Neuroprotective effects of cerebrolysin in exacerbation of blood-brain barrier breakdown, neuropathology and upregulation of nitric oxide synthase and hemeoxygenase in diabetes and hypertension after heat stroke

D.F. Muresanu, A. Sharma, J.V. Lafuente, A. Nozari, R. Patnaik, A. Ozkizilcik, Z.R. Tian, H. Mössler, H.S. Sharma
Iuliu Hațieganu University of Medicine and Pharmacy,

Keywords: heat stroke, diabetes, nitric oxide synthase, hemeoxygenase, neuroprotection, cerebrolysin


Military personnel are often exposed to heat stress in desert areas either during peacekeeping or combat operations. In such situations, they are quite vulnerable to heat stroke and brain pathology. Due to severe work stress and irregular food habits they often develop hypertension and diabetes. A combination of heat stress with diabetes and hypertension could adversely affect their brain function resulting in mental abnormalities. Thus, efforts are needed to find out suitable therapeutic strategies to reduce mortality or morbidity caused by heat stroke alone. It appears that heat stroke induced formation of free radicals could play important roles. Nitric oxide (NO) and carbon monoxide (CO) are free radical gases that are synthesized within the within the neurons, glial and endothelial cells by the enzymes nitric oxide synthase (NOS) and hemeoxygenase (HO) respectively. Massive expression of NOS and HO could contribute to breakdown of the blood-brain barrier (BBB), edema formation and neuronal injuries. Previous studies in our laboratory show that upregulation of NOS and HO occurs following whole body hyperthermia (WBH) at 38° for 4 h that is similar to clinical symptoms of brain pathology and heat stroke (HS). In separate group rats hypertension was produced by one two kidney one clip (2K1C) method and in these animals diabetes was induced by streptozotocine (50 mg/kg, i.p. for 3 consecutive days). When these diabetic and hypertensive (DBHY) rats were subjected to identical WBH these stoke symptoms and brain pathologies are exacerbated. However, upregulation of NOS and HO in DBHY rats after WBH is not well known. Thus, a possibility exists the DBHY rats after WBH may induce exacerbation of NOS and HO upregulation that could to aggravation of brain pathology. Since cerebrolysin is a balanced composition of several neurotrophic factors and active peptide fragments, in this investigation we examined the influence of nanodelivered cerebrolysin on NOS and HO upregulation in DBHY rats after WBH in relation to brain pathology in the rat model. WBH in DBHY rats resulted in several fold fold greater overexpression of neuronal NOS (nNOS) and constitutive isoform of HO (HO-2) in the cerebral cortex, hippocampus, caudate nucleus, thalamus, hypothalamus, cerebellum and brain stem than identical WBH in normal animals. BBB breakdown, brain edema and neuronal injuries were also exacerbated by several folds in DBHY rats [Fig. 1]. Treatment with TiO2 nanodelivered cerebrolysin (2.5 ml/kg, i.v.) 1 or 2 h after a 4 h WBH significantly reduced NOS or HO expression and prevented brain pathology in DBHY rats after WBH. Normal animals after WBH require 10 ml/kg, i.v. cerebrolysin to achieve neuroprotection. These observations are the first to show that nanowired cerebrolysin is capable to attenuate HO and NOS production and brain pathology following heat stroke in diabetes, not reported earlier.