Nanodelivery of Chinese traditional medicine extract of Gingko Biloba (EGb-761) induces superior neuroprotection following traumatic brain injury in heat stroke

A. Sharma, D.F. Muresanu, J.V. Lafuente, Z-Q Zhang, C. Li, R. Patnaik, Z.R. Tian, A. Ozikzilcik, H.S. Sharma
Uppsala University, Uppsala,
Sweden

Keywords: heat stroke, traumatic brain injury, EGb-761, BN-52021, nanowired delivery, neuroprotection

Summary:

Military personnel are often exposed to high summer heat resulting in heat stroke (HS) and related illnesses. HS often results in serious mental and physical consequences due to breakdown of the blood-brain barrier (BBB) to proteins, edema formation and cellular injuries. Previous results from our laboratory show that pretreatment with EGb-761 (50 mg/kg, p.o.) with or without bilobalide BN-52021 (2 mg/kg, p.o.) daily for 5 days resulted in profound neuroprotection in HS [1]. This effect of EGb-761 and/or BN-52021 is mediated through their antioxidant properties. However, our military personnel engaged in combat operations at high environmental temperature often receive traumatic brain injury (TBI) either piercing or blunt head trauma. This double CNS insults exacerbate brain pathology and functional outcome that require suitable therapeutic measures urgently. In this innovation we used TiO2 nanowired EGb-761 and BN-52021to treat TBI in HS for the first time. We have shown that TBI in HS exacerbate BBB breakdown, edema formation and cellular injuries by 3- to 6 fold depending on the duration of survival. In this investigation, rats were exposed to 2 h HS daily for 8 days in a biological oxygen demand (BOD) incubator for 4 h that does not induce brain pathology. On the 8th day, the animals were traumatized under Equithesin anesthesia by making a longitudinal lesion into the parietal cerebral cortex (2.5 mm deep and 4 mm long) after opening of the parietal bone (4mm2). Eight hours after TBI in HS exhibited 4- to 6 times greater BBB leakage to Evans blue and [131]-Iodine, 5-to 6 fold increase in brain edema in the injured side and 4- to 6-fold higher neuronal damages in the remote cortical tissues in the injured hemisphere as compared to identical TBI in naïve rats. Treatment with EGb-761 with BN-52021 in identical disease only reduced brain damage by 20 to 30 % following TBI in HS. However, when TiO2 nanowired EGb-761 or TiO2 BN-52021 were administered in identical doses more than 80 % reduction in brain pathology was observed following TBI in HS. The functional outcome e.g., walking on a tilted mesh grid (45°), staying on a Rota Rod treadmill (16 r.p.m.) and finding placing of forepaw on a wire mesh were significantly reduced by TiO2 nanowired EGb-761 and BN-52021 treated group after TBI in HS. When EGb-761 and BN-52021 were given separately suing nanowired delivery, the effects of EGB-761 were more superior than BN-52021 alone. These observations suggests that nanodelivery of EGb-761 in TBI following HS has a potential therapeutic value in TBI in HS that require further investigation. References 1. Sharma HS, Drieu K, Westman J. Antioxidant compounds EGB-761 and BN-52021 attenuate brain edema formation and hemeoxygenase expression following hyperthermic brain injury in the rat. Acta Neurochir Suppl. 2003;86:313-9.