Advertisement

Molecular Neurobiology

, Volume 55, Issue 10, pp 8188–8202 | Cite as

Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway

  • Ahmed S. KamelEmail author
  • Noha F. Abdelkader
  • Sahar S. Abd El-Rahman
  • Marwan Emara
  • Hala F. Zaki
  • Mahmoud M. Khattab
Article

Abstract

Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.

Keywords

Memory impairment Angiotensin-converting enzyme 2 activator MAS receptor PI3K/Akt Phosphorylated tau Apoptosis 

Abbreviations

AD

Alzheimer’s disease

Amyloid-β

ACE

Angiotensin-converting enzyme

ACE2

Angiotensin-converting enzyme 2

Ang(1–7)

Angiotensin (1–7)

AT1

Angiotensin receptor subtype-1

BDNF

Brain-derived neurotrophic factor

Casp-3

Caspase-3

CREB

cAMP-responsive element-binding protein

CYC

Cytochrome-c

DIZE

Diminazene

D-Gal

D-galactose

GFAP

Glial fibrillary acidic protein

GSK3β

Glycogen synthase kinase 3β

p-STAT3

Phosphorylated signal transducer and activator of transcription-3

PI3K

Phosphoinositide 3-kinase

LTP

Long-term potentiation

MasR

Mas receptor

NF-κB p65

Nuclear factor Kappa B p65

RAS

Renin angiotensin system

Akt/PKB

Protein kinase B

TNF-α

Tumor necrosis factor alpha

p-tau

Phosphorylated tau protein

MWM

Morris water maze

NOR

Novel Object recognition

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ashby EL, Kehoe PG (2013) Current status of renin-aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease. Expert Opin Investig Drugs 22:1229–1242.  https://doi.org/10.1517/13543784.2013.812631 CrossRefPubMedGoogle Scholar
  2. 2.
    Muthuraman A, Kaur P (2016) Renin-angiotensin-aldosterone system: a current drug target for the management of neuropathic pain. Curr Drug Targets 17:178–195CrossRefPubMedGoogle Scholar
  3. 3.
    Miners JS, Palmer JC, Tayler H, Palmer LE, Ashby E, Kehoe PG, Love S (2014) Abeta degradation or cerebral perfusion? Divergent effects of multifunctional enzymes. Front Aging Neurosci 6:238.  https://doi.org/10.3389/fnagi.2014.00238 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zheng J, Li G, Chen S, Bihl J, Buck J, Zhu Y, Xia H, Lazartigues E et al (2014) Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction. Neuroscience 273:39–51.  https://doi.org/10.1016/j.neuroscience.2014.04.060 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Goel R, Bhat SA, Hanif K, Nath C, Shukla R (2017) Angiotensin II receptor blockers attenuate lipopolysaccharide-induced memory impairment by modulation of NF-kappaB-mediated BDNF/CREB expression and apoptosis in spontaneously hypertensive rats. Mol Neurobiol.  https://doi.org/10.1007/s12035-017-0450-5
  6. 6.
    Villapol S, Saavedra JM (2015) Neuroprotective effects of angiotensin receptor blockers. Am J Hypertens 28:289–299.  https://doi.org/10.1093/ajh/hpu197 CrossRefPubMedGoogle Scholar
  7. 7.
    Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, Dickinson B, Scullion S et al (2011) Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci 14:545–547.  https://doi.org/10.1038/nn.2785 CrossRefPubMedGoogle Scholar
  8. 8.
    Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23:1515–1527.  https://doi.org/10.1016/j.cellsig.2011.05.004 CrossRefPubMedGoogle Scholar
  9. 9.
    Shi J, Gu JH, Dai CL, Gu J, Jin X, Sun J, Iqbal K, Liu F et al (2015) O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling. Sci Rep 5:14500.  https://doi.org/10.1038/srep14500 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zuo D, Lin L, Liu Y, Wang C, Xu J, Sun F, Li L, Li Z et al (2016) Baicalin attenuates ketamine-induced neurotoxicity in the developing rats: involvement of PI3K/Akt and CREB/BDNF/Bcl-2 pathways. Neurotox Res 30:159–172.  https://doi.org/10.1007/s12640-016-9611-y CrossRefPubMedGoogle Scholar
  11. 11.
    Hunsberger J, Austin DR, Henter ID, Chen G (2009) The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci 11:333–348PubMedPubMedCentralGoogle Scholar
  12. 12.
    Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T (2002) CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 133:135–141CrossRefPubMedGoogle Scholar
  13. 13.
    Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5:311–322.  https://doi.org/10.1038/nrneurol.2009.54 CrossRefPubMedGoogle Scholar
  14. 14.
    Barco A, Marie H (2011) Genetic approaches to investigate the role of CREB in neuronal plasticity and memory. Mol Neurobiol 44:330–349.  https://doi.org/10.1007/s12035-011-8209-x CrossRefPubMedGoogle Scholar
  15. 15.
    Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Papadopoulos P, Rosa-Neto P, Lecrux C, Imboden H et al (2014) Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis 68:126–136.  https://doi.org/10.1016/j.nbd.2014.04.018 CrossRefPubMedGoogle Scholar
  16. 16.
    Bihl JC, Zhang C, Zhao Y, Xiao X, Ma X, Chen Y, Chen S, Zhao B et al (2015) Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: role of the NFsmall ka, CyrillicB inflammatory pathway. Vascul Pharmacol 73:115–123.  https://doi.org/10.1016/j.vph.2015.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu S, Liu J, Miura Y, Tanabe C, Maeda T, Terayama Y, Turner AJ, Zou K et al (2014) Conversion of Abeta43 to Abeta40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme. J Neurosci Res 92:1178–1186.  https://doi.org/10.1002/jnr.23404 CrossRefPubMedGoogle Scholar
  18. 18.
    Xie W, Zhu D, Ji L, Tian M, Xu C, Shi J (2014) Angiotensin-(1-7) improves cognitive function in rats with chronic cerebral hypoperfusion. Brain Res 1573:44–53.  https://doi.org/10.1016/j.brainres.2014.05.019 CrossRefPubMedGoogle Scholar
  19. 19.
    Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y (2012) Suppressing inflammation by inhibiting the NF-kappaB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia. Br J Pharmacol 167:1520–1532.  https://doi.org/10.1111/j.1476-5381.2012.02105.x CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lazaroni TL, Raslan AC, Fontes WR, de Oliveira ML, Bader M, Alenina N, Moraes MF, Dos Santos RA et al (2012) Angiotensin-(1-7)/Mas axis integrity is required for the expression of object recognition memory. Neurobiol Learn Mem 97:113–123.  https://doi.org/10.1016/j.nlm.2011.10.003 CrossRefPubMedGoogle Scholar
  21. 21.
    Zhao J, Liu E, Li G, Qi L, Li J, Yang W (2015) Effects of the angiotensin-(1-7)/Mas/PI3K/Akt/nitric oxide axis and the possible role of atrial natriuretic peptide in an acute atrial tachycardia canine model. J Renin Angiotensin Aldosterone Syst 16:1069–1077.  https://doi.org/10.1177/1470320314543723 CrossRefPubMedGoogle Scholar
  22. 22.
    Gironacci MM, Cerniello FM, Longo Carbajosa NA, Goldstein J, Cerrato BD (2014) Protective axis of the renin-angiotensin system in the brain. Clin Sci (Lond) 127:295–306.  https://doi.org/10.1042/CS20130450 CrossRefGoogle Scholar
  23. 23.
    Liu L, Lu Y, Kong H, Li L, Marshall C, Xiao M, Ding J, Gao J et al (2012) Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and D-galactose injection. Int J Neuropsychopharmacol 15:55–68.  https://doi.org/10.1017/S1461145711000022 CrossRefPubMedGoogle Scholar
  24. 24.
    Kim TW, Kim CS, Kim JY, Kim CJ, Seo JH (2016) Combined exercise ameliorates ovariectomy-induced cognitive impairment by enhancing cell proliferation and suppressing apoptosis. Menopause 23:18–26.  https://doi.org/10.1097/GME.0000000000000486 CrossRefPubMedGoogle Scholar
  25. 25.
    Rehman SU, Shah SA, Ali T, Chung JI, Kim MO (2017) Anthocyanins reversed D-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol 54:255–271.  https://doi.org/10.1007/s12035-015-9604-5 CrossRefPubMedGoogle Scholar
  26. 26.
    Kulemina LV, Ostrov DA (2011) Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen 16:878–885.  https://doi.org/10.1177/1087057111413919 CrossRefPubMedGoogle Scholar
  27. 27.
    Bennion DM, Haltigan EA, Irwin AJ, Donnangelo LL, Regenhardt RW, Pioquinto DJ, Purich DL, Sumners C (2015) Activation of the neuroprotective angiotensin-converting enzyme 2 in rat ischemic stroke. Hypertension 66:141–148.  https://doi.org/10.1161/HYPERTENSIONAHA.115.05185 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mecca AP, Regenhardt RW, O'Connor TE, Joseph JP, Raizada MK, Katovich MJ, Sumners C (2011) Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke. Exp Physiol 96:1084–1096.  https://doi.org/10.1113/expphysiol.2011.058578 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    de Ceglia R, Chaabane L, Biffi E, Bergamaschi A, Ferrigno G, Amadio S, Del Carro U, Mazzocchi N et al (2015) Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by diminazene aceturate. Brain Behav Immun 45:263–276.  https://doi.org/10.1016/j.bbi.2014.12.003 CrossRefPubMedGoogle Scholar
  30. 30.
    Wang L, de Kloet AD, Pati D, Hiller H, Smith JA, Pioquinto DJ, Ludin JA, Oh SP et al (2016) Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 105:114–123.  https://doi.org/10.1016/j.neuropharm.2015.12.026 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT (2015) Resveratrol decreases the insoluble Abeta1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience 310:641–649.  https://doi.org/10.1016/j.neuroscience.2015.10.006 CrossRefPubMedGoogle Scholar
  32. 32.
    Khajuria DK, Razdan R, Mahapatra DR (2012) Description of a new method of ovariectomy in female rats. Rev Bras Reumatol 52:462–470CrossRefPubMedGoogle Scholar
  33. 33.
    Alawdi SH, El-Denshary ES, Safar MM, Eidi H, David MO, Abdel-Wahhab MA (2017) Neuroprotective effect of nanodiamond in Alzheimer’s disease rat model: a pivotal role for modulating NF-kappaB and STAT3 signaling. Mol Neurobiol 54:1906–1918.  https://doi.org/10.1007/s12035-016-9762-0 CrossRefPubMedGoogle Scholar
  34. 34.
    Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110.  https://doi.org/10.1007/s10339-011-0430-z CrossRefPubMedGoogle Scholar
  35. 35.
    Pandareesh MD, Anand T, Khanum F (2016) Cognition enhancing and neuromodulatory propensity of Bacopa monniera extract against scopolamine induced cognitive impairments in rat hippocampus. Neurochem Res 41:985–999.  https://doi.org/10.1007/s11064-015-1780-1 CrossRefPubMedGoogle Scholar
  36. 36.
    Arsad SS, Esa NM, Hamzah H (2014) Histopathologic changes in liver and kidney tissues from male Sprague Dawley rats treated with Rhaphidophora Decursiva (Roxb.) Schott extract. J Cytol Histol S4:001.  https://doi.org/10.4172/2157-7099.S4-001 CrossRefGoogle Scholar
  37. 37.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408.  https://doi.org/10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  38. 38.
    Shen J, Wu J (2015) Nicotinic cholinergic mechanisms in Alzheimer’s disease. Int Rev Neurobiol 124:275–292.  https://doi.org/10.1016/bs.irn.2015.08.002 CrossRefPubMedGoogle Scholar
  39. 39.
    Buckingham SD, Jones AK, Brown LA, Sattelle DB (2009) Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev 61:39–61.  https://doi.org/10.1124/pr.108.000562 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wang C, Chen T, Li G, Zhou L, Sha S, Chen L (2015) Simvastatin prevents beta-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through alpha7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate. Neuropharmacology 97:122–132.  https://doi.org/10.1016/j.neuropharm.2015.05.020 CrossRefPubMedGoogle Scholar
  41. 41.
    Ma Y, Sun X, Li J, Jia R, Yuan F, Wei D, Jiang W (2017) Melatonin alleviates the epilepsy-associated impairments in hippocampal LTP and spatial learning through rescue of surface GluR2 expression at hippocampal CA1 synapses. Neurochem Res 42:1438–1448.  https://doi.org/10.1007/s11064-017-2200-5 CrossRefPubMedGoogle Scholar
  42. 42.
    Wayner MJ, Armstrong DL, Phelix CF (1996) Nicotine blocks angiotensin II inhibition of LTP in the dentate gyrus. Peptides 17:1127–1133CrossRefPubMedGoogle Scholar
  43. 43.
    Olmos G, Llado J (2014) Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediators Inflamm 2014:861231.  https://doi.org/10.1155/2014/861231 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Liu S, Lau L, Wei J, Zhu D, Zou S, Sun HS, Fu Y, Liu F et al (2004) Expression of Ca(2+)-permeable AMPA receptor channels primes cell death in transient forebrain ischemia. Neuron 43:43–55.  https://doi.org/10.1016/j.neuron.2004.06.017 CrossRefPubMedGoogle Scholar
  45. 45.
    Rodriguez-Perez AI, Valenzuela R, Villar-Cheda B, Guerra MJ, Lanciego JL, Labandeira-Garcia JL (2010) Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson’s disease. Exp Neurol 224:517–526.  https://doi.org/10.1016/j.expneurol.2010.05.015 CrossRefPubMedGoogle Scholar
  46. 46.
    Pernomian L, Pernomian L, Gomes MS, da Silva CH (2015) Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists. Eur J Pharmacol 769:143–146.  https://doi.org/10.1016/j.ejphar.2015.11.009 CrossRefPubMedGoogle Scholar
  47. 47.
    Gouveia TL, Frangiotti MI, de Brito JM, de Castro Neto EF, Sakata MM, Febba AC, Casarini DE, Amado D et al (2012) The levels of renin-angiotensin related components are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy. Neurochem Int 61:54–62.  https://doi.org/10.1016/j.neuint.2012.04.012 CrossRefPubMedGoogle Scholar
  48. 48.
    Freund M, Walther T, von Bohlen Und HO (2012) Immunohistochemical localization of the angiotensin-(1-7) receptor Mas in the murine forebrain. Cell Tissue Res 348:29–35.  https://doi.org/10.1007/s00441-012-1354-3 CrossRefPubMedGoogle Scholar
  49. 49.
    Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol 25:237–258.  https://doi.org/10.14670/HH-25.237 PubMedCrossRefGoogle Scholar
  50. 50.
    Shi HR, Zhu LQ, Wang SH, Liu XA, Tian Q, Zhang Q, Wang Q, Wang JZ (2008) 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner. J Neural Transm (Vienna) 115:879–888.  https://doi.org/10.1007/s00702-008-0021-z CrossRefGoogle Scholar
  51. 51.
    Tian M, Zhu D, Xie W, Shi J (2012) Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains. FEBS Lett 586:3737–3745.  https://doi.org/10.1016/j.febslet.2012.09.004 CrossRefPubMedGoogle Scholar
  52. 52.
    Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S (2014) Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer's disease. Alzheimers Res Ther 6:35.  https://doi.org/10.1186/alzrt265 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141:859–871.  https://doi.org/10.1016/j.cell.2010.03.053 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Garcia-Mesa Y, Pareja-Galeano H, Bonet-Costa V, Revilla S, Gomez-Cabrera MC, Gambini J, Gimenez-Llort L, Cristofol R et al (2014) Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms. Psychoneuroendocrinology 45:154–166.  https://doi.org/10.1016/j.psyneuen.2014.03.021 CrossRefPubMedGoogle Scholar
  55. 55.
    Wang XL, Iwanami J, Min LJ, Tsukuda K, Nakaoka H, Bai HY, Shan BS, Kan-No H et al (2016) Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function. NPJ Aging Mech Dis 2:16024.  https://doi.org/10.1038/npjamd.2016.24 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Grimes CA, Jope RS (2001) CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem 78:1219–1232CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Walton MR, Dragunow I (2000) Is CREB a key to neuronal survival? Trends Neurosci 23:48–53CrossRefPubMedGoogle Scholar
  58. 58.
    Park SJ, Shin EJ, Min SS, An J, Li Z, Hee CY, Hoon JJ, Bach JH et al (2013) Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. Neuropsychopharmacology 38:1426–1437.  https://doi.org/10.1038/npp.2013.39 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357.  https://doi.org/10.1100/2012/756357 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Xu Y, Sheng H, Tang Z, Lu J, Ni X (2015) Inflammation and increased IDO in hippocampus contribute to depression-like behavior induced by estrogen deficiency. Behav Brain Res 288:71–78.  https://doi.org/10.1016/j.bbr.2015.04.017 CrossRefPubMedGoogle Scholar
  61. 61.
    Souza LK, Nicolau LA, Sousa NA, Araujo TS, Sousa FB, Costa DS, Souza FM, Pacifico DM et al (2016) Diminazene aceturate, an angiotensin-converting enzyme II activator, prevents gastric mucosal damage in mice: role of the angiotensin-(1-7)/Mas receptor axis. Biochem Pharmacol 112:50–59.  https://doi.org/10.1016/j.bcp.2016.05.010 CrossRefPubMedGoogle Scholar
  62. 62.
    Tao L, Qiu Y, Fu X, Lin R, Lei C, Wang J, Lei B (2016) Angiotensin-converting enzyme 2 activator diminazene aceturate prevents lipopolysaccharide-induced inflammation by inhibiting MAPK and NF-kappaB pathways in human retinal pigment epithelium. J Neuroinflammation 13:35.  https://doi.org/10.1186/s12974-016-0489-7 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Choi DW (1995) Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 18:58–60CrossRefPubMedGoogle Scholar
  64. 64.
    Stamouli EC, Politis AM (2016) Pro-inflammatory cytokines in Alzheimer’s disease. Psychiatriki 27:264–275.  https://doi.org/10.22365/jpsych.2016.274.264 CrossRefPubMedGoogle Scholar
  65. 65.
    Bennion DM, Haltigan E, Regenhardt RW, Steckelings UM, Sumners C (2015) Neuroprotective mechanisms of the ACE2-angiotensin-(1-7)-Mas axis in stroke. Curr Hypertens Rep 17:3.  https://doi.org/10.1007/s11906-014-0512-2 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sriramula S, Cardinale JP, Lazartigues E, Francis J (2011) ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovasc Res 92:401–408.  https://doi.org/10.1093/cvr/cvr242 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Chiang CS, Stalder A, Samimi A, Campbell IL (1994) Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice. Dev Neurosci 16:212–221CrossRefPubMedGoogle Scholar
  68. 68.
    Regenhardt RW, Desland F, Mecca AP, Pioquinto DJ, Afzal A, Mocco J, Sumners C (2013) Anti-inflammatory effects of angiotensin-(1-7) in ischemic stroke. Neuropharmacology 71:154–163.  https://doi.org/10.1016/j.neuropharm.2013.03.025 CrossRefPubMedGoogle Scholar
  69. 69.
    Liu Z, Huang XR, Chen HY, Penninger JM, Lan HY (2012) Loss of angiotensin-converting enzyme 2 enhances TGF-beta/Smad-mediated renal fibrosis and NF-kappaB-driven renal inflammation in a mouse model of obstructive nephropathy. Lab Invest 92:650–661.  https://doi.org/10.1038/labinvest.2012.2 CrossRefPubMedGoogle Scholar
  70. 70.
    Xu S, Zhong M, Zhang L, Wang Y, Zhou Z, Hao Y, Zhang W, Yang X et al (2009) Overexpression of Tfam protects mitochondria against beta-amyloid-induced oxidative damage in SH-SY5Y cells. FEBS J 276:3800–3809.  https://doi.org/10.1111/j.1742-4658.2009.07094.x CrossRefPubMedGoogle Scholar
  71. 71.
    Kim SM, Kim YG, Jeong KH, Lee SH, Lee TW, Ihm CG, Moon JY (2012) Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells. PLoS One 7:e39739.  https://doi.org/10.1371/journal.pone.0039739 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Aguirre-Rueda D, Guerra-Ojeda S, Aldasoro M, Iradi A, Obrador E, Ortega A, Mauricio MD, Vila JM et al (2015) Astrocytes protect neurons from Abeta1-42 peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-gamma and SIRT-1. Int J Med Sci 12:48–56.  https://doi.org/10.7150/ijms.10035 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Zhang M, Ye Y, Cong J, Pu D, Liu J, Hu G, Wu J (2013) Regulation of STAT3 by miR-106a is linked to cognitive impairment in ovariectomized mice. Brain Res 1503:43–52.  https://doi.org/10.1016/j.brainres.2013.01.052 CrossRefPubMedGoogle Scholar
  74. 74.
    Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L, Castellano RK, Ostrov DA et al (2009) Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 179:1048–1054.  https://doi.org/10.1164/rccm.200811-1678OC CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Sharma S, Yang B, Xi X, Grotta JC, Aronowski J, Savitz SI (2011) IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res 1373:189–194.  https://doi.org/10.1016/j.brainres.2010.11.096 CrossRefPubMedGoogle Scholar
  76. 76.
    Shravah J, Wang B, Pavlovic M, Kumar U, Chen DD, Luo H, Ansley DM (2014) Propofol mediates signal transducer and activator of transcription 3 activation and crosstalk with phosphoinositide 3-kinase/AKT. JAKSTAT 3:e29554.  https://doi.org/10.4161/jkst.29554 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zhang ZH, Yu LJ, Hui XC, Wu ZZ, Yin KL, Yang H, Xu Y (2014) Hydroxy-safflor yellow A attenuates Abeta(1)(-)(4)(2)-induced inflammation by modulating the JAK2/STAT3/NF-kappaB pathway. Brain Res 1563:72–80.  https://doi.org/10.1016/j.brainres.2014.03.036 CrossRefPubMedGoogle Scholar
  78. 78.
    Heberden C (2017) Sex steroids and neurogenesis. Biochem Pharmacol 141:56–62.  https://doi.org/10.1016/j.bcp.2017.05.019 CrossRefPubMedGoogle Scholar
  79. 79.
    Snigdha S, Smith ED, Prieto GA, Cotman CW (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14–24.  https://doi.org/10.1007/s12264-012-1057-5 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Uhal BD, Li X, Xue A, Gao X, Abdul-Hafez A (2011) Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis. Am J Physiol Lung Cell Mol Physiol 301:L269–L274.  https://doi.org/10.1152/ajplung.00222.2010 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Ahmed S. Kamel
    • 1
    Email author
  • Noha F. Abdelkader
    • 1
  • Sahar S. Abd El-Rahman
    • 2
  • Marwan Emara
    • 3
  • Hala F. Zaki
    • 1
  • Mahmoud M. Khattab
    • 1
  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
  2. 2.Department of Pathology, Faculty of Veterinary MedicineCairo UniversityCairoEgypt
  3. 3.Zewail City of Science and TechnologyGizaEgypt

Personalised recommendations