Neuroregeneration in Parkinson's Disease: From Proteins to Small Molecules

Abstract

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostriatal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates disease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD.

Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the progress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account.

Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cultures or animal models of PD including neurotrophic factors and small molecular weight compounds.

Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, intensive research in the field is justified.

Keywords: BDNF; BDNF mimetics; GDNF; GDNF mimetics; Neurorestoration; Parkinson's disease; RET agonists; Trk agonists; dopamine neurons; neuroprotection; neurotrophic factors..

Fig. (1)

Schematic representation of nigrostriatal dopamine pathway in healthy people (a) and Parkinsonian patients before (b) and after treatment with a neurorestorative agent (c). Dopamine neurons in healthy patients receive trophic support from neurotrophic factors (shown with dark red dots). In Parkinsonian patients, axons of dopamine neurons in the putamen are either lost or degenerated (dotted line) and the number of dopamine neuron bodies in substantia nigra pars compacta is reduced. Treatment of PD patients with growth factors (or their mimetics) stimulates regrowth and arborization of dopamine axons in the putamen (c), thus restoring the dopamine balance and abolishing motor symptoms. (The color version of the figure is available in the electronic copy of the article).

Fig. (2)

Neurotrophic factors and their receptors in dopamine neurons. Dopamine neurons express receptors of neurotrophins (TrkB and p75^NTR), GFLs (GFRa and RET), potential distant GFL member GDF15 (GFRAL and RET), neurokines (gp130, LIFR, and CNTFR). Binding of all the afore-mentioned ligands leads to activation of intracellular signaling cascades promoting the survival of neuronal cells, neurite outgrowth and arborization, migration and differentiation of neuronal precursors. MANF and CDNF transmit signals intracellularly via unfolded protein response (UPR) pathways under endoplasmic reticulum (ER) stress. The particular molecular mechanism of action of MANF and CDNF in the cells is poorly understood; however, these proteins can prevent neuronal death induced by ER stress, probably by inhibition of UPR. The ability of MANF and CDNF to protect and restore dopamine neurons when delivered externally implies the existence of a mechanism of their internalization either via yet undiscovered surface receptor (MANF/CDNFR) or via their documented interaction with lipids. Binding of proneurotrophins to p75^NTR activates the JNK pathway and leads to cell death. (The color version of the figure is available in the electronic copy of the article).

Fig. (3)

Structures of DA agonists.

Fig. (4)

The structures of compounds targeting Trk receptors and/or activating Trk-dependent signaling.

Fig. (5)

Structures of RET agonists (1, XIB4035, BT13) and LRRK2 inhibitors 2a,b.

Fig. (6)

Structures of 9-methyl-β-carboline, aminocarbazoles and guanosine.