Research report Neuroprotective effects of insulin-like growth factor-I (IGF-I) following a penetrating brain injury in rats Ilias Kazanis, Evangelos Bozas, Helen Philippidis, Fotini Stylianopoulou * Laboratory of Biology–Biochemistry, Faculty of Nursing, University of Athens, 123 Papadiamantopoulou Str., 115 27, Athens, Greece Accepted 31 July 2003 Abstract The elucidation of the molecular mechanisms involved in the response of brain tissue to trauma and the recognition of substances with neuroprotective properties is a prerequisite for the development of rational therapeutic approaches. In this study, we used a model of, unilateral, penetrating stab-like brain injury and examined the possible beneficial effects of post-injury administration of insulin-like growth factor-I (IGF-I) both at the cellular level, 4 and 12 h post-injury, and on the physical condition of the animals up to 1 week following the trauma. The consequences of injury were assessed by immunohistochemically observing the expression of heat-shock protein 70 (Hsp70), which is thought to be a marker of cell stress and injury, and by staining the tissue with the TUNEL reaction, in order to detect apoptotic cell death. Injury resulted in an increase in the number of Hsp70 and TUNEL positive cells in the peritraumatic area. The physical condition of the rats was followed by measuring body weight changes, food and water intake and by estimating their ‘‘motor activity’’. IGF-I administration resulted in a significant decrease in the number of Hsp70 and TUNEL positive cells in the peritraumatic area. Additionally, it improved the total ‘‘motor activity’’ of injured rats, increased food intake and attenuated the post-injury body weight loss. IGF-I thus emerges as a factor acting both at the cellular level as a neuroprotectant and at the systemic level as an anabolic agent. D 2003 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Trauma Keywords: Brain injury; Hsp70 (heat-shock protein 70); TUNEL; IGF-I (insulin-like growth factor-I); Food intake; Neuroprotection 1. Introduction Head injuries incurred in automobile or work accidents or as a result of the use of guns constitute a major health problem [27,35]. The financial impact of head injuries is also significant; as for only the year 1990, it was estimated to reach the sum of 50 billion dollars [3], in addition to the social and emotional burden to the patients’ families. Up to now, treatment of head injuries is limited to alleviating the symptoms and consists mainly in hyperventi- lation of the patients and stabilization of cerebral blood flow. Thus, there is a great interest in the development of rational therapeutic approaches to deal with this important health problem. Good candidates for this role are the growth factors. Growth factors are peptides with mitogenic properties on a variety of target-cells that also mediate cell differentiation and tissue repair. Among this large family of molecules, recent studies have shown insulin-like growth factor-I (IGF- I) to have beneficial effects in the treatment of amyotrophic lateral sclerosis [12,13] and to possess a regulatory auto- crine/paracrine action in response to brain injury [50]. 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 [10]. Its bioavailability is mainly regulated by six high affinity-binding proteins (IGFBP1-6), which bind to IGF-I in the circulation and the extracellular matrix [26]. While IGF-I is widely expressed in the foetal and neonatal rat brain, its distribution in the normal adult rat brain is very limited [10]. In the adult organism, the liver is the major source of IGF-I, which has an anabolic role, mainly by mediating the actions of growth hormone (GH). However, during the last decade, a number of different 0006-8993/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0006-8993(03)03525-X * Corresponding author. Tel.: +30-210-7461467; fax: +30-210- 7461489. E-mail address: fstilian@cc.uoa.gr (F. Stylianopoulou). www.elsevier.com/locate/brainres Brain Research 991 (2003) 34 – 45