Novel tactics for neuroprotection in Parkinson's disease: Role of antibiotics, polyphenols and neuropeptides

Article ID	Journal	Published Year	Pages	File Type
5739165	Progress in Neurobiology	2017	76 Pages	PDF

Abstract

Parkinson's disease is a progressive neurodegenerative disorder characterized by the degeneration of midbrain nigral dopaminergic neurons. Although its etiology remains unknown, the pathological role of several factors has been highlighted, namely oxidative stress, neuroinflammation, protein misfolding, and mitochondrial dysfunction, in addition to genetic predispositions. The current therapy is mainly symptomatic with l-DOPA aiming to replace dopamine. Novel therapeutic approaches are being investigated with the intention of influencing pathways leading to neuronal death and dysfunction. The present review summarizes three novel approaches, the use of which is promising in pre-clinical studies. Polyphenols have been shown to possess neuroprotective properties on account of their well-established antioxidative and anti-inflammatory actions but also due to their influence on protein misfolding and mitochondrial homeostasis. Within the amazing ancillary effects of antibiotics, their neuroprotective properties against neurodegenerative and neuroinflammatory processes are of great interest for the development of effective therapies against Parkinson's disease. Experimental evidence supports the potential of antibiotics as neuroprotective agents, being useful not only to prevent the formation of toxic Î±-synuclein oligomers but also to ameliorate mitochondrial dysfunction and neuroinflammation. Neuropeptides offer another approach with their diverse effects in the nervous system. Among them, pituitary adenylate cyclase-activating polypeptide, a member of the secretin/glucagon superfamily, has several advantageous effects in models of neurodegeneration, namely anti-apoptotic, anti-inflammatory and antioxidant actions, the combination of which offers a potent protective effect in dopaminergic neurons. Owing to their pleiotropic modes of action, these novel therapeutic candidates have potential in tackling the multidimensional features of Parkinson's disease.

Keywords

AMPK CREB NF-κB 6-OHDA LPS Jnk DOX CAT GFAP GSH GST Aβ HO-1 mTOR 6-Hydroxydopamine COX-2 ERK SNC VIP iNOS MCP-1 IL-1β NGF LRRK2 MPTP NMDA N-methyl-d-aspartate PINK1 GPCR PACAP DCs 1-methyl-4-phenylpyridinium LC3 GIRK2 d-cycloserine IBA1 Heme oxygenase-1 NQO-1 NTFs TLR4 GRP78 SOCS1 LAMP2A MMP9 DAergic NAD(P)H:quinone oxidoreductase-1 γ-GCS HEK-293 K-ATP human embryonic kidney-293 lysosome-associated membrane protein 2a AMP-activated protein kinase BDNF c-Jun N-terminal kinase MPO G-protein-coupled receptor l-3,4-dihydroxyphenylalanine l-DOPA MAPK MPP+PTEN-induced putative kinase 1 ROS β-Amyloid γ-glutamylcysteine synthetase Antioxidants Antibiotics Interleukin-1 beta Alzheimer's disease Parkinson's disease substantia nigra substantia nigra pars compacta tumor necrosis factor-alpha leucine-rich repeat kinase 2 tyrosine hydroxylase doxycycline CNS Dopamine Dopaminergic light chain 3 SOD BBB Blood–brain barrier suppressor of cytokine signaling 1 inducible nitric oxide synthase Superoxide dismutase central nervous system Cyclooxygenase-2 Neurotrophic factors nerve growth factor Brain-derived neurotrophic factor TNF-α nuclear factor kappa-light-chain-enhancer of activated B cells lipopolysaccharide Matrix metalloproteinase 9 ionized calcium binding adaptor molecule 1 myeloperoxidase Nitric oxide mammalian target of rapamycin Mitochondrial transmembrane potential Glial fibrillary acidic protein glucose-regulated protein 78 monocyte chemoattractant protein-1 mitogen-activated protein kinase prostaglandin Polyphenols vasoactive intestinal peptide pituitary adenylate cyclase-activating peptide Catalase ATP-sensitive K+ channels extracellular signal-regulated kinase Glutathione glutathione S-transferase Reactive oxygen species Toll-like receptor 4