Skip to main content

Advertisement

SpringerLink
Log in

Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway

  • ORIGINAL ARTICLE
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Endothelin-1 (ET-1) is a vasoactive peptide produced by activated astrocytes and microglia and is implicated in initiating and sustaining reactive gliosis in neurodegenerative diseases. We have previously suggested that ET-1 can play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Indeed, we reported that this peptide is abundantly expressed in reactive astrocytes in the spinal cord of SOD1-G93A mice and ALS patients and exerts a toxic effect on motor neurons (MNs) in an in vitro model of mixed spinal cord cultures enriched with reactive astrocytes. Here, we explored the possible mechanisms underlying the toxic effect of ET-1 on cultured MNs. We show that ET-1 toxicity is not directly caused by oxidative stress or activation of cyclooxygenase-2 but requires the synthesis of nitric oxide and is mediated by a reduced activation of the phosphoinositide 3-kinase pathway. Furthermore, we observed that ET-1 is also toxic for microglia, although its effect on MNs is independent of the presence of this type of glial cells. Our study confirms that ET-1 may contribute to MN death and corroborates the view that the modulation of ET-1 signaling might be a therapeutic strategy to slow down MN degeneration in ALS.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ALS:

Amyotrophic lateral sclerosis

COX-2:

Cyclooxygenase-2

ET-1:

Endothelin-1

GFAP:

Glial fibrillary acid protein

L-NNA:

NG-Nitro-L-arginine

MAP-2:

Microtubule-associated protein 2

MN:

Motor neuron

MMP:

Matrix metalloproteinase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

eNOS:

Endothelial nitric oxide synthase

iNOS:

Inducible nitric oxide synthase

nNOS:

Neuronal nitric oxide synthase

PI3K:

Phosphoinositide 3-kinase

References

  • An Y, Belevych N, Wang Y, Zhang H, Herschman H, Chen Q, Quan N (2014) Neuronal and nonneuronal COX-2 expression confers neurotoxic and neuroprotective phenotypes in response to excitotoxin challenge. J Neurosci Res 92(4):486–495. doi:10.1002/jnr.23317

    Article  CAS  PubMed  Google Scholar 

  • Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estévez AG, Beckman JS (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev 47(1–3):263–274

    Article  CAS  PubMed  Google Scholar 

  • Bilak M, Wu L, Wang Q, Haughey N, Conant K, St Hillaire C, Andreasson K (2004) PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis. Ann Neurol 56(2):240–248

    Article  CAS  PubMed  Google Scholar 

  • Briyal S, Philip T, Gulati A (2011) Endothelin-A receptor antagonists prevent amyloid-β-induced increase in ETA receptor expression, oxidative stress, and cognitive impairment. J Alzheimers Dis 23(3):491–503. doi:10.3233/JAD-2010-101245

    CAS  PubMed  Google Scholar 

  • Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8(10):766–775

    Article  CAS  PubMed  Google Scholar 

  • Callera GE, Tostes RC, Yogi A, Montezano AC, Touyz RM (2006) Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. Clin Sci (Lond) 110(2):243–253

    Article  CAS  Google Scholar 

  • Charbonneau A, Marette A (2010) Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice: potential role of tyrosine nitration of insulin signaling proteins. Diabetes 59(4):861–871. doi:10.2337/db09-1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Contestabile A, Monti B, Polazzi E (2012) Neuronal-glial interactions define the role of nitric oxide in neural functional processes. Current Neuropharmacol 10(4):303–310. doi:10.2174/157015912804143522

    Article  CAS  Google Scholar 

  • Covarrubias-Pinto A, Acuña AI, Beltrán FA, Torres-Díaz L, Castro MA (2015) Old things new view: ascorbic acid protects the brain in neurodegenerative disorders. Int J Mol Sci 16(12):28194–28217. doi:10.3390/ijms161226095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csibi A, Communi D, Müller N, Bottari SP (2010) Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms. PLoS One 5(4):e10070. doi:10.1371/journal.pone.0010070

    Article  PubMed  PubMed Central  Google Scholar 

  • D’Antoni S, Berretta A, Seminara G, Longone P, Giuffrida-Stella AM, Battaglia G, Sortino MA, Nicoletti F, Catania MV (2011) A prolonged pharmacological blockade of type-5 metabotropic glutamate receptors protects cultured spinal cord motor neurons against excitotoxic death. Neurobiol Dis 42(3):252–264. doi:10.1016/j.nbd.2011.01.013

    Article  PubMed  Google Scholar 

  • Davis WJ, Lehmann PZ, Li W (2015) Nuclear PI3K signaling in cell growth and tumorigenesis. Frontiers in Cell and Developmental Biology 3:24. doi:10.3389/fcell.2015.00024

    Article  PubMed  PubMed Central  Google Scholar 

  • Dewil M, Lambrechts D, Sciot R, Shaw PJ, Ince PG, Robberecht W, Van den Bosch L (2007) Vascular endothelial growth factor counteracts the loss of phospho-Akt preceding motor neurone degeneration in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 33(5):499–509

    Article  CAS  PubMed  Google Scholar 

  • Didier N, Romero IA, Créminon C, Wijkhuisen A, Grassi J, Mabondzo A (2003) Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem 86(1):246–254

    Article  CAS  PubMed  Google Scholar 

  • Dong F, Zhang X, Wold LE, Ren Q, Zhang Z, Ren J (2005) Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1. Br J Pharmacol 145(3):323–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drechsel DA, Estévez AG, Barbeito L, Beckman JS (2012) Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS. Neurotox Res 22(4):251–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dwyer MA, Bredt DS, Snyder SH (1991) Nitric oxide synthase: irreversible inhibition by L-NG-nitroarginine in brain in vitro and in vivo. Biochem Biophys Res Commun 176(3):1136–1141

    Article  CAS  PubMed  Google Scholar 

  • Elgebaly MM, Portik-Dobos V, Sachidanandam K, Rychly D, Malcom D, Johnson MH, Ergul A (2007) Differential effects of ET(A) and ET(B) receptor antagonism on oxidative stress in type 2 diabetes. Vasc Pharmacol 47(2–3):125–130

    Article  CAS  Google Scholar 

  • Filipovich T, Fleisher-Berkovich S (2008) Regulation of glial inflammatory mediators synthesis: possible role of endothelins. Peptides 29(12):2250–2256. doi:10.1016/j.peptides.2008.09.002

    Article  CAS  PubMed  Google Scholar 

  • Gadea A, Schinelli S, Gallo V (2008) Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 28:2394–2408. doi:10.1523/JNEUROSCI.5652-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galea E, Feinstein DL, Reis DJ (1992) Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci U S A 89(22):10945–10949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghasemi M, Fatemi A (2014) Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases. Neurosci Biobehav Rev 45:168–182. doi:10.1016/j.neubiorev.2014.06.002

    Article  CAS  PubMed  Google Scholar 

  • Gulati A, Kumar A, Morrison S, Shahani BT (1997) Effect of centrally administered endothelin agonists on systemic and regional blood circulation in the rat: role of sympathetic nervous system. Neuropeptides 31(4):301–309

    Article  CAS  PubMed  Google Scholar 

  • Gupta YK, Briyal S, Sharma U, Jagannathan NR, Gulati A (2005) Effect of endothelin antagonist (TAK-044) on cerebral ischemic volume, oxidative stress markers and neurobehavioral parameters in the middle cerebral artery occlusion model of stroke in rats. Life Sci 77(1):15–27

    Article  CAS  PubMed  Google Scholar 

  • Hamby ME, Uliasz TF, Hewett SJ, Hewett JA (2006) Characterization of an improved procedure for the removal of microglia from confluent monolayers of primary astrocytes. J Neurosci Methods 150(1):128–137

    Article  CAS  PubMed  Google Scholar 

  • Hammond TR, Gadea A, Dupree J, Kerninon C, Nait-Oumesmar B, Aguirre A, Gallo V (2014) Astrocyte-derived endothelin-1 inhibits remyelination through Notch activation. Neuron 81(3):588–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hemming BA, Restuccia DF (2012) PI3K-PKB/Akt pathway cold spring. Harb Perspect Biol 4(9):a011189

    Google Scholar 

  • Hostenbach S, D’haeseleer M, Kooijman R, De Keyser J (2016) The pathophysiological role of astrocytic endothelin-1. Prog Neurobiol 144:88–102. doi:10.1016/j.pneurobio.2016.04.009

    Article  CAS  PubMed  Google Scholar 

  • Hung VK, Tai LW, Qiu Q, Luo X, Wong KL, Chung SK, Cheung CW (2014) Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor. Mol Cell Neurosci 60:26–35. doi:10.1016/j.mcn.2014.02.007

    Article  CAS  PubMed  Google Scholar 

  • Hung VK, Yeung PK, Lai AK, Ho MC, Lo AC, Chan KC, Wu EX, Chung SS, Cheung CW, Chun SK (2015) Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion. J Cereb Blood Flow Metab 35(10):1687–1696. doi:10.1038/jcbfm.2015.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jebelli J, Piers T, Pocock J (2015) Selective depletion of microglia from cerebellar granule cell cultures using L-leucine methyl ester. J Vis Exp 101:e52983. doi:10.3791/52983

    Google Scholar 

  • Kang YC, Kim PK, Choi BM, Chung HT, Ha KS, Kwon YG, Kim YM (2004) Regulation of programmed cell death in neuronal cells by nitric oxide. In Vivo 18(3):367–376

    CAS  PubMed  Google Scholar 

  • Khimji AK, Rockey DC (2010) Endothelin—biology and disease. Cell Signal 22(11):1615–1625. doi:10.1016/j.cellsig.2010.05.002

    Article  CAS  PubMed  Google Scholar 

  • Kleniewska P, Kowalczyk A, Ciesla W, Goraca A (2015) Estimation of some oxidative stress parameters and blood pressure after administration of endothelin-1 (ET-1) in rats. Cell Biochem Biophys 71:1483–1489. doi:10.1007/s12013-014-0371-0

    Article  CAS  PubMed  Google Scholar 

  • Koh SH, Roh H, Lee SM, Kim HJ, Kim M, Lee KW, Kim HT, Kim J, Kim SH, Koh SH, Roh H, Lee SM, Kim HJ, Kim M, Lee KW, Kim HT, Kim J, Kim SH (2005) Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4V mutant SOD1 gene. Toxicology 213(1–2):45–55

    Article  CAS  PubMed  Google Scholar 

  • Kotni MK, Zhao M, Wei DQ (2016) Gene expression profiles and protein-protein interaction networks in amyotrophic lateral sclerosis patients with C9orf72 mutation. Orphanet J Rare Dis 11(1):148. doi:10.1186/s13023-016-0531-y

    Article  PubMed  PubMed Central  Google Scholar 

  • Koyama Y, Michinaga S (2012) Regulations of astrocytic functions by endothelins: role in the pathophysiological responses of damage brain. J Pharmacol Sci 118:401–407

    Article  CAS  PubMed  Google Scholar 

  • Koyama Y, Mizobata T, Yamamoto N, Hashimoto H, Matsuda T, Baba A (1999) Endothelins stimulate expression of cyclooxygenase 2 in rat cultured astrocytes. J Neurochem 73(3):1004–1011

    Article  CAS  PubMed  Google Scholar 

  • Kugler P, Drenckhahn D (1996) Astrocytes and Bergmann glia as an important site of nitric oxide synthase I. Glia 16(2):165–173

    Article  CAS  PubMed  Google Scholar 

  • Lederer CW, Torrisi A, Pantelidou M, Santama N, Cavallaro S (2007) Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis. BMC Genomics 8:26. doi:10.1186/1471-2164-8-26

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee J, Kosaras B, Aleyasin H, Han JA, Park DS, Ratan RR, Kowall NW, Ferrante RJ, Lee SW, Ryu H (2006) Role of cyclooxygenase-2 induction by transcription factor Sp1 and Sp3 in neuronal oxidative and DNA damage response. FASEB J 20(13):2375–2377

    Article  CAS  PubMed  Google Scholar 

  • Léger B, Vergani L, Sorarù G, Hespel P, Derave W, Gobelet C, D’Ascenzio C, Angelini C, Russell AP (2006) Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1. FASEB J 20(3):583–585

    PubMed  Google Scholar 

  • Li B, Xu W, Luo C, Gozal D, Liu R (2003) VEGF-induced activation of the PI3-K/Akt pathway reduces mutant SOD1-mediated motor neuron cell death. Brain Res Mol Brain Res 111(1–2):155–164

    Article  CAS  PubMed  Google Scholar 

  • Liang X, Wu L, Hand T, Andreasson K (2005) Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 92(3):477–486

    Article  CAS  PubMed  Google Scholar 

  • McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A, Burgess A (2014) Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 13(9):1400–1412. doi:10.4161/cc.28401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minami M, Kimura M, Iwamoto N, Arai H (1995) Endothelin-1-like immunoreactivity in cerebral cortex of Alzheimer-type dementia. Prog Neuro-Psychopharmacol Biol Psychiatry 19(3):509–513

    Article  CAS  Google Scholar 

  • Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K (2005) Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. J Neurol Sci 235(1–2):61–68

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Lipton SA (2016) Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases. Trends Pharmacol Sci 37(1):73–84. doi:10.1016/j.tips.2015.10.002

    Article  CAS  PubMed  Google Scholar 

  • Nelson J, Bagnato A, Battistini B, Nisen P (2003) The endothelin axis: emerging role in cancer. Nat Rev Cancer 3:110–116

    Article  CAS  PubMed  Google Scholar 

  • Newbern J, Taylor A, Robinson M, Li L, Milligan CE (2005) Decreases in phosphoinositide-3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling activate components of spinal motoneuron death. J Neurochem 94(6):1652–1665

    Article  CAS  PubMed  Google Scholar 

  • Nie XJ, Olsson Y (1996) Endothelin peptides in brain diseases. Rev Neurosci 7:177–186

    Article  CAS  PubMed  Google Scholar 

  • Ostrow LW, Sachs F (2005) Mechanosensation and endothelin in astrocytes-hypothetical role in CNS pathophysiology. Brain Res Rev 48:488–508

    Article  CAS  PubMed  Google Scholar 

  • Ozdemir R, Parlakpinar H, Polat A, Colak C, Ermis N, Acet A (2006) Selective endothelin a (ETA) receptor antagonist (BQ-123) reduces both myocardial infarct size and oxidant injury. Toxicology 219(1–3):142–149

    Article  CAS  PubMed  Google Scholar 

  • Peviani M, Tortarolo M, Battaglia E, Piva R, Bendotti C (2014) Specific induction of Akt3 in spinal cord motor neurons is neuroprotective in a mouse model of familial amyotrophic lateral sclerosis. Mol Neurobiol 49(1):136–148. doi:10.1007/s12035-013-8507-6

    Article  CAS  PubMed  Google Scholar 

  • Pompl PN, Ho L, Bianchi M, McManus T, Qin W, Pasinetti GM (2003) A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J 17(6):725–727

    CAS  PubMed  Google Scholar 

  • Puentes F, Malaspina A, van Noort JM, Amor S (2016) Non-neuronal cells in ALS: role of glial, immune cells and blood-CNS barriers. Brain Pathol 26(2):248–257. doi:10.1111/bpa.12352

    Article  CAS  PubMed  Google Scholar 

  • Ranno E, D’Antoni S, Spatuzza M, Berretta A, Laureanti F, Bonaccorso CM, Pellitteri R, Longone P, Spalloni A, Iyer AM, Aronica E, Catania MV (2014) Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death. Neurobiol Dis 65:160–171. doi:10.1016/j.nbd.2014.01.002

    Article  CAS  PubMed  Google Scholar 

  • Rebello S, Roy S, Saxena PR, Gulati A (1995) Systemic hemodynamic and regional circulatory effects of centrally administered endothelin-1 are mediated through ETA receptors. Brain Res 676(1):141–150

    Article  CAS  PubMed  Google Scholar 

  • Reif DW, McCreedy SA (1995) N-nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases. Arch Biochem Biophys 320(1):170–176

    Article  CAS  PubMed  Google Scholar 

  • Ricart KC, Fiszman ML (2001) Hydrogen peroxide-induced neurotoxicity in cultured cortical cells grown in serum-free and serum-containing media. Neurochem Res 26:801–808

    Article  CAS  PubMed  Google Scholar 

  • Roediger B, Armati PJ (2003) Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13(3):222–229

    Article  CAS  PubMed  Google Scholar 

  • Saha RN, Pahan K (2006) Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal 8(5–6):929–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schinelli S (2006) Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem 13:627–638

    Article  CAS  PubMed  Google Scholar 

  • Serafim KG, Navarro SA, Zarpelon AC, Pinho-Ribeiro FA, Fattori V, Cunha TM, Alves-Filho JC, Cunha FQ, Casagrande R, Verri WA Jr (2015) Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice. Naunyn Schmiedeberg’s Arch Pharmacol 388(11):1211–1221. doi:10.1007/s00210-015-1160-z

    Article  CAS  Google Scholar 

  • Sha Y, Marshall HE (2012) S-nitrosylation in the regulation of gene transcription. Biochim Biophys Acta 1820(6):701–711. doi:10.1016/j.bbagen.2011.05.008

    Article  CAS  PubMed  Google Scholar 

  • Speciale L, Sarasella M, Ruzzante S, Caputo D, Mancuso R, Calvo MG, Guerini FR, Ferrante P (2000) Endothelin and nitric oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J Neurovirol 6(2):S62–S66

    CAS  PubMed  Google Scholar 

  • Stiles JD, Ostrow PT, Balos LL, Greenberg SJ, Plunkett R, Grand W, Heffner RR Jr (1997) Correlation of endothelin-1 and transforming growth factor beta 1 with malignancy and vascularity in human gliomas. J Neuropathol Exp Neurol 56(4):435–439

    Article  CAS  PubMed  Google Scholar 

  • Teismann P, Vila M, Choi DK, Tieu K, Wu DC, Jackson-Lewis V, Przedborski S (2003) COX-2 and neurodegeneration in Parkinson’s disease. Ann N Y Acad Sci 991:272–277

    Article  CAS  PubMed  Google Scholar 

  • Tolosa L, Mir M, Asensio VJ, Olmos G, Lladó J (2008) Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem 105(4):1080–1090. doi:10.1111/j.1471-4159.2007.05206.x

    Article  CAS  PubMed  Google Scholar 

  • Virarkar M, Alappat L, Bradford PG, Awad AB (2013) L-arginine and nitric oxide in CNS function and neurodegenerative diseases. Crit Rev Food Sci Nutr 53(11):1157–1167. doi:10.1080/10408398.2011.573885

    Article  CAS  PubMed  Google Scholar 

  • Wang HH, Hsieh HL, Yang CM (2011) Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9. J Cell Physiol 226(9):2244–2256. doi:10.1002/jcp.22560

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Liao S, Geng R, Zheng Y, Liao R, Yan F, Thrimawithana T, Little PJ, Feng ZP, Lazarovici P, Zheng W (2015) IGF-1 signaling via the PI3K/Akt pathway confers neuroprotection in human retinal pigment epithelial cells exposed to sodium nitroprusside insult. J Mol Neurosci 55(4):931–940. doi:10.1007/s12031-014-0448-7

    Article  CAS  PubMed  Google Scholar 

  • Wes PD, Holtman IR, Boddeke EW, Möller T, Eggen BJ (2016) Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. Glia 64(2):197–213. doi:10.1002/glia.22866

    Article  PubMed  Google Scholar 

  • Xiang Z, Thomas S, Pasinetti G (2007) Increased neuronal injury in transgenic mice with neuronal overexpression of human cyclooxygenase-2 is reversed by hypothermia and rofecoxib treatment. Curr Neurovasc Res 4(4):274–279

    Article  CAS  PubMed  Google Scholar 

  • Yagami T, Koma H, Yamamoto Y (2015) Pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system. Mol Neurobiol 53(7):4754–4771

  • Yasukawa T, Tokunaga E, Ota H, Sugita H, Martyn JA, Kaneki M (2005) S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem 280(9):7511–7518

    Article  CAS  PubMed  Google Scholar 

  • Yin X, Ren M, Jiang H, Cui S, Wang S, Jiang H, Qi Y, Wang J, Wang X, Dong G, Leeds P, Chuang DM, Feng H (2015) Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model. Mol Cell Neurosci 68:303–313. doi:10.1016/j.mcn.2015.08.009

    Article  CAS  PubMed  Google Scholar 

  • Yuan Z, Liu B, Yuan L, Zhang Y, Dong X, Lu J (2004) Evidence of nuclear localization of neuronal nitric oxide synthase in cultured astrocytes of rats. Life Sci 74(26):3199–3209

    Article  CAS  PubMed  Google Scholar 

  • Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F (2015) Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 9:322. doi:10.3389/fncel.2015.00322

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang WW, Badonic T, Höög A, Jiang MH, Ma KC, Nie XJ, Olsson Y (1994) Astrocytes in Alzheimer’s disease express immunoreactivity to the vaso-constrictor endothelin-1. J Neurol Sci 122(1):90–96

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Annalisa Scuderi and Neda Zeinali, for their technical support in performing experimental work, and Meredith Graham for helping with image analysis. AS is a student of the University of Catania under an undergraduate training program. NZ and MG are students of the University of Cardiff who are attending the Institute of Neurological Sciences of CNR in Catania for professional training supported by the undergraduate Erasmus program.

Author information

Authors and Affiliations

  1. Institute of Neurological Sciences, National Research Council (CNR), Catania, Italy

    S. D’Antoni, E. Ranno, M. Spatuzza, S. Cavallaro & M. V. Catania

  2. IRCSS Oasi Maria SS, Troina, Enna, Italy

    M. V. Catania

Authors
  1. S. D’Antoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Ranno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Spatuzza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Cavallaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. V. Catania
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. V. Catania.

Ethics declarations

Funding

This study was supported by CNR (ME P02.011, DSB.AD009.001.018) and IRCCS Oasi Maria SS (Troina, EN). ER was supported by Programma Operativo Obiettivo Convergenza 2007–2013, FSE, Regione Siciliana, avviso n. 1 2012.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

Online Resource 1

Activation of COX-2 is not involved in ET-1 toxic effect. Percentage of surviving MNs after a treatment with ET-1 (100 nM) with/without DuP 697 (10 nM) for 48 h at 13–14 DIV. Data represent mean ± SEM of data from four experiments, each performed in quadruplicate. ***p < 0.001 versus control by one-way ANOVA followed by post hoc Holm–Sidak method; +++p < 0.001 versus DuP 697 by one-way ANOVA followed by post hoc Holm–Sidak method; ###p < 0.001 versus ET-1 by one-way ANOVA followed by post hoc Holm–Sidak method. (GIF 24 kb)

High resolution (EPS 2593 kb)

Online Resource 2

Akt is expressed in neurons and glial cells. Double immunocytochemistry experiments performed with SMI32, anti-MAP-2, anti-GFAP, and anti-Akt antibodies in mixed spinal cord cultures at 15 DIV. Scale bar = 20 μm. (GIF 112 kb)

High resolution (TIFF 17949 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

D’Antoni, S., Ranno, E., Spatuzza, M. et al. Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway. Neurotox Res 32, 58–70 (2017). https://doi.org/10.1007/s12640-017-9711-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-017-9711-3

Keywords

Search

Navigation