H.S. Sharma, J.V. Lafuente, D.F. Muresanua, R.J. Castellani, M.A. Smith, A. Nozari, R. Patnaik, Z.R. Tian, A. Ozkizilcik, H. Mössler, A. Sharma
Uppsala University, Uppsala,
Keywords: traumatic brain injury, hot environment, amyloid beta peptide, tau protein, cerebrolysin
Summary:Military personnel are often exposed to high environmental temperature in desert areas during combat operations. Since traumatic brain injury (TBI) is quite common in combat operation, a possibility exists that hot environment (HE) could affect pathophysiology of TBI. However, effects of HE on TBI are not well known. Previous reports show that hyperthermia duirng TBI could worsen the pathological outcome. However, TBI induced pathophysiological outcome following HE still require further investigation. TBI induces increase in amyloid beta peptide (AbP) and tau protein in the brain and in the cerebrospinal fluid (CSF). AbP and tau are responsible for neuronal, glial and microvascular damages leading to breakdown of the blood-brain barrier (BBB) and vasogenic edema formation. However, effects of HE on AbP and tau are unknown. In present investigation we examined whether TBI could induce an increased production of AbP and tau in HE. Furthermore to understand the role of tau in neuropathology we infused tau antibodies [Anti-Tau antibody [E178, ab32057) together with cerebrolysin (a known neuroprotective agent) in the CSF after TBI with HE. TBI was inflicted by dropping a weight of 114.6 g from 20 cm height on the exposed parietal skull bone in Equithesin anaesthetized rats acclimatized at 21±1°C (room temperature) or exposed to 34°C for 4 h per day for 2 weeks in biological oxygen demand incubator (BOD, relative humidity 45-47 %, wind speed 20-25 cm/sec). Exposure to HE alone did not result in BBB breakdown, edema formation or changes in AbP or tau levels. However, TBI in HE animals resulted in about 2-to 3-fold higher breakdown of the BBB to Evans blue albumin and radioiodine (-I) and neuronal, glial and axonal damage as compared to TBI in rats at room temperature after 24 trauma. The AbP and tau levels in TBI group after heat exposure increased by 2- to 6-fold in the CSF (control AbP ng/ml 0.23±0.04; TBI 0.82±0.05; TBI+HS 2.34±0.12; Control tau pg/ml 20±2; TBI 34±6; TBI+HS 76±8). Treatment with cerebrolysin (5 ml/kg, i.v.) together with 50 µl 1:20 tau antibodies i.c.v. 4 h after injury resulted in reduction of tau and AbP levels and brain pathology in TBI but failed to induce neuroprotection in HE group. However, when TiO2-nanowried cerebrolysin was co-administered with nanowired tau antibodies in identical conditions pronounced neuroprotection was observed in HE group with TBI. Also the tau and AbP levels were considerably reduced (AbP ng/ml 0.33±0.08; tau pg/ml 18±6) in the CSF of HE rats after TBI. This indicates that both AbP and tau levels are somehow responsible for enhanced brain pathology in TBI following HE and nanodelivery of cerebrolysin with tau antibodies have superior neuroprotective effects, not reported earlier.