yang et al., 1996, Yurek and Fletcher-Turner, 2001. However, the determination of the parallel changes of the peptides of neurotrophins is essential, particularly because there is evidence that neurotrophins are retrogradely and anterogradely transported—especially following axonal injury—and thus are present and act in areas remote to the site of their synthesis Altar and DiStefano, 1998, Curtis et al., 1998, Tonra et al., 1998.

Insulin-like Growth Factor-I (IGF-I) is a 7.5-kDa peptide with structural homology to proinsulin. IGF-I actions are mainly mediated by the type-I IGF receptors (IGF-IR) that belong to the family of insulin tyrosine kinase membrane receptors (de Pablo and de la Rosa, 1995). Its bioavailability is mainly regulated by six high-affinity binding proteins (IGFBP1-6), which bind IGF-I in the circulation and the extracellular matrix (Jones and Clemmons, 1995). While IGF-I is widely expressed in the foetal and neonatal rat brain, its presence in the normal adult rat brain is very limited (de Pablo and de la Rosa, 1995). In the adult organism, the major source of IGF-I is the liver, and IGF-I is thought to have an anabolic role, mainly by mediating the actions of Growth Hormone. However, during the last decade, several different studies have shown that IGF-I is strongly induced in the CNS after different traumatic brain injuries such as ischemia Beilharz et al., 1998, Schwab et al., 1997 and cortical injury Li et al., 1998, Nordqvist et al., 1996, Walter et al., 1997 as well as after injury of the spinal cord (Yao et al., 1995). Furthermore, IGF-I is suggested to be associated with repair processes after brain damage and with the control of regeneration of injured peripheral nerves, for example, in models of motor neuron disease (Dore et al., 1997) and to ameliorate the clinical outcome in animal models of amyotrophic lateral sclerosis (Dore et al., 1997). Following CNS injury, IGF-I is shown to exert its mitogenic and trophic effects on a variety of cell-types. The most prominent action of IGF-I is exerted on the proliferation and maturation of oligodendroglial cells and their precursors (McMorris et al., 1996), but it has also been shown to regulate astroglial responses after injury (Fernandez et al., 1997). Interestingly, recent results show that IGF-I may even act to regulate neurogenesis in the adult rat hippocampus (Aberg et al., 2000).

In this study, we used a model of focal, unilateral penetrating brain injury to examine the changes in neurotrophin BDNF and NT-3 levels. In addition, we examined the expression of IGF-I to assess whether this factor participates in the endogenous response of brain tissue to trauma. Subsequently, we studied the effect of post-traumatic IGF-I administration on BDNF, NT-3, as well as IGF-I levels.

Section snippets

Animals

Adult male Wistar rats weighing 200–250 g were used in all experiments. Animals were maintained under controlled temperature (25°C) and lighting conditions (12:12 h light–dark cycle) and given free access to rat chow and tap water. All experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and all measures were taken to minimize pain or discomfort of the animals.

Brain injury-treatment with IGF-I

Animals were anaesthetised with chloral hydrate (400 mg/kg body

Results

The penetrating injury, used in our experimental model of brain trauma, resulted in a variety of cellular changes detectable in the peritraumatic area, which included the cortex and the hippocampus, as well as the area adjacent to the peritraumatic zone (Fig. 1A). Changes were also observed in one brain area remote from the site of the lesion, the anterolateral hypothalamic area (aha) (Fig. 1A).

Discussion

The post-lesion histological examination of the brain tissue revealed that our model of injury possessed some characteristic features of penetrating injuries, observed both in animal models and in cases of human injuries. Such features were the appearance of a “conical tunnel” at the site of entrance of the foreign body, the formation of a peritraumatic area in which intraparenchymal haematomas and tissue of spongiform morphology were found as well as the appearance of a typical astroglial scar

Acknowledgements

This work was supported by the University of Athens, Special Account for Research. Anti-GFAP antibody was kindly provided by Dr. R. Matsas to which we are deeply grateful.

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