DOI QR코드

DOI QR Code

Agathobaculum butyriciproducens Shows Neuroprotective Effects in a 6-OHDA-Induced Mouse Model of Parkinson's Disease

  • Lee, Da Woon (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Ryu, Young-Kyoung (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Chang, Dong-Ho (Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Park, Hye-Yeon (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Go, Jun (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Maeng, So-Young (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Hwang, Dae Youn (Department of Biomaterials Science, College of Natural Resources and Life Science and Industry Convergence Research Institute, Pusan National University) ;
  • Kim, Byoung-Chan (Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Lee, Chul-Ho (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim, Kyoung-Shim (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
  • 투고 : 2022.05.19
  • 심사 : 2022.08.29
  • 발행 : 2022.09.28

초록

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3β signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

키워드

과제정보

This research was supported by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGS1042221) and the Bio & Medical Technology Development Program (2019M3A9F3065867 to C-HL) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea.

참고문헌

  1. Kalia LV, Lang AE. 2015. Parkinson's disease. Lancet 386: 896-912. https://doi.org/10.1016/S0140-6736(14)61393-3
  2. Hughes AJ, Daniel SE, Kilford L, Lees AJ. 1992. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55: 181-184. https://doi.org/10.1136/jnnp.55.3.181
  3. Rana AQ, Ahmed US, Chaudry ZM, Vasan S. 2015. Parkinson's disease: a review of non-motor symptoms. Expert Rev. Neurother. 15: 549-562. https://doi.org/10.1586/14737175.2015.1038244
  4. Schapira AHV, Chaudhuri KR, Jenner P. 2017. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 18: 435-450. https://doi.org/10.1038/nrn.2017.62
  5. Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. 2015. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 14: 625-639. https://doi.org/10.1016/S1474-4422(15)00007-1
  6. Santos SF, de Oliveira HL, Yamada ES, Neves BC, Pereira A, Jr. 2019. The gut and Parkinson's disease-A bidirectional pathway. Front. Neurol. 10: 574. https://doi.org/10.3389/fneur.2019.00574
  7. Cersosimo MG, Raina GB, Pecci C, Pellene A, Calandra CR, Gutierrez C, et al. 2013. Gastrointestinal manifestations in Parkinson's disease: prevalence and occurrence before motor symptoms. J. Neurol. 260: 1332-1338. https://doi.org/10.1007/s00415-012-6801-2
  8. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, Group NV. 2011. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease. Mov. Disord. 26: 399-406. https://doi.org/10.1002/mds.23462
  9. Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. 2019. The microbiota-gut-brain Axis. Physiol. Rev. 99: 1877-2013. https://doi.org/10.1152/physrev.00018.2018
  10. Braak H, Rub U, Gai WP, Del Tredici K. 2003. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural. Transm (Vienna) 110: 517-536. https://doi.org/10.1007/s00702-002-0808-2
  11. Neufeld KM, Kang N, Bienenstock J, Foster JA. 2011. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23: 255-264, e119. https://doi.org/10.1111/j.1365-2982.2010.01620.x
  12. Kawase T, Nagasawa M, Ikeda H, Yasuo S, Koga Y, Furuse M. 2017. Gut microbiota of mice putatively modifies amino acid metabolism in the host brain. Br. J. Nutr. 117: 775-783. https://doi.org/10.1017/S0007114517000678
  13. Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard Et, Taylor CM, Welsh DA, et al. 2015. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol. Psychiatry 77: 607-615. https://doi.org/10.1016/j.biopsych.2014.07.012
  14. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. 2016. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol. Psychiatry 21: 786-796. https://doi.org/10.1038/mp.2016.44
  15. Ansari F, Pourjafar H, Tabrizi A, Homayouni A. 2020. The effects of probiotics and prebiotics on mental disorders: A review on depression, anxiety, alzheimer, and autism spectrum disorders. Curr. Pharm. Biotechnol. 21: 555-565. https://doi.org/10.2174/1389201021666200107113812
  16. Huang H, Xu H, Luo Q, He J, Li M, Chen H, et al. 2019. Fecal microbiota transplantation to treat Parkinson's disease with constipation: A case report. Medicine (Baltimore) 98: e16163. https://doi.org/10.1097/md.0000000000016163
  17. Hsieh TH, Kuo CW, Hsieh KH, Shieh MJ, Peng CW, Chen YC, et al. 2020. Probiotics alleviate the progressive deterioration of motor functions in a mouse model of Parkinson's disease. Brain Sci. 10: 206. https://doi.org/10.3390/brainsci10040206
  18. Srivastav S, Neupane S, Bhurtel S, Katila N, Maharjan S, Choi H, et al. 2019. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J. Nutr. Biochem. 69: 73-86. https://doi.org/10.1016/j.jnutbio.2019.03.021
  19. Castelli V, d'Angelo M, Lombardi F, Alfonsetti M, Antonosante A, Catanesi M, et al. 2020. Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson's disease models. Aging (Albany NY) 12: 4641-4659. https://doi.org/10.18632/aging.102927
  20. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, et al. 2015. Colonic bacterial composition in Parkinson's disease. Mov. Disord. 30: 1351-1360. https://doi.org/10.1002/mds.26307
  21. Rani L, Mondal AC. 2021. Unravelling the role of gut microbiota in Parkinson's disease progression: Pathogenic and therapeutic implications. Neurosci. Res. 168: 100-112. https://doi.org/10.1016/j.neures.2021.01.001
  22. Ahn S, Jin TE, Chang DH, Rhee MS, Kim HJ, Lee SJ, et al. 2016. Agathobaculum butyriciproducens gen. nov.  sp. nov., a strict anaerobic, butyrate-producing gut bacterium isolated from human faeces and reclassification of Eubacterium desmolans as Agathobaculum desmolans comb. nov. Int. J. Syst. Evol. Microbiol. 66: 3656-3661. https://doi.org/10.1099/ijsem.0.001195
  23. Go J, Chang DH, Ryu YK, Park HY, Lee IB, Noh JR, et al. 2021. Human gut microbiota Agathobaculum butyriciproducens improves cognitive impairment in LPS-induced and APP/PS1 mouse models of Alzheimer's disease. Nutr Res. 86: 96-108. https://doi.org/10.1016/j.nutres.2020.12.010
  24. Yan J, Fu Q, Cheng L, Zhai M, Wu W, Huang L, et al. 2014. Inflammatory response in Parkinson's disease (Review). Mol. Med. Rep. 10: 2223-2233. https://doi.org/10.3892/mmr.2014.2563
  25. Troncoso-Escudero P, Parra A, Nassif M, Vidal RL. 2018. Outside in: Unraveling the role of neuroinflammation in the progression of Parkinson's disease. Front. Neurol. 9: 860. https://doi.org/10.3389/fneur.2018.00860
  26. Hirsch EC, Hunot S. 2009. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8: 382-397. https://doi.org/10.1016/S1474-4422(09)70062-6
  27. Gagne JJ, Power MC. 2010. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74: 995-1002. https://doi.org/10.1212/WNL.0b013e3181d5a4a3
  28. Whitton PS. 2010. Neuroinflammation and the prospects for anti-inflammatory treatment of Parkinson's disease. Curr. Opin. Investig. Drugs. 11: 788-794.
  29. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. 2013. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110: 9066-9071. https://doi.org/10.1073/pnas.1219451110
  30. Park HY, Ryu YK, Kim YH, Park TS, Go J, Hwang JH, et al. 2016. Gadd45beta ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model. Neurobiol. Dis. 89: 169-179. https://doi.org/10.1016/j.nbd.2016.02.013
  31. Park HY, Kang YM, Kang Y, Park TS, Ryu YK, Hwang JH, et al. 2014. Inhibition of adenylyl cyclase type 5 prevents L-DOPA-induced dyskinesia in an animal model of Parkinson's disease. J. Neurosci. 34: 11744-11753. https://doi.org/10.1523/JNEUROSCI.0864-14.2014
  32. Ryu YK, Park HY, Go J, Choi DH, Kim YH, Hwang JH, et al. 2018. Metformin inhibits the development of L-DOPA-induced dyskinesia in a murine model of Parkinson's disease. Mol. Neurobiol. 55: 5715-5726. https://doi.org/10.1007/s12035-017-0752-7
  33. Keith BJ Fraklin GP. 2007. The mouse brain in stereotaxic coordinates, Third edition Ed. Elsevier, New York, USA.
  34. Ryu YK, Go J, Park HY, Choi YK, Seo YJ, Choi JH, et al. 2020. Metformin regulates astrocyte reactivity in Parkinson's disease and normal aging. Neuropharmacology 175: 108173. https://doi.org/10.1016/j.neuropharm.2020.108173
  35. Go J, Park TS, Han GH, Park HY, Ryu YK, Kim YH, et al. 2018. Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice. Int. J. Mol. Med. 42: 1875-1884. https://doi.org/10.3892/ijmm.2018.3782
  36. Park TS, Ryu YK, Park HY, Kim JY, Go J, Noh JR, et al. 2017. Humulus japonicus inhibits the progression of Alzheimer's disease in a APP/PS1 transgenic mouse model. Int. J. Mol. Med. 39: 21-30. https://doi.org/10.3892/ijmm.2016.2804
  37. Albin RL, Young AB, Penney JB. 1989. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12: 366-375. https://doi.org/10.1016/0166-2236(89)90074-X
  38. Ryu YK, Kang Y, Go J, Park HY, Noh JR, Kim YH, et al. 2017. Humulus japonicus prevents dopaminergic neuron death in 6-hydroxydopamine-induced models of Parkinson's disease. J. Med. Food 20: 116-123. https://doi.org/10.1089/jmf.2016.3851
  39. Haavik J, Toska K. 1998. Tyrosine hydroxylase and Parkinson's disease. Mol. Neurobiol. 16: 285-309. https://doi.org/10.1007/BF02741387
  40. Franke TF, Kaplan DR, Cantley LC. 1997. PI3K: downstream AKTion blocks apoptosis. Cell 88: 435-437. https://doi.org/10.1016/S0092-8674(00)81883-8
  41. Glinka Y, Gassen M, Youdim MB. 1997. Mechanism of 6-hydroxydopamine neurotoxicity. J. Neural. Transm. Suppl. 50: 55-66. https://doi.org/10.1007/978-3-7091-6842-4_7
  42. Thiruvengadam M, Venkidasamy B, Subramanian U, Samynathan R, Ali Shariati M, Rebezov M, et al. 2021. Bioactive compounds in oxidative stress-mediated diseases: Targeting the NRF2/ARE signaling pathway and epigenetic regulation. Antioxidants (Basel). 10: 1859. https://doi.org/10.3390/antiox10121859
  43. Kramer BC, Mytilineou C. 2004. Alterations in the cellular distribution of bcl-2, bcl-x and bax in the adult rat substantia nigra following striatal 6-hydroxydopamine lesions. J. Neurocytol. 33: 213-223. https://doi.org/10.1023/B:NEUR.0000030696.62829.ec
  44. Fulling C, Dinan TG, Cryan JF. 2019. Gut microbe to brain signaling: What happens in vagus. Neuron 101: 998-1002. https://doi.org/10.1016/j.neuron.2019.02.008
  45. Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T, et al. 2013. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe. 13: 711-722. https://doi.org/10.1016/j.chom.2013.05.013
  46. Xu R, Zhang Y, Chen S, Zeng Y, Fu X, Chen T, et al. 2022. The role of the probiotic Akkermansia muciniphila in brain functions: insights underpinning therapeutic potential. Crit. Rev. Microbiol. 11: 1-26.
  47. Deumens R, Blokland A, Prickaerts J. 2002. Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175: 303-317. https://doi.org/10.1006/exnr.2002.7891
  48. Zhu Y, Zhang J, Zeng Y. 2012. Overview of tyrosine hydroxylase in Parkinson's disease. CNS Neurol. Disord. Drug Targets 11: 350-358. https://doi.org/10.2174/187152712800792901
  49. Yang L, Wang H, Liu L, Xie A. 2018. The role of insulin/IGF-1/PI3K/Akt/GSK3beta signaling in Parkinson's disease dementia. Front. Neurosci. 12: 73. https://doi.org/10.3389/fnins.2018.00073
  50. Chen G, Bower KA, Ma C, Fang S, Thiele CJ, Luo J. 2004. Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J. 18: 1162-1164. https://doi.org/10.1096/fj.04-1551fje
  51. Chung CY, Koprich JB, Endo S, Isacson O. 2007. An endogenous serine/threonine protein phosphatase inhibitor, G-substrate, reduces vulnerability in models of Parkinson's disease. J. Neurosci. 27: 8314-8323. https://doi.org/10.1523/JNEUROSCI.1972-07.2007
  52. Doble BW, Woodgett JR. 2003. GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116: 1175-1186. https://doi.org/10.1242/jcs.00384
  53. Jope RS, Johnson GV. 2004. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29: 95-102. https://doi.org/10.1016/j.tibs.2003.12.004
  54. Beaulieu JM, Del'guidice T, Sotnikova TD, Lemasson M, Gainetdinov RR. 2011. Beyond cAMP: The regulation of Akt and GSK3 by dopamine receptors. Front. Mol. Neurosci. 4: 38. https://doi.org/10.3389/fnmol.2011.00038
  55. Quesada A, Lee BY, Micevych PE. 2008. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease. Dev. Neurobiol. 68: 632-644. https://doi.org/10.1002/dneu.20609
  56. Aleyasin H, Rousseaux MW, Marcogliese PC, Hewitt SJ, Irrcher I, Joselin AP, et al. 2010. DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. Proc. Natl. Acad. Sci. USA 107: 3186-3191. https://doi.org/10.1073/pnas.0914876107
  57. Xie CL, Lin JY, Wang MH, Zhang Y, Zhang SF, Wang XJ, et al. 2016. Inhibition of Glycogen Synthase Kinase-3beta (GSK-3beta) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats. Sci. Rep. 6: 23527. https://doi.org/10.1038/srep23527
  58. Krishnankutty A, Kimura T, Saito T, Aoyagi K, Asada A, Takahashi SI, et al. 2017. In vivo regulation of glycogen synthase kinase 3beta activity in neurons and brains. Sci. Rep. 7: 8602. https://doi.org/10.1038/s41598-017-09239-5
  59. Aaseth J, Dusek P, Roos PM. 2018. Prevention of progression in Parkinson's disease. Biometals 31: 737-747. https://doi.org/10.1007/s10534-018-0131-5
  60. Percario S, da Silva Barbosa A, Varela ELP, Gomes ARQ, Ferreira MES, de Nazare Araujo Moreira T, et al. 2020. Oxidative stress in Parkinson's disease: Potential benefits of antioxidant supplementation. Oxid. Med. Cell Longev. 2020: 2360872.
  61. de Oliveira MR, Ferreira GC, Schuck PF. 2016. Protective effect of carnosic acid against paraquat-induced redox impairment and mitochondrial dysfunction in SH-SY5Y cells: Role for PI3K/Akt/Nrf2 pathway. Toxicol. In Vitro 32: 41-54. https://doi.org/10.1016/j.tiv.2015.12.005
  62. Li L, Dong H, Song E, Xu X, Liu L, Song Y. 2014. Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chem. Biol. Interact. 209: 56-67. https://doi.org/10.1016/j.cbi.2013.12.005
  63. Reiter RJ. 1998. Oxidative damage in the central nervous system: protection by melatonin. Prog. Neurobiol. 56: 359-384. https://doi.org/10.1016/S0301-0082(98)00052-5
  64. Miao L, St Clair DK. 2009. Regulation of superoxide dismutase genes: implications in disease. Free Radic. Biol. Med. 47: 344-356. https://doi.org/10.1016/j.freeradbiomed.2009.05.018
  65. Oh YJ, Wong SC, Moffat M, O'Malley KL. 1995. Overexpression of Bcl-2 attenuates MPP+, but not 6-ODHA, induced cell death in a dopaminergic neuronal cell line. Neurobiol. Dis. 2: 157-167. https://doi.org/10.1006/nbdi.1995.0017
  66. Sun J, Xu J, Ling Y, Wang F, Gong T, Yang C, et al. 2019. Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry 9: 189. https://doi.org/10.1038/s41398-019-0525-3
  67. Zhao Z, Ning J, Bao XQ, Shang M, Ma J, Li G, et al. 2021. Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome 9: 226. https://doi.org/10.1186/s40168-021-01107-9
  68. Liddelow SA, Barres BA. 2017. Reactive astrocytes: Production, function, and therapeutic potential. Immunity 46: 957-967. https://doi.org/10.1016/j.immuni.2017.06.006
  69. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131: 1164-1178. https://doi.org/10.1016/j.cell.2007.10.036
  70. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481-487. https://doi.org/10.1038/nature21029
  71. Gorshkov K, Aguisanda F, Thorne N, Zheng W. 2018. Astrocytes as targets for drug discovery. Drug Discov. Today 23: 673-680. https://doi.org/10.1016/j.drudis.2018.01.011
  72. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. 2012. Host-gut microbiota metabolic interactions. Science 336: 1262-1267. https://doi.org/10.1126/science.1223813
  73. Holscher HD. 2017. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes 8: 172-184. https://doi.org/10.1080/19490976.2017.1290756
  74. Cantu-Jungles TM, Rasmussen HE, Hamaker BR. 2019. Potential of prebiotic butyrogenic fibers in Parkinson's disease. Front. Neurol. 10: 663. https://doi.org/10.3389/fneur.2019.00663
  75. Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. 2011. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc. Natl. Acad. Sci. USA 108 Suppl 1: 4586-4591. https://doi.org/10.1073/pnas.1000097107
  76. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, et al. 2016. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat. Disord. 32: 66-72. https://doi.org/10.1016/j.parkreldis.2016.08.019
  77. Liu J, Wang F, Liu S, Du J, Hu X, Xiong J, et al. 2017. Sodium butyrate exerts protective effect against Parkinson's disease in mice via stimulation of glucagon like peptide-1. J. Neurol. Sci. 381: 176-181.