Funded Studies
Objective/Rationale:
Inflammation in the brain (neuroinflammation) is an ongoing process in Parkinson's disease and contributes to cell death. Anti-inflammatory compounds are neuroprotective in pre-clinical models of PD and may reduce the risk to people of developing the disease. However, long-term treatment with high-dose anti-inflammatory steroids is inappropriate for patients with PD and the effect of non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors) are modest. An alternative means of ameliorating neuroinflammation in the brain would be to target inflammatory pathways (other than cyclooxygenase derivatives) that are modulated by protease-activated receptor-2 (PAR2).
Project Description:
This project will examine PAR2 expression and endogenous inhibitors and activators of the receptor in post-mortem parkinsonian brain and will compare it to brain from individuals who died without PD. To do this we will use immunohistochemistry (antibody staining) and cell counting techniques. We will examine brain regions that degenerate and are subject to neuroinflammation as well as brain regions that do not degenerate in PD, since this may provide insight as to why certain neuronal populations are vulnerable to neurodegeneration while others remain unaffected.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Reducing the harmful effect of neuroinflammation in brain using PAR2 ligands to augment or inhibit PAR2 activity (i.e. agonist or antagonist drugs depending upon whether we find PAR2 to be pro- or anti- inflammatory) should slow the progression of the disease and prolong the useful time that levodopa can be used to manage symptoms.
Anticipated Outcome:
We expect to learn whether PAR2 is pro- or anti-inflammatory in Parkinson’s disease and would then be able to devise a therapeutic strategy to reduce neuroinflammation in the brain. This will support future studies using PAR2 ligands (which are already available for research use) to prevent or reduce neuroinflammation in inflammation-based pre-clinical models of Parkinson’s disease. If successful this could ultimately lead to a neuroprotective agent for use in a pilot clinical trial.
Final Outcome
Inappropriate inflammation in the brain can contribute to cell loss seen in Parkinson’s disease. Inhibiting such inflammation could be neuroprotective. Protease-activated receptor-2 and associated governing molecules are involved in the control of inflammation. We found that the level of protease-activated receptor 2 and some of its activators and inhibitors were altered in post-mortem brain from patients dying with Parkinson’s disease in comparison to brain tissue from individuals dying without the disorder. This suggests that PAR2 is involved in Parkinson’s disease pathology and indicates that PAR2 may be a suitable drug target for reducing inflammation in the brain of people suffering with Parkinson’s disease. Further work is required to confirm if this is indeed the case, but the finding is encouraging.
June 2014