The Role of the Neuropeptide Substance P in the Pathogenesis of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) was first described by James Parkinson in 1815 as “shaking palsy syndrome”. Today, it is the second most common neurodegenerative disorder, with a lifetime risk of 1 in 45 of developing the debilitating disease and currently affecting 1% of the population over the age of 65 (G. Alves, et al., 2008). PD is characterized by a slow and progressive loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta (SNc). This loss of dopaminergic neurons is often accompanied by a loss of the noradrenergic pigmented neurons of the locus ceruleus, and in the later stages of the disease, both the cholinergic neurons of the nucleus basalis of Meynert and the serotoninergic neurons of the dorsal raphe nucleus may also degenerate (MareySemper, et al., 1995). In remaining DA neurons proteinaceous cytoplasmic inclusions called Lewy bodies (LBs) are found. They are filamentous in nature and predominantly contain alpha-synuclein and ubiquitin proteins (Bennett, 2005). Although LBs are also found in other diseases, such as diffuse Lewy body dementia and incidental Lewy body disease, they are considered to be the pathological hallmark of PD (Greenfields, 1992). The dopaminergic neurons of the SNc are part of the basal ganglia (BG), an integral part of the brain that ensures smooth execution of movement. Accordingly motor symptoms such as resting tremor, bradykinesia, akinesia, rigidity and postural instability are most common. Degeneration of dopaminergic neurons is slow, with progressive loss of about 5% per year (Blum, et al., 2001), suggesting that a therapy could halt or slow down the progression of the disease, but to date no known neuroprotective therapy exists. Instead, current treatment involves managing patients’ symptoms. Normally this treatment is L-DOPA, the precursor to DA. The rationale for this therapy is to restore DA levels to near normal and therefore restore normal function of the basal ganglia for a period of time. Unfortunately, following prolonged use many patients fail to maintain a good response and often experience “wearing off” effects, which is a reduction in the length of time that L-DOPA effectively alleviates symptoms (Krasnova, et al., 2000). Furthermore, motor complications like dyskinesia, or involuntary movements, occur in approximately 50-80% of PD patients who have been on L-DOPA for more than 5-10 years. These side effects are often more debilitating than the original motor deficits (Chen, et al., 2004). In addition to the loss of dopaminergic neurons, there is also a reduction in the expression of the neuropeptide, substance P (SP), an important neurotransmitter in the BG, which is essential for proper execution of function. However, this loss of SP has been observed in