Identification of molecular network of gut‐brain axis associated with neuroprotective effects of PPARδ‐ligand erucic acid in rotenone‐induced Parkinson's disease model in zebrafish

• Published in: The European journal of neuroscience 2023-02, Vol.57 (4), p.585-606
• Main Authors: Ünal, İsmail, Cansız, Derya, Sürmen, Mustafa Gani, Sürmen, Saime, Sezer, Zehra, Beler, Merih, Üstündağ, Ünsal Veli, Güzel, Elif, Alturfan, A. Ata, Emekli‐Alturfan, Ebru
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Agonists; Alkaline phosphatase; Animals; Brain injury; Brain-Gut Axis; Chromatography, Liquid; Cytoskeleton; Danio rerio; Digestive system; Disease Models, Animal; Erucic Acids; Fatty acids; Gastrointestinal tract; Glutathione; gut‐brain axis; LC–MS/MS analyses; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Ligands; Lipid peroxidation; Liquid chromatography; Locomotor activity; LRRK2 protein; Mass spectrometry; Mass spectroscopy; Movement disorders; Neurodegenerative diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nitric oxide; Oxidants; PARK7 protein; Parkinson Disease - metabolism; Parkinson's disease; Peroxisome proliferator-activated receptors; PPAR delta; Proteins; Proteomes; PTEN-induced putative kinase; Rotenone; Scientific imaging; Tandem Mass Spectrometry; Zebrafish; Zebrafish Proteins; ω9‐fatty acids
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15904

Disruption of the gut‐brain axis in Parkinson's disease (PD) may lead to motor symptoms and PD pathogenesis. Recently, the neuroprotective potential of different PPARδ‐agonists has been shown. We aimed to reveal the effects of erucic acid, peroxisome proliferator‐activated receptors (PPARs)‐ligand in rotenone‐induced PD model in zebrafish, focusing on the gut‐brain axis. Adult zebrafish were exposed to rotenone and erucic acid for 30 days. Liquid chromatography‐mass spectrometry and tandem mass spectrometry (LC–MS/MS) analysis was performed. Raw files were analysed by Proteome Discoverer 2.4 software; peptide lists were searched against Danio rerio proteins. STRING database was used for protein annotations or interactions. Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione S‐transferase (GST), acetylcholinesterase and the expressions of PD‐related genes were determined. Immunohistochemical tyrosine hydroxylase (TH) staining was performed. LC–MS/MS analyses allowed identification of over 2000 proteins in each sample. The 2502 and 2707 proteins overlapped for intestine and brain. The 196 and 243 significantly dysregulated proteins in the brain and intestines were found in rotenone groups. Erucic acid treatment corrected the changes in the expression of proteins associated with cytoskeletal organisation, transport and localisation and improved locomotor activity, expressions of TH, PD‐related genes (lrrk2, park2, park7, pink1) and oxidant‐damage in brain and intestines in the rotenone group as evidenced by decreased LPO, No and increased GST. Our results showed beneficial effects of erucic acid as a PPARδ‐ligand in neurotoxin‐induced PD model in zebrafish. We believe that our study will shed light on the mechanism of the effects of PPARδ agonists and ω9‐fatty acids in the gut‐brain axis of PD. Liquid chromatography‐mass spectrometry and tandem mass spectrometry (LC–MS/MS) analyses showed 196 and 243 significantly dysregulated proteins in brain and intestines in the rotenone group. Erucic acid treatment improved locomotor activity, immunohistochemical TH expression, expressions of PD‐related genes and oxidant damage both in brain and intestines in the rotenone group.