Treatment of Parkinson's Disease: What's in the Non-dopaminergic Pipeline?

Abstract

Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…Thus agonists and antagonists at the same type of receptor may both offer therapeutic benefit in the alleviation of various motor symptoms associated with PD through actions at different sites in the neural pathways regulating motor function. However, despite the fact that much of this evidence has been available for more than 5 years, neither NOP receptor agonists nor NOP receptor antagonists are currently identified in recent reviews of potential new drug therapies for PD (e.g., Hung and Schwarzschild, 2014;Stayte and Vissel, 2014). The reasons for this lack of attention to the potential therapeutic benefits of NOP receptor ligands in the treatment of PD are not entirely clear, but may be related to the biphasic dose-response curves displayed by NOP receptor antagonists in relieving the motor symptoms of PD (Volta et al, 2011) and the potential for NOP receptor antagonists to exacerbate LID in PD patients receiving L-DOPA.…”

Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions

“…Thus, the altered inhibitory (via D2 receptors) and excitatory (via D5 receptors) actions of dopamine on ChIs activity might be partly responsible for striatal cholinergic changes in parkinsonism . Striatal ChIs also express receptors that are coexpressed with dopamine receptors and negatively affected in PD, such as the adenosine A 2A receptors, which are currently the target of multiple clinical studies . Furthermore, anatomical and functional changes in nondopaminergic afferents and efferents of ChIs must also be considered.…”

Unmet needs in Parkinson's disease: New horizons in a changing landscape

“…However, as might be expected, there has been a time lag in drug development with few novel therapies coming to market in recent years [98,99]. For PD research to move forward, we need to consider the impact of the numerous recent insights on the development of new drugs and tailored strategies.…”