This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson's disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson's disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson's disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.

Department of Pharmacology Institute of Pharmacy Nirma University Ahmedabad Gujarat 382481 India

Department of Physiology Faculty of Medicine Masaryk University Kamenice 753 5 Brno 62500 Czechia

International Clinical Research Centre Faculty of Medicine Masaryk University Kamenice 753 5 Brno 62500 Czechia

International Clinical Research Centre St Anne's University Hospital Brno Czech Republic ICRC FNUSA Brno 60200 Czechia

Zobrazit více v PubMed

Zhu J.; Cui Y.; Zhang J.; Yan R.; Su D.; Zhao D.; Wang A.; Feng T. Temporal Trends in the Prevalence of Parkinson’s Disease from 1980 to 2023: A Systematic Review and Meta-Analysis. Lancet Healthy Longev 2024, 5 (7), e464–e479. 10.1016/S2666-7568(24)00094-1. PubMed DOI

Sharma N.; Soni R.; Sharma M.; Chatterjee S.; Parihar N.; Mukarram M.; kale R.; Sayyed A. A.; Behera S. K.; Khairnar A. Chlorogenic Acid: A Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson’s Disease by GLP-1 Secretion. Mol. Neurobiol 2022, 59 (11), 6834–6856. 10.1007/s12035-022-03005-z. PubMed DOI

Poewe W.; Seppi K.; Tanner C. M.; Halliday G. M.; Brundin P.; Volkmann J.; Schrag A. E.; Lang A. E. Parkinson Disease. Nat. Rev. Dis Primers 2017, 3, 1–21. 10.1038/nrdp.2017.13. PubMed DOI

Yang L.; Wang H.; Liu L.; Xie A. The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson’s Disease Dementia. Fron. Neurosci. 2018, 12, 73.10.3389/fnins.2018.00073. PubMed DOI PMC

Soni R.; Shah J. Deciphering Intertwined Molecular Pathways Underlying Metabolic Syndrome Leading to Parkinson’s Disease. ACS Chemical Neuroscience. 2022, 13, 2240–2251. 10.1021/acschemneuro.2c00165. PubMed DOI

Athauda D.; Foltynie T. Protective Effects of the GLP-1 Mimetic Exendin-4 in Parkinson’s Disease. Neuropharmacology 2018, 136, 260–270. 10.1016/j.neuropharm.2017.09.023. PubMed DOI

Athauda D.; Wyse R.; Brundin P.; Foltynie T. Is Exenatide a Treatment for Parkinson’s Disease?. J. Parkinsons Dis 2017, 7 (3), 451–458. 10.3233/JPD-171192. PubMed DOI

Blesa J.; Phani S.; Jackson-Lewis V.; Przedborski S. Classic and New Animal Models of Parkinson’s Disease. J. Biomed. Biotechnol. 2012, 2012, 84561810.1155/2012/845618. PubMed DOI PMC

Dehay B.; Fernagut P. O. Alpha-Synuclein-Based Models of Parkinson’s Disease. Rev. Neurol (Paris) 2016, 172 (6–7), 371–378. 10.1016/j.neurol.2016.04.003. PubMed DOI

Sharma M.; Kaur J.; Rakshe S.; Sharma N.; Khunt D.; Khairnar A. Intranasal Exposure to Low-Dose Rotenone Induced Alpha-Synuclein Accumulation and Parkinson’s Like Symptoms Without Loss of Dopaminergic Neurons. Neurotox Res. 2022, 40 (1), 215–229. 10.1007/s12640-021-00436-9. PubMed DOI

Sharma M.; Sharma N.; Khairnar A. Intranasal Rotenone Induces Alpha-Synuclein Accumulation, Neuroinflammation and Dopaminergic Neurodegeneration in Middle-Aged Mice. Neurochem. Res. 2023, 48 (5), 1543–1560. 10.1007/s11064-022-03847-y. PubMed DOI

Sasajima H.; Miyazono S.; Noguchi T.; Kashiwayanagi M. Intranasal Administration of Rotenone in Mice Attenuated Olfactory Functions through the Lesion of Dopaminergic Neurons in the Olfactory Bulb. Neurotoxicology 2015, 51, 106–115. 10.1016/j.neuro.2015.10.006. PubMed DOI

Prediger R. D. S.; Aguiar A. S.; Rojas-Mayorquin A. E.; Figueiredo C. P.; Matheus F. C.; Ginestet L.; Chevarin C.; Del Bel E.; Mongeau R.; Hamon M.; Lanfumey L.; Raisman-Vozari R. Single Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine in C57BL/6 Mice Models Early Preclinical Phase of Parkinson’s Disease. Neurotoxic. Res. 2010, 17 (2), 114–129. 10.1007/s12640-009-9087-0. PubMed DOI

Pan-Montojo F.; Anichtchik O.; Dening Y.; Knels L.; Pursche S.; Jung R.; Jackson S.; Gille G.; Spillantini M. G.; Reichmann H.; Funk R. H. W.; Kleinschnitz C. Progression of Parkinson’s Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice. PLoS One 2010, 5 (1), e876210.1371/journal.pone.0008762. PubMed DOI PMC

Wang T.; Li X.; Zhou B.; Li H.; Zeng J.; Gao W. Anti-Diabetic Activity in Type 2 Diabetic Mice and α-Glucosidase Inhibitory, Antioxidant and Anti-Inflammatory Potential of Chemically Profiled Pear Peel and Pulp Extracts (Pyrus Spp.). J. Funct Foods 2015, 13, 276–288. 10.1016/j.jff.2014.12.049. DOI

Kong C.; Gao R.; Yan X.; Huang L.; Qin H. Probiotics Improve Gut Microbiota Dysbiosis in Obese Mice Fed a High-Fat or High-Sucrose Diet. Nutrition 2019, 60, 175–184. 10.1016/j.nut.2018.10.002. PubMed DOI

Rathod H.; Soni R. M.; Shah J. S. C-Phycocyanin Shows Neuroprotective Effect against Rotenone-Induced Parkinson’s Disease in Mice. Asian Pac. J. Trop. Biomed. 2024, 14 (7), 279–287. 10.4103/apjtb.apjtb_229_24. DOI

Yan R.; Zhang J.; Park H. J.; Park E. S.; Oh S.; Zheng H.; Junn E.; Voronkov M.; Stock J. B.; Mouradian M. M. Synergistic Neuroprotection by Coffee Components Eicosanoyl-5-Hydroxytryptamide and Caffeine in Models of Parkinson’s Disease and DLB. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (51), E12053–E12062. 10.1073/pnas.1813365115. PubMed DOI PMC

Glajch K. E.; Fleming S. M.; Surmeier D. J.; Osten P. Sensorimotor Assessment of the Unilateral 6-Hydroxydopamine Mouse Model of Parkinson’s Disease. Behavioural Brain Research 2012, 230 (2), 309–316. 10.1016/j.bbr.2011.12.007. PubMed DOI PMC

Rahman I.; Kode A.; Biswas S. K. Assay for Quantitative Determination of Glutathione and Glutathione Disulfide Levels Using Enzymatic Recycling Method. Nat. Protoc 2006, 1 (6), 3159–3165. 10.1038/nprot.2006.378. PubMed DOI

Khoubnasabjafari M.; Ansarin K.; Jouyban A. Reliability of Malondialdehyde as a Biomarker of Oxidative Stress in Psychological Disorders. BioImpacts 2015, 5 (3), 123–127. 10.15171/bi.2015.20. PubMed DOI PMC

De Pablo-Fernandez E.; Sierra-Hidalgo F.; Benito-León J.; Bermejo-Pareja F. Association between Parkinson’s Disease and Diabetes: Data from NEDICES Study. Acta Neurologica Scandinavica. 2017, 136, 732–736. 10.1111/ane.12793. PubMed DOI

Maruthur N. M. The Growing Prevalence of Type 2 Diabetes: Increased Incidence or Improved Survival?. Curr. Diab Rep 2013, 13 (6), 786–794. 10.1007/s11892-013-0426-4. PubMed DOI

Pugazhenthi S.; Qin L.; Reddy P. H. Common Neurodegenerative Pathways in Obesity, Diabetes, and Alzheimer’s Disease. Biochim Biophys Acta Mol. Basis Dis 2017, 1863 (5), 1037–1045. 10.1016/j.bbadis.2016.04.017. PubMed DOI PMC

Jeong S. M.; Han K.; Kim D.; Rhee S. Y.; Jang W.; Shin D. W. Body Mass Index, Diabetes, and the Risk of Parkinson’s Disease. Movement Disorders 2020, 35 (2), 236–244. 10.1002/mds.27922. PubMed DOI

Sergi D.; Renaud J.; Simola N.; Martinoli M. G. Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences. Front. Aging Neurosci. 2019, 11, 302.10.3389/fnagi.2019.00302. PubMed DOI PMC

Cardoso S.; Moreira P. I. Antidiabetic Drugs for Alzheimer’s and Parkinson’s Diseases: Repurposing Insulin, Metformin, and Thiazolidinediones. Int. Rev. Neurobiol. 2020, 155, 37–64. 10.1016/bs.irn.2020.02.010. PubMed DOI

Mendonça I. P.; de Paiva I. H. R.; Duarte-Silva E. P.; de Melo M. G.; da Silva R. S.; de Oliveira W. H.; da Costa B. L. D. S. A.; Peixoto C. A. Metformin and Fluoxetine Improve Depressive-like Behavior in a Murine Model of Parkinsońs Disease through the Modulation of Neuroinflammation, Neurogenesis and Neuroplasticity. Int. Immunopharmacol. 2022, 102, 10841510.1016/j.intimp.2021.108415. PubMed DOI

Ulusoy G. K.; Celik T.; Kayir H.; Gürsoy M.; Isik A. T.; Uzbay T. I. Effects of Pioglitazone and Retinoic Acid in a Rotenone Model of Parkinson’s Disease. Brain Res. Bull. 2011, 85 (6), 380–384. 10.1016/j.brainresbull.2011.05.001. PubMed DOI

Badawi G. A.; Abd El Fattah M. A.; Zaki H. F.; El Sayed M. I. Sitagliptin and Liraglutide Reversed Nigrostriatal Degeneration of Rodent Brain in Rotenone-Induced Parkinson’s Disease. Inflammopharmacology 2017, 25 (3), 369–382. 10.1007/s10787-017-0331-6. PubMed DOI

Chou S.-Y.; Chan L.; Chung C.-C.; Chiu J.-Y.; Hsieh Y.-C.; Hong C.-T. Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson’s Disease. Front. Cell Dev. Biol. 2020, 8, 56464110.3389/fcell.2020.564641. PubMed DOI PMC

Samim Khan S.; Janrao S.; Srivastava S.; Bala Singh S.; Vora L.; Kumar Khatri D. GSK-3β: An Exuberating Neuroinflammatory Mediator in Parkinson’s Disease. Biochem. Pharmacol. 2023, 210, 11549610.1016/j.bcp.2023.115496. PubMed DOI

Medunjanin S.; Schleithoff L.; Fiegehenn C.; Weinert S.; Zuschratter W.; Braun-Dullaeus R. C. GSK-3β Controls NF-KappaB Activity via IKKγ/NEMO. Sci. Rep. 2016, 6, 1–11. 10.1038/srep38553. PubMed DOI PMC

Lei P.; Ayton S.; Bush A. I.; Adlard P. A. GSK-3 in Neurodegenerative Diseases. Int. J. Alzheimers Dis. 2011, 2011, 18924610.4061/2011/189246. PubMed DOI PMC

Maurer U.; Preiss F.; Brauns-Schubert P.; Schlicher L.; Charvet C. GSK-3 -at the Crossroads of Cell Death and Survival. J. Cell Sci. 2014, 127 (7), 1369–1378. 10.1242/jcs.138057. PubMed DOI

Kumar Jha S.; Kumar Jha N.; Kar R.; Ambasta R. K.; Kumar P. P38 MAPK and PI3K/AKT Signalling Cascades in Parkinson’s Disease. Int. J. Mol. Cell. Med. 2015, 67. PubMed PMC

Chen J.; Luo Y.; Li Y.; Chen D.; Yu B.; He J. Chlorogenic Acid Attenuates Oxidative Stress-Induced Intestinal Epithelium Injury by Co-Regulating the Pi3k/Akt and Iκbα/Nf-Κb Signaling. Antioxidants 2021, 10 (12), 1915.10.3390/antiox10121915. PubMed DOI PMC

Lv Y. Q.; Yuan L.; Sun Y.; Dou H. W.; Su J. H.; Hou Z. P.; Li J. Y.; Li W. Long-Term Hyperglycemia Aggravates α-Synuclein Aggregation and Dopaminergic Neuronal Loss in a Parkinson’s Disease Mouse Model. Transl. Neurodegener. 2022, 11 (1), 14.10.1186/s40035-022-00288-z. PubMed DOI PMC