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Pyruvate Prevents Dopaminergic Neurodegeneration and Motor Deficits in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopamine(DA)rgic neurons in the substantia nigra of the midbrain, and primarily causes motor symptoms. While the pathological cause of PD remains uncertain, oxidative damage, neuroinflammation, and energy metabolic perturbation have been implicated. Pyruvate has been shown neuroprotective in animal models for many neurological disorders, presumably owing to its potent anti-oxidative, anti-inflammatory, and energy metabolic properties. We therefore investigated whether exogenous pyruvate could also protect nigral DA neurons from degeneration and reverse the associated motor deficits in an animal model of PD using the DA neuron-specific toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP (20 mg/kg) was injected four times every 2 h into the peritoneum of mice, which resulted in a massive loss of DA neurons as well as an increase in neuronal death and cytosolic labile zinc overload. There were rises in inflammatory and oxidative responses, a drop in the striatal DA level, and the emergence of PD-related motor deficits. In comparison, when sodium pyruvate was administered intraperitoneally at a daily dose of 250 mg/kg for 7 days starting 2 h after the final MPTP treatment, significant relief in the MPTP-induced neuropathology, neurodegeneration, DA depletion, and motor symptoms was observed. Equiosmolar dose of NaCl had no neuroprotective effect, and lower doses of sodium pyruvate did not have any statistically significant effects. These findings suggest that pyruvate has therapeutic potential for the treatment of PD and related neurodegenerative diseases.

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Data Availability

The data obtained during the present study are available from the corresponding author on reasonable request.

Abbreviations

COX-2:

Cyclooxygenase-2

DA:

Dopamine

DAT:

Dopamine transporter

GFAP:

Glial fibrillary acid protein

HPLC:

High-performance liquid chromatography

HRP:

Horseradish peroxide

6-OHDA:

6-Hydroxydopamine

Iba-1:

Ionized calcium–binding adapter molecule-1

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

MMP-9:

Matrix metalloproteinase-9

MPP+ :

1-Methyl-4-phenylpyridinium ion

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NADPH:

Nicotinamide adenine dinucleotide phosphate

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SN:

Substantia nigra

SP:

Sodium pyruvate

TFLZn:

N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

References

  1. Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:120–131. https://doi.org/10.1111/j.1749-6632.2003.tb07470.x

    Article  CAS  PubMed  Google Scholar 

  2. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909. https://doi.org/10.1016/s0896-6273(03)00568-3

    Article  CAS  PubMed  Google Scholar 

  3. Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228. https://doi.org/10.1111/j.1749-6632.2003.tb07478.x

    Article  CAS  PubMed  Google Scholar 

  4. Mattson MP, Pedersen WA, Duan W, Culmsee C, Camandola S (1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893:154–175. https://doi.org/10.1111/j.1749-6632.1999.tb07824.x

    Article  CAS  PubMed  Google Scholar 

  5. Blaszczyk JW (2018) The emerging role of energy metabolism and neuroprotective strategies in Parkinson’s disease. Front Aging Neurosci 10:301. https://doi.org/10.3389/fnagi.2018.00301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Forno LS, DeLanney LE, Irwin I, Langston JW (1993) Similarities and differences between MPTP-induced parkinsonsim and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608

    CAS  PubMed  Google Scholar 

  7. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52:1830–1836. https://doi.org/10.1111/j.1471-4159.1989.tb07264.x

    Article  CAS  PubMed  Google Scholar 

  8. Jenner P (1993) Altered mitochondrial function, iron metabolism and glutathione levels in Parkinson’s disease. Acta Neurol Scand Suppl 146:6–13

    Article  CAS  Google Scholar 

  9. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520. https://doi.org/10.1111/j.1471-4159.1989.tb09150.x

    Article  CAS  PubMed  Google Scholar 

  10. Perry TL, Yong VW (1986) Idiopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett 67:269–274. https://doi.org/10.1016/0304-3940(86)90320-4

    Article  CAS  PubMed  Google Scholar 

  11. Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease. Neurosci Lett 142:128–130. https://doi.org/10.1016/0304-3940(92)90355-b

    Article  CAS  PubMed  Google Scholar 

  12. Sanders LH, Greenamyre JT (2013) Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 62:111–120. https://doi.org/10.1016/j.freeradbiomed.2013.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McGeer PL, McGeer EG (2004) Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 10 (Suppl 1):S3-7. https://doi.org/10.1016/j.parkreldis.2004.01.005

    Article  PubMed  Google Scholar 

  14. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483. https://doi.org/10.1002/mds.21751

    Article  PubMed  Google Scholar 

  15. Meredith GE, Rademacher DJ (2011) MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis 1:19–33. https://doi.org/10.3233/JPD-2011-11023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–1016. https://doi.org/10.1126/science.272.5264.1013

    Article  CAS  PubMed  Google Scholar 

  17. Sorensen JC, Mattsson B, Andreasen A, Johansson BB (1998) Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res 812:265–269. https://doi.org/10.1016/s0006-8993(98)00943-3

    Article  CAS  PubMed  Google Scholar 

  18. Lee JM, Zipfel GJ, Park KH, He YY, Hsu CY, Choi DW (2002) Zinc translocation accelerates infarction after mild transient focal ischemia. Neuroscience 115:871–878. https://doi.org/10.1016/s0306-4522(02)00513-4

    Article  CAS  PubMed  Google Scholar 

  19. Frederickson CJ, Hernandez MD, Goik SA, Morton JD, McGinty JF (1988) Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: a histofluorescence study. Brain Res 446:383–386. https://doi.org/10.1016/0006-8993(88)90899-2

    Article  CAS  PubMed  Google Scholar 

  20. Frederickson CJ, Hernandez MD, McGinty JF (1989) Translocation of zinc may contribute to seizure-induced death of neurons. Brain Res 480:317–321. https://doi.org/10.1016/0006-8993(89)90199-6

    Article  CAS  PubMed  Google Scholar 

  21. Lee JY, Cole TB, Palmiter RD, Koh JY (2000) Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin. J Neurosci 20:RC79. https://doi.org/10.1523/JNEUROSCI.20-11-j0003.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Suh SW, Chen JW, Motamedi M, Bell B, Listiak K, Pons NF, Danscher G, Frederickson CJ (2000) Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res 85:268–273. https://doi.org/10.1016/s0006-8993(99)02095-8

    Article  Google Scholar 

  23. Suh SW, Garnier P, Aoyama K, Chen Y, Swanson RA (2004) Zinc release contributes to hypoglycemia-induced neuronal death. Neurobiol Dis 16:538–545. https://doi.org/10.1016/j.nbd.2004.04.017

    Article  CAS  PubMed  Google Scholar 

  24. Tonder N, Johansen FF, Frederickson CJ, Zimmer J, Diemer NH (1990) Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat. Neurosci Lett 109:247–252. https://doi.org/10.1016/0304-3940(90)90002-q

    Article  CAS  PubMed  Google Scholar 

  25. Aizenman E, Stout AK, Hartnett KA, Dineley KE, McLaughlin B, Reynolds IJ (2000) Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J Neurochem 75:1878–1888. https://doi.org/10.1046/j.1471-4159.2000.0751878.x

    Article  CAS  PubMed  Google Scholar 

  26. Lee JY, Kim JH, Palmiter RD, Koh JY (2003) Zinc released from metallothionein-III may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp Neurol 184:337–347. https://doi.org/10.1016/s0014-4886(03)00382-0

    Article  CAS  PubMed  Google Scholar 

  27. Chung J, Chang S, Kim Y, Shin H (2000) Zinc increases the excitability of dopaminergic neurons in rat substantia nigra. Neurosci Lett 286:183–186. https://doi.org/10.1016/s0304-3940(00)01120-4

    Article  CAS  PubMed  Google Scholar 

  28. Noh J, Chung JM (2019) Modulation of dopaminergic neuronal excitability by zinc through the regulation of calcium-related channels. Exp Neurobiol 28:578–592. https://doi.org/10.5607/en.2019.28.5.578

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P et al (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4):1953–1975. https://doi.org/10.1093/brain/114.4.1953

    Article  PubMed  Google Scholar 

  30. Tamano H, Nishio R, Morioka H, Takeda A (2019) Extracellular Zn(2+) influx into nigral dopaminergic neurons plays a key role for pathogenesis of 6-hydroxydopamine-induced Parkinson’s disease in rats. Mol Neurobiol 56:435–443. https://doi.org/10.1007/s12035-018-1075-z

    Article  CAS  PubMed  Google Scholar 

  31. Sikora J, Kieffer BL, Paoletti P, Ouagazzal AM (2020) Synaptic zinc contributes to motor and cognitive deficits in 6-hydroxydopamine mouse models of Parkinson’s disease. Neurobiol Dis 134:104681. https://doi.org/10.1016/j.nbd.2019.104681

    Article  CAS  PubMed  Google Scholar 

  32. Lee JY, Son HJ, Choi JH, Cho E, Kim J, Chung SJ, Hwang O, Koh JY (2009) Cytosolic labile zinc accumulation in degenerating dopaminergic neurons of mouse brain after MPTP treatment. Brain Res 1286:208–214. https://doi.org/10.1016/j.brainres.2009.06.046

    Article  CAS  PubMed  Google Scholar 

  33. Sonsalla PK, Heikkila RE (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur J Pharmacol 129:339–345. https://doi.org/10.1016/0014-2999(86)90444-9

    Article  CAS  PubMed  Google Scholar 

  34. Desagher S, Glowinski J, Premont J (1997) Pyruvate protects neurons against hydrogen peroxide-induced toxicity. J Neurosci 17:9060–9067. https://doi.org/10.1523/JNEUROSCI.17-23-09060.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang XF, Cynader MS (2001) Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. J Neurosci 21:3322–3331. https://doi.org/10.1523/JNEUROSCI.21-10-03322.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Relja B, Omid N, Wagner N, Mors K, Werner I, Juengel E, Perl M, Marzi I (2016) Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells. Int J Mol Med 37:517–525. https://doi.org/10.3892/ijmm.2015.2431

    Article  CAS  PubMed  Google Scholar 

  37. Sheline CT, Behrens MM, Choi DW (2000) Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J Neurosci 20:3139–3146. https://doi.org/10.1523/JNEUROSCI.20-09-03139.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee JY, Kim YH, Koh JY (2001) Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci 21:RC171. https://doi.org/10.1523/JNEUROSCI.21-20-j0002.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maus M, Marin P, Israel M, Glowinski J, Premont J (1999) Pyruvate and lactate protect striatal neurons against N-methyl-D-aspartate-induced neurotoxicity. Eur J Neurosci 11:3215–3224. https://doi.org/10.1046/j.1460-9568.1999.00745.x

    Article  CAS  PubMed  Google Scholar 

  40. Yi JS, Kim TY, Kyu Kim D, Koh JY (2007) Systemic pyruvate administration markedly reduces infarcts and motor deficits in rat models of transient and permanent focal cerebral ischemia. Neurobiol Dis 26:94–104. https://doi.org/10.1016/j.nbd.2006.12.007

    Article  CAS  PubMed  Google Scholar 

  41. Wang Q, van Hoecke M, Tang XN, Lee H, Zheng Z, Swanson RA, Yenari MA (2009) Pyruvate protects against experimental stroke via an anti-inflammatory mechanism. Neurobiol Dis 36:223–231. https://doi.org/10.1016/j.nbd.2009.07.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim TY, Yi JS, Chung SJ, Kim DK, Byun HR, Lee JY, Koh JY (2007) Pyruvate protects against kainate-induced epileptic brain damage in rats. Exp Neurol 208:159–167. https://doi.org/10.1016/j.expneurol.2007.08.013

    Article  CAS  PubMed  Google Scholar 

  43. Fukushima M, Lee SM, Moro N, Hovda DA, Sutton RL (2009) Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma 26:1095–1110. https://doi.org/10.1089/neu.2008.0771

    Article  PubMed  PubMed Central  Google Scholar 

  44. Moro N, Sutton RL (2010) Beneficial effects of sodium or ethyl pyruvate after traumatic brain injury in the rat. Exp Neurol 225:391–401. https://doi.org/10.1016/j.expneurol.2010.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Suh SW, Aoyama K, Matsumori Y, Liu J, Swanson RA (2005) Pyruvate administered after severe hypoglycemia reduces neuronal death and cognitive impairment. Diabetes 54:1452–1458. https://doi.org/10.2337/diabetes.54.5.1452

    Article  CAS  PubMed  Google Scholar 

  46. O’Donnell-Tormey J, Nathan CF, Lanks K, DeBoer CJ, de la Harpe J (1987) Secretion of pyruvate. An antioxidant defense of mammalian cells. J Exp Med 165:500–514. https://doi.org/10.1084/jem.165.2.500

    Article  CAS  PubMed  Google Scholar 

  47. Das UN (2006) Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. Med Sci Monit 12:RA79-84

    CAS  PubMed  Google Scholar 

  48. Zilberter Y, Gubkina O, Ivanov AI (2015) A unique array of neuroprotective effects of pyruvate in neuropathology. Front Neurosci 9:17. https://doi.org/10.3389/fnins.2015.00017

    Article  PubMed  PubMed Central  Google Scholar 

  49. Liu R, Wang SM, Liu XQ, Guo SJ, Wang HB, Hu S, Zhou FQ, Sheng ZY (2016) Pyruvate alleviates lipid peroxidation and multiple-organ dysfunction in rats with hemorrhagic shock. Am J Emerg Med 34:525–530. https://doi.org/10.1016/j.ajem.2015.12.040

    Article  CAS  PubMed  Google Scholar 

  50. Effenberger-Neidnicht K, Brauckmann S, Jagers J, Patyk V, Waack IN, Kirsch M (2019) Protective effects of sodium pyruvate during systemic inflammation limited to the correction of metabolic acidosis. Inflammation 42:598–605. https://doi.org/10.1007/s10753-018-0917-1

    Article  CAS  PubMed  Google Scholar 

  51. Zeng J, Yang GY, Ying W, Kelly M, Hirai K, James TL, Swanson RA, Litt L (2007) Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices. J Cereb Blood Flow Metab 27:304–315. https://doi.org/10.1038/sj.jcbfm.9600335

    Article  CAS  PubMed  Google Scholar 

  52. Kim SW, Lee HK, Kim HJ, Yoon SH, Lee JK (2016) Neuroprotective effect of ethyl pyruvate against Zn(2+) toxicity via NAD replenishment and direct Zn(2+) chelation. Neuropharmacology 105:411–419. https://doi.org/10.1016/j.neuropharm.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  53. Miao Y, Qiu Y, Lin Y, Miao Z, Zhang J, Lu X (2011) Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism. Mol Biol Rep 38:3235–3242. https://doi.org/10.1007/s11033-010-9998-0

    Article  CAS  PubMed  Google Scholar 

  54. Alvarez G, Ramos M, Ruiz F, Satrustegui J, Bogonez E (2003) Pyruvate protection against β-amyloid-induced neuronal death: role of mitochondrial redox state. J Neurosci Res 73:260–269. https://doi.org/10.1002/jnr.10648

    Article  CAS  PubMed  Google Scholar 

  55. Wang X, Perez E, Liu R, Yan LJ, Mallet RT, Yang SH (2007) Pyruvate protects mitochondria from oxidative stress in human neuroblastoma SK-N-SH cells. Brain Res 1132:1–9. https://doi.org/10.1016/j.brainres.2006.11.032

    Article  CAS  PubMed  Google Scholar 

  56. Ariyannur PS, Xing G, Barry ES, Benford B, Grunberg NE, Sharma P (2021) Effects of pyruvate administration on mitochondrial enzymes, neurological behaviors, and neurodegeneration after traumatic brain injury. Aging Dis 12:983–999. https://doi.org/10.14336/AD.2020.1015

    Article  PubMed  PubMed Central  Google Scholar 

  57. Isopi E, Granzotto A, Corona C, Bomba M, Ciavardelli D et al (2015) Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer’s disease without reducing amyloid and tau pathology. Neurobiol Dis 81:214–224. https://doi.org/10.1016/j.nbd.2014.11.013

    Article  CAS  PubMed  Google Scholar 

  58. Wang X, Hu X, Yang Y, Takata T, Sakurai T (2015) Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer’s disease. Exp Neurol 271:145–154. https://doi.org/10.1016/j.expneurol.2015.06.008

    Article  CAS  PubMed  Google Scholar 

  59. Ryu JK, Kim SU, McLarnon JG (2003) Neuroprotective effects of pyruvate in the quinolinic acid rat model of Huntington’s disease. Exp Neurol 183:700–704. https://doi.org/10.1016/s0014-4886(03)00214-0

    Article  CAS  PubMed  Google Scholar 

  60. Mazzio E, Soliman KF (2003) Pyruvic acid cytoprotection against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and hydrogen peroxide toxicities in vitro. Neurosci Lett 337:77–80. https://doi.org/10.1016/s0304-3940(02)01327-7

    Article  CAS  PubMed  Google Scholar 

  61. Sheline CT, Zhu J, Zhang W, Shi C, Cai AL (2013) Mitochondrial inhibitor models of Huntington’s disease and Parkinson’s disease induce zinc accumulation and are attenuated by inhibition of zinc neurotoxicity in vitro or in vivo. Neurodegener Dis 11:49–58. https://doi.org/10.1159/000336558

    Article  CAS  PubMed  Google Scholar 

  62. Fedotova EI, Dolgacheva LP, Abramov AY, Berezhnov AV (2022) Lactate and pyruvate activate autophagy and mitophagy that protect cells in toxic model of Parkinson’s disease. Mol Neurobiol 59:177–190. https://doi.org/10.1007/s12035-021-02583-8

    Article  CAS  PubMed  Google Scholar 

  63. Meyer OA, Tilson HA, Byrd WC, Riley MT (1979) A method for the routine assessment of fore- and hindlimb grip strength of rats and mice. Neurobehav Toxicol 1:233–236

    CAS  PubMed  Google Scholar 

  64. Lee JY, Cho E, Ko YE, Kim I, Lee KJ, Kwon SU, Kang DW, Kim JS (2012) Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, protects against ischemic brain injury in rats. Brain Res 1431:97–106. https://doi.org/10.1016/j.brainres.2011.11.007

    Article  CAS  PubMed  Google Scholar 

  65. Dunham NW, Miya TS (1957) A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc 46:208–209. https://doi.org/10.1002/jps.3030460322

    Article  CAS  PubMed  Google Scholar 

  66. Oh SB, Kim MS, Park S, Son H, Kim SY, Kim MS, Jo DG, Tak E et al (2019) Clusterin contributes to early stage of Alzheimer’s disease pathogenesis. Brain Pathol 29:217–231. https://doi.org/10.1111/bpa.12660

    Article  CAS  PubMed  Google Scholar 

  67. Lee JA, Kim HR, Son HJ, Shin N, Han SH, Cheong CS, Kim DJ, Hwang O (2020) A novel pyrazolo [3,4-d] pyrimidine, KKC080106, activates the Nrf2 pathway and protects nigral dopaminergic neurons. Exp Neurol 332:113387. https://doi.org/10.1016/j.expneurol.2020.113387

    Article  CAS  PubMed  Google Scholar 

  68. Lee JA, Kim JH, Woo SY, Son HJ, Han SH, Jang BK, Choi JW, Kim DJ et al (2015) A novel compound VSC2 has anti-inflammatory and antioxidant properties in microglia and in Parkinson’s disease animal model. Br J Pharmacol 172:1087–1100. https://doi.org/10.1111/bph.12973

    Article  CAS  PubMed  Google Scholar 

  69. Son HJ, Lee JA, Shin N, Choi JH, Seo JW, Chi DY, Lee CS, Kim EM et al (2012) A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson’s disease induced by MPTP. Br J Pharmacol 165:2213–2227. https://doi.org/10.1111/j.1476-5381.2011.01692.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Stayte S, Laloli KJ, Rentsch P, Lowth A, Li KM, Pickford R, Vissel B (2020) The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain. Exp Neurol 323:113062. https://doi.org/10.1016/j.expneurol.2019.113062

    Article  CAS  PubMed  Google Scholar 

  71. Biju KC, Evans RC, Shrestha K, Carlisle DCB, Gelfond J, Clark RA (2018) Methylene blue ameliorates olfactory dysfunction and motor deficits in a chronic MPTP/probenecid mouse model of Parkinson’s disease. Neuroscience 380:111–122. https://doi.org/10.1016/j.neuroscience.2018.04.008

    Article  CAS  PubMed  Google Scholar 

  72. Miao Q, Chai Z, Song LJ, Wang Q, Song GB, Wang J, Yu JZ, Xiao BG et al (2022) The neuroprotective effects and transdifferentiation of astrocytes into dopaminergic neurons of Ginkgolide K on Parkinson’ disease mice. J Neuroimmunol 364:577806. https://doi.org/10.1016/j.jneuroim.2022.577806

    Article  CAS  PubMed  Google Scholar 

  73. Kim YH, Koh JY (2002) The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture. Exp Neurol 177:407–418. https://doi.org/10.1006/exnr.2002.7990

    Article  CAS  PubMed  Google Scholar 

  74. Cosi C, Marien M (1998) Decreases in mouse brain NAD+ and ATP induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP): prevention by the poly(ADP-ribose) polymerase inhibitor, benzamide. Brain Res 80:58–67. https://doi.org/10.1016/s0006-8993(98)00829-4

    Article  Google Scholar 

  75. Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM et al (1999) Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci USA 96:5774–5779. https://doi.org/10.1073/pnas.96.10.5774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ryou MG, Flaherty DC, Hoxha B, Gurji H, Sun J, Hodge LM, Olivencia-Yurvati AH, Mallet RT (2010) Pyruvate-enriched cardioplegia suppresses cardiopulmonary bypass-induced myocardial inflammation. Ann Thorac Surg 90:1529–1535. https://doi.org/10.1016/j.athoracsur.2010.06.010

    Article  PubMed  Google Scholar 

  77. Sharma AB, Barlow MA, Yang SH, Simpkins JW, Mallet RT (2008) Pyruvate enhances neurological recovery following cardiopulmonary arrest and resuscitation. Resuscitation 76:108–119. https://doi.org/10.1016/j.resuscitation.2007.04.028

    Article  CAS  PubMed  Google Scholar 

  78. Nguyen AQ, Cherry BH, Scott GF, Ryou MG, Mallet RT (2014) Erythropoietin: powerful protection of ischemic and post-ischemic brain. Exp Biol Med (Maywood) 239:1461–1475. https://doi.org/10.1177/1535370214523703

    Article  CAS  Google Scholar 

  79. Mongan PD, Karaian J, Van Der Schuur BM, Via DK, Sharma P (2003) Pyruvate prevents poly-ADP ribose polymerase (PARP) activation, oxidative damage, and pyruvate dehydrogenase deactivation during hemorrhagic shock in swine. J Surg Res 112:180–188. https://doi.org/10.1016/s0022-4804(03)00148-3

    Article  CAS  PubMed  Google Scholar 

  80. Ryu JK, Kim SU, McLarnon JG (2004) Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington’s disease. Exp Neurol 187:150–159. https://doi.org/10.1016/j.expneurol.2004.01.006

    Article  CAS  PubMed  Google Scholar 

  81. Park JH, Hong YH, Kim HJ, Kim SM, Kim MJ, Park KS, Sung JJ, Lee KW (2007) Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model. Neurosci Lett 413:265–269. https://doi.org/10.1016/j.neulet.2006.11.058

    Article  CAS  PubMed  Google Scholar 

  82. Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111. https://doi.org/10.1523/JNEUROSCI.20-23-j0001.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ahmed SS, Santosh W, Kumar S, Christlet HT (2009) Metabolic profiling of Parkinson’s disease: evidence of biomarker from gene expression analysis and rapid neural network detection. J Biomed Sci 16:63. https://doi.org/10.1186/1423-0127-16-63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mallet D, Dufourd T, Decourt M, Carcenac C, Bossu P et al (2022) A metabolic biomarker predicts Parkinson’s disease at the early stages in patients and animal models. J Clin Invest 132:e146400. https://doi.org/10.1172/JCI146400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Conn AR, Steele RD (1982) Transport of alpha-keto analogues of amino acids across blood-brain barrier in rats. Am J Physiol 243:E272-277. https://doi.org/10.1152/ajpendo.1982.243.4.E272

    Article  CAS  PubMed  Google Scholar 

  86. Oldendorf WH (1973) Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am J Physiol 224:1450–1453. https://doi.org/10.1152/ajplegacy.1973.224.6.1450

    Article  CAS  PubMed  Google Scholar 

  87. Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299

    Article  CAS  Google Scholar 

  88. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14. https://doi.org/10.1111/j.1471-4159.2005.03168.x

    Article  CAS  PubMed  Google Scholar 

  89. Gray LR, Tompkins SC, Taylor EB (2014) Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci 71:2577–2604. https://doi.org/10.1007/s00018-013-1539-2

    Article  CAS  PubMed  Google Scholar 

  90. Poon HF, Frasier M, Shreve N, Calabrese V, Wolozin B, Butterfield DA (2005) Mitochondrial associated metabolic proteins are selectively oxidized in A30P α-synuclein transgenic mice—a model of familial Parkinson’s disease. Neurobiol Dis 18:492–498. https://doi.org/10.1016/j.nbd.2004.12.009

    Article  CAS  PubMed  Google Scholar 

  91. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS et al (2010) PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2:52ra73. https://doi.org/10.1126/scitranslmed.3001059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miki Y, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2017) Alteration of mitochondrial protein PDHA1 in Lewy body disease and PARK14. Biochem Biophys Res Commun 489:439–444. https://doi.org/10.1016/j.bbrc.2017.05.162

    Article  CAS  PubMed  Google Scholar 

  93. Smith AM, Depp C, Ryan BJ, Johnston GI, Alegre-Abarrategui J et al (2018) Mitochondrial dysfunction and increased glycolysis in prodromal and early Parkinson’s blood cells. Mov Disord 3:1580–1590. https://doi.org/10.1002/mds.104

    Article  CAS  Google Scholar 

  94. Stacpoole PW (2012) The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell 11:371–377. https://doi.org/10.1111/j.1474-9726.2012.00805.x

    Article  CAS  PubMed  Google Scholar 

  95. Ghosh A, Tyson T, George S, Hildebrandt EN, Steiner JA et al (2016) Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease. Sci Transl Med 8:368ra174. https://doi.org/10.1126/scitranslmed.aag2210

    Article  CAS  PubMed  Google Scholar 

  96. Cai R, Zhang Y, Simmering JE, Schultz JL, Li Y et al (2019) Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases. J Clin Invest 129:4539–4549. https://doi.org/10.1172/JCI129987

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the National Research Foundation, Ministry of Science & ICT (MSIT), Republic of Korea (NRF-2020R1F1A1048577 to JYL) and the Asan Institute for Life Sciences, Asan Medical Center (2022IL0011 to JYL).

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Authors and Affiliations

  1. Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Yun-Mi Kim & Su Yeon Choi

  2. Asan Institute for Life Sciences, Asan Medical Center, Seoul, 05505, Republic of Korea

    Yun-Mi Kim, Su Yeon Choi & Joo-Yong Lee

  3. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Onyou Hwang

  4. Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Joo-Yong Lee

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  1. Yun-Mi Kim
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Contributions

Co-corresponding authors (JYL and OH) contributed to the study conception and design. All authors participated in experimental performance, and data analysis and interpretation, and wrote, reviewed and approved this manuscript and the publication.

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Correspondence to Onyou Hwang or Joo-Yong Lee.

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Animal study was pre-reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) and performed under the Guideline for Laboratory Animal Care and Use of the Asan Institute for Life Sciences (Asan Medical Center; Seoul, Korea).

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Kim, YM., Choi, S.Y., Hwang, O. et al. Pyruvate Prevents Dopaminergic Neurodegeneration and Motor Deficits in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease. Mol Neurobiol 59, 6956–6970 (2022). https://doi.org/10.1007/s12035-022-03017-9

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