TiO 2 -nanowired delivery of cerebrolysin thwarts exacerbation of sleep deprivation induced decline in regional brain derived neurotrophic factor, brain pathology and behavioral dysfunctions following emotional stress Aruna Sharma 1,3,4 , Dafin Fior Muresanu 2,3 , José Vicente Lafuente 4,9,10 , Ala Nozari 5 , Ranjana Patnaik 6 , Asya Ozkizilcik 7 , Z Ryan Tian 8 , Herbert Mössler 3 , Hari Shanker Sharma 1,3,4 1 International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine,Uppsala University Hospital, Uppsala University, SE-75185 Uppsala, Sweden Email: Sharma@surgsci.uu.se; Aruna.Sharma@surgsci.uu.se 2 Dept. Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; 3 ‘‘RoNeuro’’ Institute for Neurological Research and Diagnostic, 37 Mircea Eliade Street, 400364, Cluj-Napoca, Romania 4 LaNCE, Dpt. Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain 5 Anesthesiology, Massachusetts General Hospital, Harvard University, Boston MA, USA 6 School of Biomedical Engineering, Dept. of Biomaterials, Indian Institute of technology, Banaras Hindu University, Varanasi, India 7 Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA 8 Dept. Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA 9 Nanoneurosurgery Group, BioCruces Health Research Institute, 48903 Barakaldo, Bizkaia, Spain 10 Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile ABSTRACT Sleep deprivation (SD) is a serious problem in military personnel during combat operations. Normally they have only a few hours of sleep under severe stressful conditions. In this innovation we demonstrated that a combination of emotional stress and sleep deprivation (SD) exacerbates brain pathology and behavioral dysfunction in a rat model. Thus, in these animals several fold increase in BBB permeability to Evans blue albumin (EBA) and radioiodine ( [131] -I) was observed in several brain regions associated with neuronal injuries as compared to normal animals after SD. Behavioral disturbances were also exacerbated in this model. Interestingly, the brain derived neurotrophic factor (BDNF) levels showed greater decline in stressed animals after SD. Treatment with cerebrolysin (2.5 ml/kg, i.v.) in normal rats 4 to 6 h after SD significantly increased BDNF levels and reduced brain pathology. However, in stressed rats after SD TiO2 nanowired cerebrolysin (2.5 ml/kg, i.v.) is needed to enhance BDNF levels and attenuate brain pathology. TiO2 nanowired cerebrolysin also improved behavioral functions significantly in stressed rats after SD. These observations are the first to show that nanodelivery of cerebrolysin has profound neuroprotective effects in SD following emotions stress, not reported earlier. Keywords: Sleep deprivation in Military, brain pathology, Brain derived neurotrophic factor, Cerebrolsyin, nanodelivery, Immobilization stress 1 INTRODUCTION Sleep deprivation (SD) is a serious problem in military personnel during combat operations. Normally they have only a few hours of sleep under severe stressful conditions [1]. This leads to profound mental and cognitive dysfunctions. Previous studies from our laboratory show that 12 to 48 h of SD results in widespread breakdown of the blood-brain barrier (BBB) associated with brain edema and cellular injuries. Since emotional stress is always associated with SD in military, in this investigation we examined a combination of emotional stress and SD on brain pathology and behavioral dysfunction in a rat model [1,2]. To understand the role of neurotrophic factor in SD and emotional stress we measured regional distribution of brain derived neurotrophic factor (BDNF) and Insulin like growth factor-1 (IGF-1) in SD. In addition, we used exogenous supplement of Cerebrolysin alone or tagged with nanowires (TiO2- nanowired cerebrolysin) that is a balanced composition of several neurotrophic factors and active peptide fragments [4-6] to reduce SD induced brain pathology and behavioral dysfunction. 83 Biotech, Biomaterials and Biomedical: TechConnect Briefs 2017