D.F. Muresanu, A. Sharma, J.V. Lafuente, R. Patnaik, Z.R. Tian, A. Ozikzilcik, H. Mössler, H.S. Sharma
University of Medicine & Pharmacy,
Keywords: ubiquitin carboxyl-terminal esterase-L1 (UCHL1), Cerebrolysin, TiO2-nanodelivery, brain pathology, Alzheimer's Disease
Summary:Our military personnel during combat operations are vulnerable to various kinds of traumatic brain injuries. These soldiers are prone to develop neurodegenerative diseases e.g., Alzheimer’s Disease (AD) over time. Thus, efforts should be made to reduce the consequences of brain injury or development of AD pathology. Recent studies show that brain injury alone or followed by AD leads to enhanced levels of plasma and cerebrospinal fluid (CSF) concentrations of neuron-specific ubiquitin carboxyl-terminal esterase-L1 (UCHL1). The kevel of UCHL1 correlates well with neurological symptoms of AD as well as brain pathologies. The UCHL1 is a protein selectively expressed in neurons due to alterations in ubiquitin proteasome pathways. An accumulation, overload or malfunction of UCHL1 results in protein aggregation in the AD brain This would result in structural changes in the protein substrates thereby preventing the recognition and degradation of Amyloid beta protein (AbP) by the UCHL1. Altered UCHL1 levels indicate defective proteolysis that could cause synaptic dysfunction as well as clearance of AbP from the brain. Thus, regulation of UCHL1 for therapeutic purposes may affect the pathogenesis of AD. There are also reports that UCHL1 is facilitating lysosomal degradation of Amyloid precursor protein (APP) by increasing free ubiquitin levels. Thus, it remains to be seen whether enhanced levels of UCHL1 is reducing the AD pathology in the brain or multimodal drugs e.g., cerebrolysin that is known neuroprotective agent in AD may affect UCHL1 regulation in AD. AD like brain pathology was induced by AP (1-40) administration intraventricularly (i.c.v.) in the left lateral ventricle 250 ng/10 µl once daily for 4 weeks. After 30 days of the 1st AP infusion, the rats exhibited breakdown of the blood-brain barrier (BBB) extravasation of endogenous/exogenous protein tracers, brain edema formation, AP deposits in several parts of the brain. The brain pathology showed neuronal, glial and axonal changes. In these AD brains the UCHL1 measured using ELISA showed profound rise by 250 to 300 % in the cortex, hippocampus and cerebellum in association with AP deposits, gliosis and neuronal damages. When TiO2 nanowired Cerebrolysin (25 µl, NWCBL) was infused into the left cerebral ventricles daily starting from 1 week after the onset of AP infusion and terminated 1 week before the last infusion, there was a significant reduction in the UCHL1 levels in various parts of the brain as well ass brain pathology was significantly reduced. Neuronal loss, gliosis and AbP deposits were significantly reduced indicating that UCHL1 is modulating AD pathology, not reported earlier. On the other hand normal cerebrolysin when administered in higher doses (100 µl) under identical conditions was able to achieve comparable reduction inUCHL1 level and pathological changes in the above brain areas. This indicates that TiO2 nanodelivery has superior effects on UCHL1 level resulting in reduction in AD pathology, not reported earlier.