Develop drug to treat neurodegenerative disease
Currently there are no treatments that can reverse or even halt
the progress of neurodegeneration. Inflammation is the major component
of all neurodegenerative disease including Multiple
sclerosis, Alzheimer, Parkinson’s disease. So, I am particularly
interested to identify novel anti-inflammatory agent as potential
Neuroprotective agents. Also, the effects of a range of novel
anti-inflammatory compounds with good brain penetration in cellular.
However, these agents cross the blood brain barrier poorly and
consequently very large doses would be required.
I need to write proposal for BHD application to University in subject of pharmacology and experimental of drugs which treatment of neurodegenerative disease.(1500-2000 words)
primary research, Is it exploration of the available anti-inflammatory and neuroprotective agents, their efficacy/safety.Research methods to be used In the first instance these compounds will be investigated in cell culture models of Parkinson’s disease. Initially chatecholaminergic neuroblastoma cell lines (SYSY5Y or N1E115) will be used. The neuroprotective effect of thearylsulphonamides will be tested against MPP+or 6-OHDA-induced cell death using LDH or trypan blue exclusion to measure cell death. Promising molecules may then be tested in rat primary culture following treatment with MPP+, and the number of dopaminergic cells will be counted using immunocytochemistry. Two-three of the most potent molecules will then be tested in vivo. Male wistar rats will be treated with 6-OHDA or lipopolysaccharide alone or plus the arylsulphonamide. The neuroprotective effect of the arylsulphonamide will be assessed behaviourally using amphetamine induced rotations, and biochemically using immunohistochemistry for tyrosine hydroxylase positive neurons and for microglial and astrocytic activity. The project provides training in a range of in vitro and in vivo techniques relevant to modern neuropharmacology and drug discovery that form useful transferable skills for the student. The student will learn cell culture techniques for cell lines and primary mesencephalic culture in order to determine the neuroprotective effects of the test compounds using the LHA ot trypan blue assays or immunocytochemistry for dopamine containing cells. In addition the student will learn how to use the in vivo models of Parkinson’s disease including the 6-OHDA and lipopolysaccharide rodent models of Parkinson’s and the MPTP-primate PD model. They will learn the behavioural assessment associated with these models in order to assess motor dysfunction and dyskinesia. In addition they will learn the techniques required to assess dopaminergic damage ex vivo, including immunohistochemistry, western blot. The programme of work will address a question of considerable scientific merit and it this will have translational value to clinical neurology. Overall, the project provides excellent research training in a laboratory renowned for its expertise in PD and it will put the student at the cutting edge of current thinking on PD.