The role of substance P in early experimental Parkinson’s disease.

Parkinson's disease (PD) is one of the most common motor neurodegenerative diseases, affecting 1-2% of the world's population over the age of 65. It is characterised by a loss of dopamine neurons within the substantia nigra, which is an integral part of the basal ganglia (BG) where dopamine is the most important modulating neurotransmitter. As the BG is primarily involved with the execution of movement, the lack of dopamine input results in dysfunctional motor control. The current PD treatment, L-DOPA, improves these motor symptoms, however only provides patients 5 to 10 years of improved quality of life before debilitating side effects, often worse than the original symptoms, begin. The neuropeptide substance P (SP) is found in high concentration in the substantia nigra, and BG in general, where it is involved in dopamine release. In the late stages of PD, SP content within the substantia nigra and BG is decreased, thus implicating SP in the pathophysiology of PD. However, SP production has not been examined in the early stages of PD when dopaminergic degeneration is first initiated. This thesis therefore sought to characterise the role of SP in dopaminergic degeneration in an experimental model of early PD, the 6-hydroxydopamine model in rats. In contrast to the prevailing dogma that a decline in SP is associated with neurodegeneration in PD, this thesis demonstrates that SP is actually increased within the striatum in early PD, particular in perivascular tissue and within surviving dopaminergic neurons during the degenerative process. Increasing exposure of the dopaminergic neurons to SP, either by inhibition of substance P breakdown with Captopril or by direct injection with SP, exacerbated the disease progression as indicated by more profound neurogenic inflammation, functional deficits and increased dopaminergic cell death. However, when SP was inhibited by treatment with a SP NK₁ receptor antagonist, dopaminergic neurons were conserved, the inflammatory response was reduced and motor function was returned to near normal levels. We conclude that SP is increased in early PD, and that increased SP plays an important role in the degenerative process, specifically, in the genesis of BBB breakdown and initiation of neurogenic inflammation. Treatment with an NK1 antagonist may thus represent a novel therapeutic approach to early stage Parkinson’s disease.Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 200