TiO2 nanowired delivery of cerebrolysin induces superior neuroprotection following exacerbation of blast brain injury pathophysiology in diabetes

D.F. Muresanu, A. Sharma, J.V. Lafuente, A. Nozari, R. Patnaik, A. Nozari, A. Ozkizilcik, Z.R. Tian, H. Mössler, H.S. Sharma
University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania,

Keywords: blast brain injury, diabetes, nanowired drug delivery, cerebrolysin


Blast brain injury (bBI), a combination of pressure, rotation, penetration of sharp objects and chemical exposure is prevalent in military personnel during combat operations causing laceration, perforation and tissue loss in the brain. Since combat stress could induce wide variety of cardiovascular and endocrine deregulation, it is unclear whether bBI could exacerbate brain pathology in diabetes. Thus, in present investigation influence of diabetes on bBI was investigated in a rat model. bBI was produced using a shock tube blast devise in which compressed air-and compressed helium-driven membrane rupture induces pressure waves to simulate some aspects of bBI. The rats were anesthetized with Equithesin (3 ml/kg, i.p.) and their head was exposed to overpressure blast (100, 150 or 200 kPa) in the shock-tube with a shockwave velocity of ca. 400 to 450 m/sec). After the bBI the animals were allowed to survive 8 and 12 h after trauma. Identical procedures were applied for bBI in diabetic rats that were produced by streptozotocine (50 mg/kg, i.p.) administration once daily for 3 days. The animals develop clinical diabetes after 4 to 6 weeks (blood glucose level 220-25 mM/L, control 5-6 mM/L). In both normal and diabetic rats blood-brain barrier breakdown to Evans blue albumin and radioiodine ([131]-I), brain edema formation and neuronal, glial and axonal injuries were evaluated. In addition, regional cerebral blood flow (rCBF) was also examined using standard procedures. A progressive increase in the BBB permeability to EBA and radioiodine in the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus and brain stem was seen that correlates well with the blast overpressure strength. In these brain areas rCBF was reduced by -30 to -58 %. Brain edema formation as measured using water content exhibited a 2- to 4 % increase (ca. 8 to 16 % volume swelling). Expansion of neuropil, sponginess and neuronal, glial and myelin damages are quite frequent. These pathophysiological changes were 2-to 5-fold exacerbated in diabetic animals after bBI. Treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) 30 min to 1 h after bBI (5 to 10 ml/kg, i.v.) significantly reduced brain pathology in normal animals. However, TiO2 nanodelivery of cerebrolysin (5 ml/kg, i.v.) is needed to induce neuroprotection in bBI in diabetic animals. These observations are the first to show that (i) bBI is exacerbated in diabetes, (ii) cerebrolysin has the potential to reduce brain pathology in bBI in healthy animals, whereas, TiO2-nanowired cerebrolysin is needed to induce neuroprotection in diabetic animals after bBI, not reported earlier.