Molecular Neurobiology

, Volume 56, Issue 7, pp 4945–4959 | Cite as

Involvement of the Cholinergic Parameters and Glial Cells in Learning Delay Induced by Glutaric Acid: Protection by N-Acetylcysteine

  • Fernanda Silva Rodrigues
  • Viviane Nogueira de Zorzi
  • Marla Parizzi Funghetto
  • Fernanda Haupental
  • Alexandra Seide Cardoso
  • Sara Marchesan
  • Andréia M. Cardoso
  • Maria Rosa C. Schinger
  • Alencar Kolinski Machado
  • Ivana Beatrice Mânica da Cruz
  • Marta Maria Medeiros Frescura Duarte
  • Léder L. Xavier
  • Ana Flavia Furian
  • Mauro Schneider Oliveira
  • Adair Roberto Soares Santos
  • Luiz Fernando Freire Royes
  • Michele Rechia FigheraEmail author


Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight−1, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.


Glutaric acid Striatum N-acetylcysteine Procedural learning Memory Acetylcholinesterase activity α7nAChR Inflammation 


Funding Information

This work was supported by the CNPq (grants: Pronem 11/2082-4). M.R. Fighera, L.F.F. Royes, A.F. Furian, M. Schneider-Oliveira, and A.R.S. Santos are recipients of CNPq fellowships.

Compliance with Ethical Standards

Laboratory experiments were performed in accordance with national and international legislations (Brazilian College of Animal Experimentation (COBEA) and the US Public Health Service’s Policy on Humane Care and Use of Laboratory Animals-PHS Policy) and approved by the Ethics Committee for Animal Research of Universidade Federal de Santa Maria (UFSM; Permit Number: 116/2010) and Universidade Federal de Santa Catarina (UFSC; Permit Number: 5386180317).

Conflict of interest

All authors confirm that there is no competing financial conflict of interest.

Supplementary material

12035_2018_1395_MOESM1_ESM.docx (350 kb)
ESM 1 (DOCX 349 kb)


  1. 1.
    Deffains M, Bergman H (2015) Striatal cholinergic interneurons and cortico-striatal synaptic plasticity in health and disease. Mov Disord 30(8):1014–1025. CrossRefPubMedGoogle Scholar
  2. 2.
    Oberholzer VG, Levin B, Burgess EA, Young WF (1967) Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child 42(225):492–504CrossRefGoogle Scholar
  3. 3.
    Olivera-Bravo S, Fernandez A, Sarlabos MN, Rosillo JC, Casanova G, Jimenez M, Barbeito L (2011) Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. PLoS One 6(6):e20831. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Moustafa AA, Chakravarthy S, Phillips JR, Crouse JJ, Gupta A, Frank MJ, Hall JM, Jahanshahi M (2016) Interrelations between cognitive dysfunction and motor symptoms of Parkinson’s disease: behavioral and neural studies. Rev Neurosci 27(5):535–548. CrossRefPubMedGoogle Scholar
  5. 5.
    Gabbi P, Nogueira V, Haupental F, Rodrigues FS, do Nascimento PS, Barbosa S, Arend J, Furian AF et al (2018) Ammonia role in glial dysfunction in methylmalonic acidemia. Toxicol Lett 295:237–248. CrossRefPubMedGoogle Scholar
  6. 6.
    Gottfries CG, Adolfsson R, Aquilonius SM, Carlsson A, Eckernas SA, Nordberg A, Oreland L, Svennerholm L et al (1983) Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT). Neurobiol Aging 4(4):261–271CrossRefGoogle Scholar
  7. 7.
    Picconi B, Passino E, Sgobio C, Bonsi P, Barone I, Ghiglieri V, Pisani A, Bernardi G et al (2006) Plastic and behavioral abnormalities in experimental Huntington’s disease: a crucial role for cholinergic interneurons. Neurobiol Dis 22(1):143–152. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Perez-Lloret S, Barrantes FJ (2016) Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. NPJ Parkinsons Dis 2:16001. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ferreira GK, Carvalho-Silva M, Goncalves CL, Vieira JS, Scaini G, Ghedim FV, Deroza PF, Zugno AI et al (2012) L-tyrosine administration increases acetylcholinesterase activity in rats. Neurochem Int 61(8):1370–1374. CrossRefPubMedGoogle Scholar
  10. 10.
    Gabbi P, Ribeiro LR, Jessie Martins G, Cardoso AS, Haupental F, Rodrigues FS, Machado AK, Sperotto Brum J et al (2017) Methylmalonate induces inflammatory and apoptotic potential: a link to glial activation and neurological dysfunction. J Neuropathol Exp Neurol 76(3):160–178. CrossRefPubMedGoogle Scholar
  11. 11.
    Gomes LM, Scaini G, Carvalho-Silva M, Gomes ML, Malgarin F, Kist LW, Bogo MR, Rico EP et al (2018) Antioxidants reverse the changes in the cholinergic system caused by L-tyrosine administration in rats. Neurotox Res. CrossRefGoogle Scholar
  12. 12.
    Goodman SI, Norenberg MD, Shikes RH, Breslich DJ, Moe PG (1977) Glutaric aciduria: biochemical and morphologic considerations. J Pediatr 90(5):746–750CrossRefGoogle Scholar
  13. 13.
    Goodman SI (2001) Prenatal diagnosis of glutaric acidemias. Prenat Diagn 21(13):1167–1168CrossRefGoogle Scholar
  14. 14.
    Strauss KA, Morton DH (2003) Type I glutaric aciduria, part 2: a model of acute striatal necrosis. Am J Med Genet C: Semin Med Genet 121C(1):53–70. CrossRefGoogle Scholar
  15. 15.
    Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI (1991) Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 41(1):89–95. CrossRefPubMedGoogle Scholar
  16. 16.
    Hoffmann GF, Zschocke J (1999) Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis 22(4):381–391CrossRefGoogle Scholar
  17. 17.
    Patil N, Shinde S, Karande S, Kulkarni M (2004) Glutaric aciduria type I associated with learning disability. Indian J Pediatr 71(10):948PubMedGoogle Scholar
  18. 18.
    Cayzac S, Delcasso S, Paz V, Jeantet Y, Cho YH (2011) Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease. Proc Natl Acad Sci U S A 108(22):9280–9285. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    El Massioui N, Ouary S, Cheruel F, Hantraye P, Brouillet E (2001) Perseverative behavior underlying attentional set-shifting deficits in rats chronically treated with the neurotoxin 3-nitropropionic acid. Exp Neurol 172(1):172–181. CrossRefPubMedGoogle Scholar
  20. 20.
    Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65(5):585–596. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bonsi P, Cuomo D, Martella G, Madeo G, Schirinzi T, Puglisi F, Ponterio G, Pisani A (2011) Centrality of striatal cholinergic transmission in basal ganglia function. Front Neuroanat 5:6. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhou FM, Liang Y, Dani JA (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 4(12):1224–1229. CrossRefPubMedGoogle Scholar
  23. 23.
    Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, Jacobs AH, Herholz K et al (2005) Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 65(11):1716–1722. CrossRefPubMedGoogle Scholar
  24. 24.
    Bosboom JL, Stoffers D, Wolters E (2003) The role of acetylcholine and dopamine in dementia and psychosis in Parkinson’s disease. J Neural Transm Suppl 65:185–195CrossRefGoogle Scholar
  25. 25.
    Williams-Gray CH, Foltynie T, Lewis SJ, Barker RA (2006) Cognitive deficits and psychosis in Parkinson’s disease: a review of pathophysiology and therapeutic options. CNS Drugs 20(6):477–505CrossRefGoogle Scholar
  26. 26.
    Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36(2):96–108. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wessler I, Kirkpatrick CJ (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154(8):1558–1571. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Echeverria V, Yarkov A, Aliev G (2016) Positive modulators of the alpha7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer’s disease. Prog Neurobiol 144:142–157. CrossRefPubMedGoogle Scholar
  29. 29.
    Morris GP, Clark IA, Zinn R, Vissel B (2013) Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 105:40–53. CrossRefPubMedGoogle Scholar
  30. 30.
    Dallerac G, Rouach N (2016) Astrocytes as new targets to improve cognitive functions. Prog Neurobiol 144:48–67. CrossRefPubMedGoogle Scholar
  31. 31.
    Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC et al (2012) Glial cells in (patho)physiology. J Neurochem 121(1):4–27. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    De Keyser J, Steen C, Mostert JP, Koch MW (2008) Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance. J Cereb Blood Flow Metab 28(10):1645–1651. CrossRefPubMedGoogle Scholar
  33. 33.
    Olivera-Bravo S, Barbeito L (2015) A role of astrocytes in mediating postnatal neurodegeneration in glutaric acidemia-type 1. FEBS Lett 589(22):3492–3497. CrossRefPubMedGoogle Scholar
  34. 34.
    Olivera-Bravo S, Isasi E, Fernandez A, Casanova G, Rosillo JC, Barbeito L (2016) Astrocyte dysfunction in developmental neurometabolic diseases. Adv Exp Med Biol 949:227–243. CrossRefPubMedGoogle Scholar
  35. 35.
    Olivera S, Fernandez A, Latini A, Rosillo JC, Casanova G, Wajner M, Cassina P, Barbeito L (2008) Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: possible implications for GAI pathogenesis. Neurobiol Dis 32(3):528–534. CrossRefPubMedGoogle Scholar
  36. 36.
    da Costa Ferreira G, Schuck PF, Viegas CM, Tonin A, Ribeiro CA, Pettenuzzo LF, Pereira LO, Netto CA et al (2008) Chronic early postnatal glutaric acid administration causes cognitive deficits in the water maze. Behav Brain Res 187(2):411–416. CrossRefPubMedGoogle Scholar
  37. 37.
    Goncalves JF, Fiorenza AM, Spanevello RM, Mazzanti CM, Bochi GV, Antes FG, Stefanello N, Rubin MA et al (2010) N-acetylcysteine prevents memory deficits, the decrease in acetylcholinesterase activity and oxidative stress in rats exposed to cadmium. Chem Biol Interact 186(1):53–60. CrossRefPubMedGoogle Scholar
  38. 38.
    Kay C, Harper DN, Hunt M (2010) Differential effects of MDMA and scopolamine on working versus reference memory in the radial arm maze task. Neurobiol Learn Mem 93(2):151–156. CrossRefPubMedGoogle Scholar
  39. 39.
    Prediger RD, Batista LC, Medeiros R, Pandolfo P, Florio JC, Takahashi RN (2006) The risk is in the air: Intranasal administration of MPTP to rats reproducing clinical features of Parkinson’s disease. Exp Neurol 202(2):391–403. CrossRefPubMedGoogle Scholar
  40. 40.
    Morris RG, Garrud P, Rawlins JN, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683CrossRefGoogle Scholar
  41. 41.
    Leite MR, Cechella JL, Pinton S, Nogueira CW, Zeni G (2016) A diphenyl diselenide-supplemented diet and swimming exercise promote neuroprotection, reduced cell apoptosis and glial cell activation in the hypothalamus of old rats. Exp Gerontol 82:1–7. CrossRefPubMedGoogle Scholar
  42. 42.
    Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefGoogle Scholar
  43. 43.
    Peres CMC (2005) Como cultivar células’.1ª ed., p. 3–4Google Scholar
  44. 44.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  45. 45.
    Meshorer E, Soreq H (2006) Virtues and woes of AChE alternative splicing in stress-related neuropathologies. Trends Neurosci 29(4):216–224. CrossRefPubMedGoogle Scholar
  46. 46.
    Gnatek Y, Zimmerman G, Goll Y, Najami N, Soreq H, Friedman A (2012) Acetylcholinesterase loosens the brain’s cholinergic anti-inflammatory response and promotes epileptogenesis. Front Mol Neurosci 5:66. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Easton A, Douchamps V, Eacott M, Lever C (2012) A specific role for septohippocampal acetylcholine in memory? Neuropsychologia 50(13):3156–3168. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Rodrigues FS, Souza MA, Magni DV, Ferreira AP, Mota BC, Cardoso AM, Paim M, Xavier LL et al (2013) N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups. PLoS One 8(10):e78332. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Laus MF, Vales LD, Costa TM, Almeida SS (2011) Early postnatal protein-calorie malnutrition and cognition: a review of human and animal studies. Int J Environ Res Public Health 8(2):590–612. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Perez-Garcia G, Guzman-Quevedo O, Da Silva Aragao R, Bolanos-Jimenez F (2016) Early malnutrition results in long-lasting impairments in pattern-separation for overlapping novel object and novel location memories and reduced hippocampal neurogenesis. Sci Rep 6:21275. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Matthews BR (2015) Memory dysfunction. Continuum 21(3 Behavioral Neurology and Neuropsychiatry):613–626. CrossRefPubMedGoogle Scholar
  52. 52.
    Barnes TD, Kubota Y, Hu D, Jin DZ, Graybiel AM (2005) Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature 437(7062):1158–1161. CrossRefPubMedGoogle Scholar
  53. 53.
    Marrone MC, Marinelli S, Biamonte F, Keller F, Sgobio CA, Ammassari-Teule M, Bernardi G, Mercuri NB (2006) Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Eur J Neurosci 24(7):2061–2070. CrossRefPubMedGoogle Scholar
  54. 54.
    Kirkby RJ (1969) Caudate nucleus lesions impair spontaneous alternation. Percept Mot Skills 29(2):550. CrossRefPubMedGoogle Scholar
  55. 55.
    Devan BD, Goad EH, Petri HL (1996) Dissociation of hippocampal and striatal contributions to spatial navigation in the water maze. Neurobiol Learn Mem 66(3):305–323. CrossRefPubMedGoogle Scholar
  56. 56.
    Boy N, Heringer J, Haege G, Glahn EM, Hoffmann GF, Garbade SF, Kolker S, Burgard P (2015) A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I. Orphanet J Rare Dis 10:163. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Havekes R, Abel T, Van der Zee EA (2011) The cholinergic system and neostriatal memory functions. Behav Brain Res 221(2):412–423. CrossRefPubMedGoogle Scholar
  58. 58.
    Da Cunha C, Gomez AA, Blaha CD (2012) The role of the basal ganglia in motivated behavior. Rev Neurosci 23(5–6):747–767. CrossRefPubMedGoogle Scholar
  59. 59.
    Graybiel AM (1990) Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 13(7):244–254CrossRefGoogle Scholar
  60. 60.
    Contant C, Umbriaco D, Garcia S, Watkins KC, Descarries L (1996) Ultrastructural characterization of the acetylcholine innervation in adult rat neostriatum. Neuroscience 71(4):937–947CrossRefGoogle Scholar
  61. 61.
    Araujo DM, Lapchak PA, Collier B, Quirion R (1989) Localization of interleukin-2 immunoreactivity and interleukin-2 receptors in the rat brain: interaction with the cholinergic system. Brain Res 498(2):257–266CrossRefGoogle Scholar
  62. 62.
    Egea J, Buendia I, Parada E, Navarro E, Leon R, Lopez MG (2015) Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97(4):463–472. CrossRefPubMedGoogle Scholar
  63. 63.
    Young JW, Meves JM, Tarantino IS, Caldwell S, Geyer MA (2011) Delayed procedural learning in alpha7-nicotinic acetylcholine receptor knockout mice. Genes Brain Behav 10(7):720–733. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Licheri V, Lagstrom O, Lotfi A, Patton MH, Wigstrom H, Mathur B, Adermark L (2018) Complex control of striatal neurotransmission by nicotinic acetylcholine receptors via excitatory inputs onto medium spiny neurons. J Neurosci 38(29):6597–6607. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729. CrossRefPubMedGoogle Scholar
  66. 66.
    Valles AS, Borroni MV, Barrantes FJ (2014) Targeting brain alpha7 nicotinic acetylcholine receptors in Alzheimer’s disease: rationale and current status. CNS Drugs 28(11):975–987. CrossRefPubMedGoogle Scholar
  67. 67.
    Sharma G, Vijayaraghavan S (2008) Nicotinic receptors containing the alpha7 subunit: a model for rational drug design. Curr Med Chem 15(28):2921–2932CrossRefGoogle Scholar
  68. 68.
    Kaiser S, Wonnacott S (2000) alpha-bungarotoxin-sensitive nicotinic receptors indirectly modulate [(3)H]dopamine release in rat striatal slices via glutamate release. Mol Pharmacol 58(2):312–318CrossRefGoogle Scholar
  69. 69.
    Lovinger DM (2010) Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology 58(7):951–961. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Rosas-Ballina M, Tracey KJ (2009) Cholinergic control of inflammation. J Intern Med 265(6):663–679. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Nizri E, Hamra-Amitay Y, Sicsic C, Lavon I, Brenner T (2006) Anti-inflammatory properties of cholinergic up-regulation: a new role for acetylcholinesterase inhibitors. Neuropharmacology 50(5):540–547. CrossRefPubMedGoogle Scholar
  72. 72.
    Ratnakumari L, Qureshi IA, Butterworth RF (1994) Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency. Neurosci Lett 178(1):63–65CrossRefGoogle Scholar
  73. 73.
    Fighera MR, Royes LF, Furian AF, Oliveira MS, Fiorenza NG, Frussa-Filho R, Petry JC, Coelho RC et al (2006) GM1 ganglioside prevents seizures, Na+,K+-ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole. Neurobiol Dis 22(3):611–623. CrossRefGoogle Scholar
  74. 74.
    Kumar A, Chaudhary T, Mishra J (2013) Minocycline modulates neuroprotective effect of hesperidin against quinolinic acid induced Huntington’s disease like symptoms in rats: behavioral, biochemical, cellular and histological evidences. Eur J Pharmacol 720(1–3):16–28. CrossRefPubMedGoogle Scholar
  75. 75.
    Schain M, Kreisl WC (2017) Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep 17(3):25. CrossRefPubMedGoogle Scholar
  76. 76.
    Latini A, Ferreira GC, Scussiato K, Schuck PF, Solano AF, Dutra-Filho CS, Vargas CR, Wajner M (2007) Induction of oxidative stress by chronic and acute glutaric acid administration to rats. Cell Mol Neurobiol 27(4):423–438. CrossRefPubMedGoogle Scholar
  77. 77.
    Magni DV, Souza MA, Oliveira AP, Furian AF, Oliveira MS, Ferreira J, Santos AR, Mello CF et al (2011) Lipopolysaccharide enhances glutaric acid-induced seizure susceptibility in rat pups: behavioral and electroencephalographic approach. Epilepsy Res 93(2–3):138–148. CrossRefPubMedGoogle Scholar
  78. 78.
    Seminotti B, Amaral AU, Ribeiro RT, Rodrigues MDN, Colin-Gonzalez AL, Leipnitz G, Santamaria A, Wajner M (2016) Oxidative stress, disrupted energy metabolism, and altered signaling pathways in glutaryl-CoA dehydrogenase knockout mice: potential implications of quinolinic acid toxicity in the neuropathology of glutaric acidemia type I. Mol Neurobiol 53(9):6459–6475. CrossRefPubMedGoogle Scholar
  79. 79.
    Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Tanaka S, Ide M, Shibutani T, Ohtaki H, Numazawa S, Shioda S, Yoshida T (2006) Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 83(4):557–566. CrossRefPubMedGoogle Scholar
  81. 81.
    Block ML, Hong JS (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 35(Pt 5):1127–1132. CrossRefPubMedGoogle Scholar
  82. 82.
    Park SE, Sapkota K, Kim S, Kim H, Kim SJ (2011) Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol 164(3):1008–1025. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P et al (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274(2):1156–1163CrossRefGoogle Scholar
  84. 84.
    Zhao Y, Li S, Childs EE, Kuharsky DK, Yin XM (2001) Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury. J Biol Chem 276(29):27432–27440. CrossRefPubMedGoogle Scholar
  85. 85.
    Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290. CrossRefPubMedGoogle Scholar
  86. 86.
    Tian F, Fu X, Gao J, Ying Y, Hou L, Liang Y, Ning Q, Luo X (2014) Glutaric acid-mediated apoptosis in primary striatal neurons. Biomed Res Int 2014:484731. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Arakawa M, Ito Y (2007) N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 6(4):308–314. CrossRefPubMedGoogle Scholar
  88. 88.
    Costa M, Bernardi J, Fiuza T, Costa L, Brandao R, Pereira ME (2016) N-acetylcysteine protects memory decline induced by streptozotocin in mice. Chem Biol Interact 253:10–17. CrossRefPubMedGoogle Scholar
  89. 89.
    Smaga I, Pomierny B, Krzyzanowska W, Pomierny-Chamiolo L, Miszkiel J, Niedzielska E, Ogorka A, Filip M (2012) N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 39(2):280–287. CrossRefGoogle Scholar
  90. 90.
    Wan FJ, Tung CS, Shiah IS, Lin HC (2006) Effects of alpha-phenyl-N-tert-butyl nitrone and N-acetylcysteine on hydroxyl radical formation and dopamine depletion in the rat striatum produced by d-amphetamine. Eur Neuropsychopharmacol 16(2):147–153. CrossRefPubMedGoogle Scholar
  91. 91.
    Palacio JR, Markert UR, Martinez P (2011) Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res 60(7):695–704. CrossRefPubMedGoogle Scholar
  92. 92.
    Agrawal R, Tyagi E, Shukla R, Nath C (2009) A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology 56(4):779–787CrossRefGoogle Scholar
  93. 93.
    Costa M et al (2015) N-acetyl cysteine decreases mice brain acetyl cholinesterase activity: an in vitro kinetic study. Enz Eng 5:1000135–1000135.
  94. 94.
    Suzuki T, Hide I, Matsubara A, Hama C, Harada K, Miyano K, Andra M, Matsubayashi H et al (2006) Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res 83(8):1461–1470. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fernanda Silva Rodrigues
    • 1
    • 2
    • 3
    • 4
  • Viviane Nogueira de Zorzi
    • 1
    • 2
  • Marla Parizzi Funghetto
    • 1
    • 2
  • Fernanda Haupental
    • 1
    • 2
  • Alexandra Seide Cardoso
    • 1
    • 2
  • Sara Marchesan
    • 5
  • Andréia M. Cardoso
    • 5
  • Maria Rosa C. Schinger
    • 5
  • Alencar Kolinski Machado
    • 6
  • Ivana Beatrice Mânica da Cruz
    • 6
  • Marta Maria Medeiros Frescura Duarte
    • 6
  • Léder L. Xavier
    • 7
  • Ana Flavia Furian
    • 6
  • Mauro Schneider Oliveira
    • 6
  • Adair Roberto Soares Santos
    • 3
    • 4
  • Luiz Fernando Freire Royes
    • 2
    • 4
    • 5
    • 6
  • Michele Rechia Fighera
    • 1
    • 2
    • 4
    • 5
    • 6
    Email author
  1. 1.Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Laboratório de Neuropsiquiatria Experimental e ClínicoUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX)Universidade Federal de Santa MariaSanta MariaBrazil
  3. 3.Centro de Ciências Biológicas, Laboratório de Neurobiologia da Dor e InflamaçãoUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  4. 4.Centro de Ciências Biológicas, Programa de Pós-Graduação em NeurociênciasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  5. 5.Centro de Ciências Naturais e Exatas, Programa de Pós-graduação em Ciências Biológicas: Bioquímica ToxicológicaUniversidade Federal de Santa MariaSanta MariaBrazil
  6. 6.Centro de Ciências da Saúde Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e FarmacologiaUniversidade Federal de Santa MariaSanta MariaBrazil
  7. 7.Faculdade de Biociências, Laboratório Central de Microscopia e Microanálise, Departamento de Ciências FisiológicaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations