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Exendin-4 promotes recovery of both behavioural and neurochemical deficits in a "pre-motor" rodent model of Parkinson's disease

Rampersaud, Nazir; (2011) Exendin-4 promotes recovery of both behavioural and neurochemical deficits in a "pre-motor" rodent model of Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal (NS) pathway; however, post-mortem studies have demonstrated that other brain regions are significantly affected as well (Jellinger, 1999). These other regions include the locus coeruleus (LC) and raphe nuclei (RN), which are principal sites of noradrenergic and serotonergic synthesis, respectively. Degeneration of these crucial neuronal cell bodies is generally thought to occur prior to the deterioration of dopaminergic neurons in the NS pathway and hence predates the appearance of the motor symptoms that characterize PD. Many patients in the early "pre-motor" stage of PD suffer from comorbid depression, anxiety, and cognitive deficits. These deficits may be the result of a loss in noradrenergic and serotonergic innervation given the prominent role of these neurotransmitters in both emotional and cognitive function (Cummings et al., 1999). These psychiatric disturbances greatly affect the patient's quality of life. We have thus set out to create a "pre-motor" rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were ultilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a premotor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Behavioral deficits were assessed using a wide array of tests including sucrose preference, open field exploration, forced swim test, and novel object recognition. Neurochemical deficiencies were assessed using in vivo microdialysis, tissue content levels, and immunohistochemistry. We then sought to evaluate the therapeutic value of Exendin-4 (EX-4) on our premotor rodent model. It has been previously demonstrated that EX-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is neuroprotective in rodent models of PD (Bertilsson et al., 2008; Harkavyi et al., 2008). We found that EX-4 was able to reverse all neurochemical and behavioural deficits exhibited by our model and exhibits anti-depressant like properties. EX-4 preserved the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain premotor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exendin-4 promotes recovery of both behavioural and neurochemical deficits in a "pre-motor" rodent model of Parkinson's disease
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Behavioural; Deficits; Exendin-4; Motor; Neurochemical; Parkinson; Pre-motor; Promotes; Recovery
URI: https://discovery.ucl.ac.uk/id/eprint/10107030
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