TiO2 Nanodelivery of Cerebrolysin Reduces Brain Pathology in Parkinson's Disease

Objectives:Parkinson’s Disease (PD) is a severe lifetime motor neuron degenerative disease affecting more than 80 000 Americans each year. The cost estimate for treatment and work loss is considered to be higher than 25 Billion US dollar per year. Thus, detailed knowledge on the factors affective PD and its modulation with novel drug strategies are needed to enhance quality of life of PD victims. There are reasons to believe that stress and environmental factors affect PD pathology generating oxidative stress leading to brain pathology. Since sleep deprivation  (SD) is a profound stress in Military, we examined role of SD on PD pathology in a mouse model. Furthermore, neuroprotective effects of a Cerebrolsyin, a multimodal drug containing several neurotrophic factors and active peptide fragments were examined on brain pathology in PD using normal and nanowired delivery. Methods:SD was induced in mice using an inverted flowerpot model for 24 and 48 hours. The PD like symptoms were induced by four injections of METH (10 mg/kg, i.p.) or MPTP (20 mg/kg, i.p.) within two h intervals daily for 5 days. In separate groups Normal Cerebrolysin (5 or 10 ml/kg, i.v., Ever NeuroPharma, Austria) or TiO2 Nanowired-Cerebrolsyin was administered in identical manners for one week and brain pathology was examined. Results: On the 8^thday, METH or MPTP reduced the dopamine (DA) content in striatum (ST) (control 26±4 ng/mg protein to MPTP 5±2 ng/mg protein; METH 6±2 ng/mg protein, P <0.01) that were further reduced (-30 to -50 %) in SD mice.  Pronounced activation of microglia, astrocytes and neuronal damages together with loss of tryptophan hydroxylase (TH) positive neurons in striatum (ST) and substantia niagra (SN) occurred in MPTP or METH treated mice that were further exacerbated in SD mice in a time dependent manner. Treatment with Cerebrolsyin (5 ml) significantly reduced these brain pathologies in normal mice but require higher dose of the compound (10 ml) for neuroprotection in SD mice.  Interestingly, TiO2-delivered cerebrolysin was quite effective in reducing brain pathology in SD mice following PD like symptoms in a dose of 5 ml. In normal mice TiO2-nanowired cerebrolysin only 2.5 ml was needed to induce marked neuroprotection and restoration of DA levels. Conclusions: These observations are the first to show that the SD could aggravate PD pathology and nanowired delivery of cerebrolysin could be a new useful tool in attenuating brain pathology in PD, not reported earlier.