Abuirmeileh, Amjad N; (2008) The CRF-like peptide urocortin reverses key indicators of nigrostriatal damage in rodent models of Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parkinson's disease (PD) is an irreversible neurodegenerative disorder with no cure and current treatments have limited efficacy and unpleasant side effects. The aetiology of PD is complex involving apoptotic, excitotoxic, free radical mediated and inflammatory events. This work involved studying the effect of the corticotrophin releasing factor (CRF)-like peptide urocortin (UCN) on two distinct rodent models of PD, the well established 6-OHDA rat model and the more recently introduced LPS model. UCN's effects were examined in these models immediately after the lesion was induced and also after the lesion had significantly progressed. The mechanisms of action for UCN were examined through the use of selective CRF-R2 agonists UCNII and UCNIII to determine whether they exerted the same actions as UCN. The non selective antagonist a-helical CRF was also used in conjunction with UCN to examine whether reversed the effect of UCN. Another selective CRF-R1 antagonist, NBI-27914, was also used with UCN to confirm those findings. Experiments were carried out in rats, and the effects of the different treatments used were evaluated through the use of multiple assessments. When UCN was given at the same time as 6-OHDA or LPS, this peptide reversed/restored key indicators of PD-Like damage. These included behavioral effects, loss of tissue and extracellular dopamine, loss of tyrosine hydroxylase (TH) activity and protein levels, in addition to the loss of TH immuno-reactivity in nigral sections. The effects of reversing/restoring these key indicators of PD-like damage were also observed when UCN was given seven days after 6-OHDA or LPS treatment, when the lesion had significantly progressed. When the pharmacology of the UCN phenomenon was studied using CRF receptor agonists and antagonists, it was determined that UCN was acting via CRF-R1 receptors, a finding which may prove significant for development of new medications and exploring CRF-R1 as a new target in PD treatment. It was concluded that an extension of these observations to the clinic could have potential benefits for PD patients.

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