Nanodelivery of cerebrolysin reduces functionalized Gold Nanoparticles induced Blood-brain barrier disruption, brain edema formation and brain pathology

A. Sharma, P.K. Menon, D.F. Muresanu, J.V. Lafuente, A. Nozari, R. Patnaik, A. Ozkizilcik, Z.R. Tian, H. Mössler, H.S. Sharma
Uppsala University,
Sweden

Keywords: AuNPs, neurotoxicity, nanodelivery of cerebrolysin, brain pathology, neuroprotection

Summary:

Recently, gold nanoparticles (AuNPs) are used for drug delivery in treating several neurological disorders e.g., Alzheimer’s disease (AD), Parkinson’s disease, Stroke and trauma. In addition, use of AuNPs for diagnostic purposes in various diseases are also common in clinical medicine. However, the neurotoxic effects of AuNPs in vivo studies are not well explored. Thus, it would be interesting to examine AuNPs neurotoxicity in vivo models in relation to size related effects on brain pathology. We examined the effects of moderate doses of AuNPs of 3 different sizes (5 nm, 10 nm and 40 nm) administered either though intraperitoneally (10 mg/kg, i.p.), intravenously (5 mg/kg, i.v.), intracarotidly (2 mg/kg, i.c.a.) or intracerebroventricularly (20 µg in 20 µl, i.c.v.) in rats (Age 20 to 25 weeks). Blood-brain barrier (BBB) breakdown to Evans blue albumin (EBA 3 ml/kg, i.v.) and [131]-Iodine (100 µCi/kg, i.v.) was examined 24 h after AuNPs administration in the brain in relation to edema formation and neuronal or glial injuries using standard procedures. Marked BBB breakdown in several brain areas e.g., cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus and brain stem was seen following administration of 5 to 10 nm AuNPs irrespective of the routs of administration after 24 h. However, intracarotid administration exhibited more profound leakage of these tracers in the ipsilateral side whereas i.c.v. administration showed leakage of tracers on the dorsal surface of the ipsilateral hemisphere. Brain edema and neuronal injuries were tightly correlated with BBB breakdown. Activation of astrocytes and neuronal damages were also evident in the areas showing BBB leakage. Interestingly, there was an inverse relationship between AuNPs size and brain damage. Interestingly, co-administration of cerebrolysin (2.5 ml/kg, i.v.) using TiO2 nanowired delivery significantly reduced the BBB breakdown, edema formation and brain damage following AyNPs administration to any route after 24 h. These observations are the first to show that AuNPs induced neurotoxicity is size and rote of administration related and nanodelivery of cerebrolysin significantly attenuate AuNPs neurotoxicity. This indicates that cerebrolysin could be sued as an adjunct therapy where AuNPs are employed either for therapeutic or diagnostic purposes.