SpringerLink
Log in

Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Neuroinflammation and imbalance of neurotransmitters play pivotal roles in seizures and epileptogenesis. Aucubin (AU) is an iridoid glycoside derived from Eucommia ulmoides that possesses anti-inflammatory and neuroprotective effects. However, the anti-seizure effects of AU have not been reported so far. The present study was designed to investigate the effects of AU on pilocarpine (PILO) induced seizures and its role in the regulation of neuroinflammation and neurotransmission. We found that AU reduced seizure intensity and prolonged the latency of seizures. AU significantly attenuated the activation of astrocytes and microglia and reduced the levels of interleukine-1 beta (IL-1β), high mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α). Furthermore, the contents of γ-aminobutyric acid (GABA) were increased while the levels of glutamate were decreased in the hippocampus with AU treatment. The expression of γ-aminobutyric acid type A receptor subunit α1 (GABAARα1) and glutamate transporter-1 (GLT-1) protein were up-regulated in AU treatment group. However, AU had no significant effect on N-methyl-d-aspartate receptor subunit 2B (NR2B) expression in status epilepticus (SE). In conclusion, our findings provide the first evidence that AU can exert anti-seizure effects by attenuating gliosis and regulating neurotransmission. The results suggest that AU may be developed as a drug candidate for the treatment of epilepsy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472

    Article  PubMed  Google Scholar 

  2. Singh A, Trevick S (2016) The epidemiology of global epilepsy. Neurol Clin 34:837–847

    Article  PubMed  Google Scholar 

  3. Loscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52:657–678

    Article  PubMed  Google Scholar 

  4. Patel DC, Wilcox KS, Metcalf CS (2017) Novel targets for develo** antiseizure and, potentially, antiepileptogenic drugs. Epilepsy Curr 17:293–298

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yuen AWC, Keezer MR, Sander JW (2018) Epilepsy is a neurological and a systemic disorder. Epilepsy & Behav E&B 78:57–61

    Article  Google Scholar 

  6. Amtul Z, Aziz AA (2017) Microbial proteins as novel industrial biotechnology hosts to treat epilepsy. Mol Neurobiol 54:8211–8224

    Article  CAS  PubMed  Google Scholar 

  7. Guerriero RM, Giza CC, Rotenberg A (2015) Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep 15:27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Qin ZH (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis 15:1382–1402

    Article  CAS  PubMed  Google Scholar 

  9. Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, de Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43

    Article  CAS  PubMed  Google Scholar 

  10. Werner FM, Covenas R (2011) Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs. Curr Med Chem 18:4933–4948

    Article  CAS  PubMed  Google Scholar 

  11. Raol YH, Lund IV, Bandyopadhyay S, Zhang G, Roberts DS, Wolfe JH, Russek SJ, Brooks-Kayal AR (2006) Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J Neurosci 26:11342–11346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184

    Article  CAS  PubMed  Google Scholar 

  13. Dambach H, Hinkerohe D, Prochnow N, Stienen MN, Moinfar Z, Haase CG, Hufnagel A, Faustmann PM (2014) Glia and epilepsy: experimental investigation of antiepileptic drugs in an astroglia/microglia co-culture model of inflammation. Epilepsia 55:184–192

    Article  CAS  PubMed  Google Scholar 

  14. Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21

    Article  CAS  PubMed  Google Scholar 

  15. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23:8692–8700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Librizzi L, Noe F, Vezzani A, de Curtis M, Ravizza T (2012) Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann Neurol 72:82–90

    Article  PubMed  Google Scholar 

  17. Shimada T, Takemiya T (2014) Role of inflammatory mediators in the pathogenesis of epilepsy. Mediators Inflamm 2014:901902

  18. Najjar S, Pearlman D, Miller DC, Devinsky O (2011) Refractory epilepsy associated with microglial activation. Neurologist 17:249–254

    Article  PubMed  Google Scholar 

  19. Mikati MA, Kurdi R, El-Khoury Z, Rahi A, Raad W (2010) Intravenous immunoglobulin therapy in intractable childhood epilepsy: open-label study and review of the literature. Epilepsy & Behav E&B 17:90–94

    Article  Google Scholar 

  20. Crow AR, Song S, Semple JW, Freedman J, Lazarus AH (2007) A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg? Blood 109:155–158

    Article  CAS  PubMed  Google Scholar 

  21. Li D, Li P, He Z, Cen D, Meng Z, Liang L, Luo X (2012) Human intravenous immunoglobulins suppress seizure activities and inhibit the activation of GFAP-positive astrocytes in the hippocampus of picrotoxin-kindled rats. Int J Neurosci 122:200–208

    Article  CAS  PubMed  Google Scholar 

  22. Dey A, Kang X, Qiu J, Du Y, Jiang J (2016) Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharmacol Sci 37:463–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao Y, Li Y, Wang X, Sun W (2008) The experimental study of Cortex Eucommiae on meridian tropsim: the distribution study of aucubin in rat tissues. J Pharm Biomed Anal 46:368–373

    Article  CAS  PubMed  Google Scholar 

  24. Lv PY, Feng H, Huang WH, Tian YY, Wang YQ, Qin YH, Li XH, Hu K, Zhou HH, Ouyang DS (2017) Aucubin and its hydrolytic derivative attenuate activation of hepatic stellate cells via modulation of TGF-beta stimulation. Environ Toxicol Pharmacol 50:234–239

    Article  CAS  PubMed  Google Scholar 

  25. Jeong HJ, Koo HN, Na HJ, Kim MS, Hong SH, Eom JW, Kim KS, Shin TY, Kim HM (2002) Inhibition of TNF-alpha and IL-6 production by Aucubin through blockade of NF-kappaB activation RBL-2H3 mast cells. Cytokine 18:252–259

    Article  CAS  PubMed  Google Scholar 

  26. Park KS, Chang IM (2004) Anti-inflammatory activity of aucubin by inhibition of tumor necrosis factor-alpha production in RAW 264.7 cells. Planta Med 70:778–779

    Article  CAS  PubMed  Google Scholar 

  27. Wang SN, **e GP, Qin CH, Chen YR, Zhang KR, Li X, Wu Q, Dong WQ, Yang J, Yu B (2015) Aucubin prevents interleukin-1 beta induced inflammation and cartilage matrix degradation via inhibition of NF-kappaB signaling pathway in rat articular chondrocytes. Int Immunopharmacol 24:408–415

    Article  CAS  PubMed  Google Scholar 

  28. Wang J, Li Y, Huang WH, Zeng XC, Li XH, Li J, Zhou J, **ao J, **ao B, Ouyang DS, Hu K (2017) The protective effect of aucubin from Eucommia ulmoides against status epilepticus by inducing autophagy and inhibiting necroptosis. Am J Chin Med 45:557–573

    Article  CAS  PubMed  Google Scholar 

  29. Kim YM, Sim UC, Shin Y, Kim Kwon Y (2014) Aucubin promotes neurite outgrowth in neural stem cells and axonal regeneration in sciatic nerves. Exp Neurobiol 23:238–245

    Article  PubMed  PubMed Central  Google Scholar 

  30. Song M, Kim H, Park S, Kwon H, Joung I, Kim Kwon Y (2018) Aucubin promotes differentiation of neural precursor cells into GABAergic neurons. Exp Neurobiol 27:112–119

    Article  PubMed  PubMed Central  Google Scholar 

  31. Inoue O, Sugiyama E, Hasebe N, Tsuchiya N, Hosoi R, Yamaguchi M, Abe K, Gee A (2009) Methyl ethyl ketone blocks status epilepticus induced by lithium-pilocarpine in rats. Br J Pharmacol 158:872–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. He X, Wang J, Li M, Hao D, Yang Y, Zhang C, He R, Tao R (2014) Eucommia ulmoides Oliv.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. J Ethnopharmacol 151:78–92

    Article  PubMed  Google Scholar 

  33. Xue HY, ** L, ** LJ, Li XY, Zhang P, Ma YS, Lu YN, **a YQ, Xu YP (2009) Aucubin prevents loss of hippocampal neurons and regulates antioxidative activity in diabetic encephalopathy rats. Phytother Res 23:980–986

    Article  CAS  PubMed  Google Scholar 

  34. Curia G, Longo D, Biagini G, Jones RS, Avoli M (2008) The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172:143–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nirwan N, Siraj F, Vohora D (2018) Inverted-U response of lacosamide on pilocarpine-induced status epilepticus and oxidative stress in C57BL/6 mice is independent of hippocampal collapsin response mediator protein-2. Epilepsy Res 145:93–101

    Article  CAS  PubMed  Google Scholar 

  36. Martin E, Pozo M (2006) Animal models for the development of new neuropharmacological therapeutics in the status epilepticus. Curr Neuropharmacol 4:33–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Choi J, Koh S (2008) Role of brain inflammation in epileptogenesis. Yonsei Med J 49:1–18

    Article  PubMed  PubMed Central  Google Scholar 

  38. Aronica E, Crino PB (2011) Inflammation in epilepsy: clinical observations. Epilepsia 52 Suppl 3:26–32

    Article  Google Scholar 

  39. Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune responses in epilepsy. Glia 60:1258–1268

    Article  PubMed  Google Scholar 

  40. Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS inflammation. FEBS Lett 585:3798–3805

    Article  CAS  PubMed  Google Scholar 

  41. Friedman A, Kaufer D, Heinemann U (2009) Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. Epilepsy Res 85:142–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. de Lanerolle NC, Lee TS, Spencer DD (2010) Astrocytes and epilepsy. Neurotherapeutics 7:424–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  44. Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the epileptic brain. Neuron 58:168–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13:584–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M (2002) Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 952:159–169

    Article  CAS  PubMed  Google Scholar 

  47. Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi ME, Vezzani A (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16:413–419

    Article  CAS  PubMed  Google Scholar 

  48. van Vliet EA, Aronica E, Vezzani A, Ravizza T (2018) Review: Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol 44:91–111

    Article  PubMed  Google Scholar 

  49. Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40

    Article  CAS  PubMed  Google Scholar 

  50. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640

    Article  CAS  PubMed  Google Scholar 

  51. Liu W, Tang Y, Feng J (2011) Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 89:141–146

    Article  CAS  PubMed  Google Scholar 

  52. Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25:3219–3228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E (2006) Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 173:188–195

    Article  CAS  PubMed  Google Scholar 

  54. Park KS (2013) Aucubin, a naturally occurring iridoid glycoside inhibits TNF-alpha-induced inflammatory responses through suppression of NF-kappaB activation in 3T3-L1 adipocytes. Cytokine 62:407–412

    Article  CAS  PubMed  Google Scholar 

  55. Young IC, Chuang ST, Hsu CH, Sun YJ, Liu HC, Chen YS, Lin FH (2017) Protective effects of aucubin on osteoarthritic chondrocyte model induced by hydrogen peroxide and mechanical stimulus. BMC Complement Altern Med 17:91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhou Y, Li P, Duan JX, Liu T, Guan XX, Mei WX, Liu YP, Sun GY, Wan L, Zhong WJ, Ouyang DS, Guan CX (2017) Aucubin alleviates bleomycin-induced pulmonary fibrosis in a mouse model. Inflammation 40:2062–2073

    Article  CAS  PubMed  Google Scholar 

  57. Xue HY, Lu YN, Fang XM, Xu YP, Gao GZ, ** LJ (2012) Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats. Mol Biol Rep 39:9311–9318

    Article  CAS  PubMed  Google Scholar 

  58. Gomez CD, Buijs RM, Sitges M (2014) The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1beta and TNF-alpha expression in rat hippocampus. J Neurochem 130:770–779

    Article  CAS  PubMed  Google Scholar 

  59. Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694

    Article  PubMed  Google Scholar 

  60. Cavus I, Pan JW, Hetherington HP, Abi-Saab W, Zaveri HP, Vives KP, Krystal JH, Spencer SS, Spencer DD (2008) Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients. Epilepsia 49:1358–1366

    Article  PubMed  Google Scholar 

  61. Soukupova M, Binaschi A, Falcicchia C, Palma E, Roncon P, Zucchini S, Simonato M (2015) Increased extracellular levels of glutamate in the hippocampus of chronically epileptic rats. Neuroscience 301:246–253

    Article  CAS  PubMed  Google Scholar 

  62. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  63. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, ** L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686

    Article  CAS  PubMed  Google Scholar 

  64. Kong Q, Takahashi K, Schulte D, Stouffer N, Lin Y, Lin CL (2012) Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. Neurobiol Dis 47:145–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ueda Y, Willmore LJ (2000) Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis. Exp Brain Res 133:334–339

    Article  CAS  PubMed  Google Scholar 

  66. Wang XM, Bausch SB (2004) Effects of distinct classes of N-methyl-D-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro: suppression by NR2B-selective antagonists. Neuropharmacology 47:1008–1020

    Article  CAS  PubMed  Google Scholar 

  67. Kammerer M, Brawek B, Freiman TM, Jackisch R, Feuerstein TJ (2011) Effects of antiepileptic drugs on glutamate release from rat and human neocortical synaptosomes. Naunyn Schmiedebergs Arch Pharmacol 383:531–542

    Article  CAS  PubMed  Google Scholar 

  68. Barnard EA, Darlison MG, Fujita N, Glencorse TA, Levitan ES, Reale V, Schofield PR, Seeburg PH, Squire MD, Stephenson FA (1988) Molecular biology of the GABAA receptor. Adv Exp Med Biol 236:31–45

    Article  CAS  PubMed  Google Scholar 

  69. Gibbs JW, Sombati S, DeLorenzo RJ, Coulter DA (1997) Physiological and pharmacological alterations in postsynaptic GABA(A) receptor function in a hippocampal culture model of chronic spontaneous seizures. J Neurophysiol 77:2139–2152

    Article  CAS  PubMed  Google Scholar 

  70. Macdonald RL, Twyman RE, Ryan-Jastrow T, Angelotti TP (1992) Regulation of GABAA receptor channels by anticonvulsant and convulsant drugs and by phosphorylation. Epilepsy Res 9:265–277

    CAS  Google Scholar 

  71. Uusi-Oukari M, Korpi ER (2010) Regulation of GABA(A) receptor subunit expression by pharmacological agents. Pharmacol Rev 62:97–135

    Article  CAS  PubMed  Google Scholar 

  72. Grabenstatter HL, Russek SJ, Brooks-Kayal AR (2012) Molecular pathways controlling inhibitory receptor expression. Epilepsia 53 Suppl 9:71–78

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Development of Key Novel Drugs for Special Projects of China (Grant No.: 2017ZX09304014), the Natural Science Foundation of Hunan Province (Grant No.: 2016JJ4116) and the Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples (2017TP1037).

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, ** Zhou, Chaopeng Li, ** Zhou, Chaopeng Li, **nyi Huang & Dong-Sheng Ouyang

  2. Department of Pharmacy, **angya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Qi Huang

  3. Hunan Key Laboratory of Pharmacodynamics and Safety Evaluation of New Drugs & Hunan Provincial Research Center for Safety Evaluation of Drugs, Changsha, 410331, People’s Republic of China

    Guirong Zeng

  4. Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd, Changsha, 411000, People’s Republic of China

    **ntong Wang, Lulu Chen & Dong-Sheng Ouyang

  5. Department of Neurology, **angya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Kai Hu

Authors
  1. Siyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. **angchang Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen**g Zong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. **ntong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lulu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lu** Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chaopeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. **nyi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guirong Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kai Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dong-Sheng Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kai Hu or Dong-Sheng Ouyang.

Ethics declarations

Conflict of interest

None.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, S., Zeng, X., Zong, W. et al. Aucubin Alleviates Seizures Activity in Li-Pilocarpine-Induced Epileptic Mice: Involvement of Inhibition of Neuroinflammation and Regulation of Neurotransmission. Neurochem Res 44, 472–484 (2019). https://doi.org/10.1007/s11064-018-2700-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2700-y

Keywords

Search

Navigation