Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson's disease.

Abstract

Parkinson's disease (PD) is the most common motor neurodegenerative disorder affecting approximately 4 million people worldwide. Although PD presents primarily with motor dysfunction, non-motor symptoms including cognitive decline, mood disorders, reduced olfaction and constipation are also often present, with some of these non-motor symptoms even presenting prior to the onset of motor symptoms. It is well known that PD is largely caused by the gradual degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNc), along with the presence of protein aggregates called Lewy bodies, which consist primarily of α-synuclein and are found in the cytoplasm of surviving neurons. This ongoing cell loss and Lewy body pathology is not confined to the SNc, but is also seen in other brain regions implicated in PD pathogenesis such as the locus ceruleus. Nonetheless, the cause of cell death in PD still remains somewhat elusive. Numerous secondary cell injury cascades have been linked to this progressive dopaminergic cell death, including inflammation, blood brain barrier (BBB) dysfunction, oxidative stress, glutamate excitotoxicity and mitochondrial dysfunction. Despite this, current PD treatment does not protect dopaminergic neurons but rather provides symptomatic benefit by replacing lost striatal dopamine (DA) either directly or by preventing its breakdown. The “gold-standard” treatment for PD is L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor to DA, combined with a peripheral dopa decarboxylase inhibitor such as benseraside. Since its inception as a PD therapeutic over 50 years ago, L-DOPA has primarily been administered in a pulsatile manner. This type of L-DOPA delivery results in maladaptive changes to brain signaling pathways and expression of L-DOPA induced dyskinesia (LID), or involuntary abnormal movements. Unfortunately, all patients will develop LID at some stage throughout their treatment, which they often find much more debilitating than the motor symptoms they presented with at diagnosis. Current research is thus focused on developing novel neuroprotective therapies that aim to treat the underlying cause of the disease, as well discovering possible adjunct therapies to L-DOPA that inhibit the expression of LID without interfering with L-DOPA motor improvement. Our recent studies have identified the neuropeptide substance P (SP) and its tachykinin NK1 receptor (NK1-R) as novel neuroprotective targets for both ongoing dopaminergic degeneration and mild to moderate LID. Thus treatment with an NK1-R antagonist may provide a new PD therapeutic that shows particular efficacy in the early stages of PD and LID (Thornton and Vink, 2012; Thornton et al., 2014).