NEUROPROTECTION IN ALZHEIMER'S DISEASE BY NANODELIVERY OF NEPRILYSIN WITH CEREBROLYSIN

Neprilysin (NPL) is an endogenous enzyme that functions as rate-limiting step in amyloid-beta peptide (AbP) degradation. An imbalance between production and clearance of AbP results in its accumulation leading to Alzheimer’s disease (AD). In several cases of AD brain concentration of NPL is decreased. Also NPL knocked out mice exhibited AD like brain pathology and behavioural dysfunctions. This suggests that enhancing the NPL concentartions may reduce AD brain pathology. Since traumatic brain injury (TBI) alone could results in deposition of AbP and reduction in NPL in the brain. Thus, it would be interesting to explore whether TBI could further exacerbate AbP infusion induced brain pathology and enhancing the NPL level has any protective effects in Ad models either alone or together with other neuroprotective gents e.g., cerebrolysin. AD like brain pathology was induced by AbP (1-40) administration intraventricularly (i.c.v.) in the left lateral ventricle 250 ng/10 µl once daily for 4 weeks in control or in rats following TBI. The TBI was produced by a longitudinal incision over the right parietal cerebral cortex (2 mm deep and 4 mm long) after opening of the skull under anesthesia. After 30 days of the 1^st AbP infusion, the rats exhibited breakdown of the blood-brain barrier (BBB) to proteins, brain edema formation, and AbP deposits in several parts of the brain. The brain pathology showed neuronal, glial and axonal changes. In separate group of rats, TiO2 nanowired Cerebrolysin (25 µl, NWCBL) and/or TiO2 nanowired NPL (1 µg in 10 µl) was infused into the left cerebral ventricles daily starting from 1 week after the onset of AbP infusion and terminated 1 week before the last infusion. Our results show that AbP infusion in TBI group exacerbated brain pathology in cerebral cortex, hippocampus, thalamus, hypothalamus and cerebellum. TiO2 NWCBL or NPL alone was able to thwarts brain pathology in AD cases in healthy and rats. On the other hand a combination of NWCBL and NW-NPL resulted in profound neuroprotection in TBI following AbP infusion indicating that a combination of nanodelivered NPL and CBL has additive effects on neuroprotection in AD, not reported earlier.