International Journal of Clinical and Experimental Neurology:

Home » Journal » IJCEN » Archive » Volume 2, Issue 1

Article

Lipocalin-2: a New Regulator of Non-Pathogen-Associated Neuroinflammation

1Department of Biomedical Sciences, Texas Tech University HSC, Amarillo, Amarillo, TX


International Journal of Clinical and Experimental Neurology. 2014, 2(1), 8-15
DOI: 10.12691/ijcen-2-1-3
Copyright © 2014 Science and Education Publishing

Cite this paper:
Manoj Banjara. Lipocalin-2: a New Regulator of Non-Pathogen-Associated Neuroinflammation. International Journal of Clinical and Experimental Neurology. 2014; 2(1):8-15. doi: 10.12691/ijcen-2-1-3.

Correspondence to: Manoj  Banjara, Department of Biomedical Sciences, Texas Tech University HSC, Amarillo, Amarillo, TX. Email: manoj.banjara@ttuhsc.edu

Abstract

Lipocalin is a family of small molecules transporting extracellular proteins. Lipocalin-2 (LCN2) is a member of the family that sequesters iron-bound bacterial siderophores. The well-accepted function of LCN2 protein is its anti-bacterial behavior, however, its role in iron regulation, cellular migration, death and morphology modulation have been speculated. Several reports have correlated the presence of LCN2 in the infected, injured and stressed brain, and its effect in neuronal and non-neuronal cell types in the central nervous system. This article reviews studies that demonstrated mechanisms and functions of LCN2 expression in inflammed brain (acute and chronic), particularly in non-pathogen-associated neuroinflammation. This review predicts that LCN2 can be an attractive target to reduce mortality and morbidity associated with uncontrollable neuroinflammation.

Keywords

References

[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[
[[1]  Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 413: 732-738.
 
[[2]  Asea A (2008) Heat shock proteins and toll-like receptors. Handb Exp Pharmacol: 111-127.
 
[[3]  Ashhab MU, Omran A, Kong H, Gan N, He F, Peng J, Yin F (2013) Expressions of tumor necrosis factor alpha and microRNA-155 in immature rat model of status epilepticus and children with mesial temporal lobe epilepsy. J Mol Neurosci. 51: 950-958.
 
[[4]  Axelsson L, Bergenfeldt M, Ohlsson K (1995) Studies of the release and turnover of a human neutrophil lipocalin. Scand J Clin Lab Invest. 55: 577-588.
 
[[5]  Bahmani P, Halabian R, Rouhbakhsh M, Roushandeh AM, Masroori N, Ebrahimi M, Samadikuchaksaraei A, Shokrgozar MA, Roudkenar MH (2010) Neutrophil gelatinase-associated lipocalin induces the expression of heme oxygenase-1 and superoxide dismutase 1, 2. Cell Stress Chaperones. 15: 395-403.
 
Show More References
[6]  Basu A, Krady JK, Levison SW (2004) Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 78: 151-156.
 
[7]  Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A (2008) Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat. 108: 389-397.
 
[8]  Berger T, Cheung CC, Elia AJ, Mak TW (2010) Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc Natl Acad Sci U S A. 107: 2995-3000.
 
[9]  Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia XG, Zhou H (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A. 110: 4069-4074.
 
[10]  Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl). 83: 876-886.
 
[11]  Bong JJ, Seol MB, Kim HH, Han O, Back K, Baik M (2004) The 24p3 gene is induced during involution of the mammary gland and induces apoptosis of mammary epithelial cells. Mol Cells. 17: 29-34.
 
[12]  Bradbury MW (1997) Transport of iron in the blood-brain-cerebrospinal fluid system. J Neurochem. 69: 443-454.
 
[13]  Brea D, Blanco M, Ramos-Cabrer P, Moldes O, Arias S, Perez-Mato M, Leira R, Sobrino T, Castillo J (2011) Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab. 31: 1424-1431.
 
[14]  Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res. 66: 1198-1207.
 
[15]  Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta. 1826: 129-169.
 
[16]  Chang SY, Kim DB, Ko SH, Jo YH, Kim MJ (2013) Induction mechanism of lipocalin-2 expression by co-stimulation with interleukin-1beta and interferon-gamma in RINm5F beta-cells. Biochem Biophys Res Commun. 434: 577-583.
 
[17]  Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G (2011) Role of iron in brain injury after intraventricular hemorrhage. Stroke. 42: 465-470.
 
[18]  Chia WJ, Dawe GS, Ong WY (2011) Expression and localization of the iron-siderophore binding protein lipocalin 2 in the normal rat brain and after kainate-induced excitotoxicity. Neurochem Int. 59: 591-599.
 
[19]  Choi J, Lee HW, Suk K (2011) Increased plasma levels of lipocalin 2 in mild cognitive impairment. J Neurol Sci. 305: 28-33.
 
[20]  Clausen BH, Lambertsen KL, Babcock AA, Holm TH, Dagnaes-Hansen F, Finsen B (2008) Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflammation. 5: 46.
 
[21]  Coles M, Diercks T, Muehlenweg B, Bartsch S, Zolzer V, Tschesche H, Kessler H (1999) The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin. J Mol Biol. 289: 139-157.
 
[22]  Correnti C, Richardson V, Sia AK, Bandaranayake AD, Ruiz M, Suryo Rahmanto Y, Kovacevic Z, Clifton MC, Holmes MA, Kaiser BK, Barasch J, Raymond KN, Richardson DR, Strong RK (2012) Siderocalin/Lcn2/NGAL/24p3 Does Not Drive Apoptosis Through Gentisic Acid Mediated Iron Withdrawal in Hematopoietic Cell Lines. PLoS One. 7: e43696.
 
[23]  Cowland JB, Sorensen OE, Sehested M, Borregaard N (2003) Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol. 171: 6630-6639.
 
[24]  Crutcher KA, Gendelman HE, Kipnis J, Perez-Polo JR, Perry VH, Popovich PG, Weaver LC (2006) Debate: "is increasing neuroinflammation beneficial for neural repair?". J Neuroimmune Pharmacol. 1: 195-211.
 
[25]  Danielisova V, Gottlieb M, Burda J (2002) Iron deposition after transient forebrain ischemia in rat brain. Neurochem Res. 27: 237-242.
 
[26]  Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 122: 1377-1392.
 
[27]  Devireddy LR, Gazin C, Zhu X, Green MR (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 123: 1293-1305.
 
[28]  Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 141: 1006-1017.
 
[29]  Dong M, Xi G, Keep RF, Hua Y (2013) Role of iron in brain lipocalin 2 upregulation after intracerebral hemorrhage in rats. Brain Res. 1505: 86-92.
 
[30]  Dringen R, Bishop GM, Koeppe M, Dang TN, Robinson SR (2007) The pivotal role of astrocytes in the metabolism of iron in the brain. Neurochem Res. 32: 1884-1890.
 
[31]  Fernandez-Pol JA (1978) Isolation and characterization of a siderophore-like growth factor from mutants of SV40-transformed cells adapted to picolinic acid. Cell. 14: 489-499.
 
[32]  Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 432: 917-921.
 
[33]  Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG (2009) Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 4: 47.
 
[34]  Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 20: 269-287.
 
[35]  Glaros T, Fu Y, Xing J, Li L (2012) Molecular mechanism underlying persistent induction of LCN2 by lipopolysaccharide in kidney fibroblasts. PLoS One. 7: e34633.
 
[36]  Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK (2002) The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 10: 1033-1043.
 
[37]  Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z, Xuan Y, Khan O, Garbern J, Grossman RI (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging. 29: 537-544.
 
[38]  He RL, Zhou J, Hanson CZ, Chen J, Cheng N, Ye RD (2009) Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood. 113: 429-437.
 
[39]  Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 303: 1526-1529.
 
[40]  Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH, 3rd, Ma Q, Dastrala S, Bennett M, Mitsnefes M, Devarajan P (2007) NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol. 22: 2089-2095.
 
[41]  Iori V, Maroso M, Rizzi M, Iyer AM, Vertemara R, Carli M, Agresti A, Antonelli A, Bianchi ME, Aronica E, Ravizza T, Vezzani A (2013) Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures. Neurobiol Dis. 58: 102-114.
 
[42]  Ip JP, Nocon AL, Hofer MJ, Lim SL, Muller M, Campbell IL (2011) Lipocalin 2 in the central nervous system host response to systemic lipopolysaccharide administration. J Neuroinflammation. 8: 124.
 
[43]  Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin S, Flavell RA, Leemans JC, Sutterwala FS (2009) Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 106: 20388-20393.
 
[44]  Jang E, Kim JH, Lee S, Kim JH, Seo JW, Jin M, Lee MG, Jang IS, Lee WH, Suk K (2013a) Phenotypic polarization of activated astrocytes: the critical role of lipocalin-2 in the classical inflammatory activation of astrocytes. J Immunol. 191: 5204-5219.
 
[45]  Jang E, Lee S, Kim JH, Kim JH, Seo JW, Lee WH, Mori K, Nakao K, Suk K (2013b) Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J. 27: 1176-1190.
 
[46]  Jayaraman A, Roberts KA, Yoon J, Yarmush DM, Duan X, Lee K, Yarmush ML (2005) Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis. Biotechnol Bioeng. 91: 502-515.
 
[47]  Jones RL, Peterson CM, Grady RW, Cerami A (1980) Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth. J Exp Med. 151: 418-428.
 
[48]  Kim H, Lee S, Park HC, Lee WH, Lee MS, Suk K (2011) Modulation of glial and neuronal migration by lipocalin-2 in zebrafish. Immune Netw. 11: 342-347.
 
[49]  Kooncumchoo P, Sharma S, Porter J, Govitrapong P, Ebadi M (2006) Coenzyme Q(10) provides neuroprotection in iron-induced apoptosis in dopaminergic neurons. J Mol Neurosci. 28: 125-141.
 
[50]  Kratchmarova I, Kalume DE, Blagoev B, Scherer PE, Podtelejnikov AV, Molina H, Bickel PE, Andersen JS, Fernandez MM, Bunkenborg J, Roepstorff P, Kristiansen K, Lodish HF, Mann M, Pandey A (2002) A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes. Mol Cell Proteomics. 1: 213-222.
 
[51]  Kubben FJ, Sier CF, Hawinkels LJ, Tschesche H, van Duijn W, Zuidwijk K, van der Reijden JJ, Hanemaaijer R, Griffioen G, Lamers CB, Verspaget HW (2007) Clinical evidence for a protective role of lipocalin-2 against MMP-9 autodegradation and the impact for gastric cancer. Eur J Cancer. 43: 1869-1876.
 
[52]  Lee S, Kim JH, Kim JH, Seo JW, Han HS, Lee WH, Mori K, Nakao K, Barasch J, Suk K (2011) Lipocalin-2 Is a chemokine inducer in the central nervous system: role of chemokine ligand 10 (CXCL10) in lipocalin-2-induced cell migration. J Biol Chem. 286: 43855-43870.
 
[53]  Lee S, Lee J, Kim S, Park JY, Lee WH, Mori K, Kim SH, Kim IK, Suk K (2007) A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol. 179: 3231-3241.
 
[54]  Lee S, Park JY, Lee WH, Kim H, Park HC, Mori K, Suk K (2009) Lipocalin-2 is an autocrine mediator of reactive astrocytosis. J Neurosci. 29: 234-249.
 
[55]  Lee YC, Elangovan N, Tzeng WF, Chu ST (2005) Mouse uterine 24p3 protein as a suppressor of sperm acrosome reaction. Mol Biol Rep. 32: 237-245.
 
[56]  Liu Q, Nilsen-Hamilton M (1995) Identification of a new acute phase protein. J Biol Chem. 270: 22565-22570.
 
[57]  Liu QS, Nilsen-Hamilton M, Xiong SD (2003) Synergistic regulation of the acute phase protein SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines. Sheng li xue bao : [Acta physiologica Sinica]. 55: 525-529.
 
[58]  Lively S, Brown IR (2008) Extracellular matrix protein SC1/hevin in the hippocampus following pilocarpine-induced status epilepticus. J Neurochem. 107: 1335-1346.
 
[59]  Luheshi NM, Kovacs KJ, Lopez-Castejon G, Brough D, Denes A (2011) Interleukin-1alpha expression precedes IL-1beta after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues. J Neuroinflammation. 8: 186.
 
[60]  Macco R, Pelizzoni I, Consonni A, Vitali I, Giacalone G, Martinelli Boneschi F, Codazzi F, Grohovaz F, Zacchetti D (2013) Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation. J Neuroinflammation. 10: 130.
 
[61]  MacManus JP, Graber T, Luebbert C, Preston E, Rasquinha I, Smith B, Webster J (2004) Translation-state analysis of gene expression in mouse brain after focal ischemia. J Cereb Blood Flow Metab. 24: 657-667.
 
[62]  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.
 
[63]  Meheus LA, Fransen LM, Raymackers JG, Blockx HA, Van Beeumen JJ, Van Bun SM, Van de Voorde A (1993) Identification by microsequencing of lipopolysaccharide-induced proteins secreted by mouse macrophages. J Immunol. 151: 1535-1547.
 
[64]  Mesquita SD, Ferreira AC, Falcao AM, Sousa JC, Oliveira TG, Correia-Neves M, Sousa N, Marques F, Palha JA (2013) Lipocalin 2 produced in response to amyloid beta. Paper presented at the Society for Neuroscience, San Diego, CA, Sunday, Nov 10, 2013
 
[65]  Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, Mercik K, Medvedev N, Wilczek E, De Roo M, Zuschratter W, Muller D, Wilczynski GM, Mozrzymas JW, Stewart MG, Kaczmarek L, Wlodarczyk J (2011) Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J Cell Sci. 124: 3369-3380.
 
[66]  Mills E, Dong XP, Wang F, Xu H (2010) Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med Chem. 2: 51-64.
 
[67]  Mucha M, Skrzypiec AE, Schiavon E, Attwood BK, Kucerova E, Pawlak R (2011) Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation. Proc Natl Acad Sci U S A. 108: 18436-18441.
 
[68]  Naude PJ, Nyakas C, Eiden LE, Ait-Ali D, van der Heide R, Engelborghs S, Luiten PG, De Deyn PP, den Boer JA, Eisel UL (2012) Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease. FASEB J. 26: 2811-2823.
 
[69]  Ni J, Ma X, Zhou M, Pan X, Tang J, Hao Y, Lu Z, Gao M, Bao Y, Jia W (2013) Serum lipocalin-2 levels positively correlate with coronary artery disease and metabolic syndrome. Cardiovasc Diabetol. 12: 176.
 
[70]  Nocon AL, Ip JP, Terry R, Lim SL, Getts DR, Muller M, Hofer MJ, King NJ, Campbell IL (2014) The bacteriostatic protein lipocalin 2 is induced in the central nervous system of mice with west Nile virus encephalitis. J Virol. 88: 679-689.
 
[71]  Okuma Y, Liu K, Wake H, Zhang J, Maruo T, Date I, Yoshino T, Ohtsuka A, Otani N, Tomura S, Shima K, Yamamoto Y, Yamamoto H, Takahashi HK, Mori S, Nishibori M (2012) Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Ann Neurol. 72: 373-384.
 
[72]  Oudit GY, Trivieri MG, Khaper N, Husain T, Wilson GJ, Liu P, Sole MJ, Backx PH (2004) Taurine supplementation reduces oxidative stress and improves cardiovascular function in an iron-overload murine model. Circulation. 109: 1877-1885.
 
[73]  Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol. 290: C917-924.
 
[74]  Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 279: 7370-7377.
 
[75]  Pekar T, Stojakovic T, Haas J, Simmet NE, Scharnagl H, Gattringer T, Fazekas F, Storch MK, Seifert-Held T (2013) Plasma neutrophil gelatinase-associated lipocalin and functional outcome in ischemic stroke. J Neurol Sci. 333: e171.
 
[76]  Pico RM, Gall CM (1994) Hippocampal epileptogenesis produced by electrolytic iron deposition in the rat dentate gyrus. Epilepsy Res. 19: 27-36.
 
[77]  Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 282: 2085-2088.
 
[78]  Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci. 9: 481-493.
 
[79]  Provatopoulou X, Gounaris A, Kalogera E, Zagouri F, Flessas I, Goussetis E, Nonni A, Papassotiriou I, Zografos G (2009) Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer. 9: 390.
 
[80]  Qian ZM, To Y, Tang PL, Feng YM (1999) Transferrin receptors on the plasma membrane of cultured rat astrocytes. Exp Brain Res. 129: 473-476.
 
[81]  Raz E, Jensen JH, Ge Y, Babb JS, Miles L, Reaume J, Grossman RI, Inglese M (2011) Brain iron quantification in mild traumatic brain injury: a magnetic field correlation study. AJNR Am J Neuroradiol. 32: 1851-1856.
 
[82]  Reis K, Halldin J, Fernaeus S, Pettersson C, Land T (2006) NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysaccharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells. J Neurosci Res. 84: 1047-1052.
 
[83]  Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol. 9: 429-439.
 
[84]  Sandri S, Rodriguez D, Gomes E, Monteiro HP, Russo M, Campa A (2008) Is serum amyloid A an endogenous TLR4 agonist? J Leukoc Biol. 83: 1174-1180.
 
[85]  Sato M, Sano H, Iwaki D, Kudo K, Konishi M, Takahashi H, Takahashi T, Imaizumi H, Asai Y, Kuroki Y (2003) Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J Immunol. 171: 417-425.
 
[86]  Savage CD, Lopez-Castejon G, Denes A, Brough D (2012) NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury. Front Immunol. 3: 288.
 
[87]  Schulze J, Zierath D, Tanzi P, Cain K, Shibata D, Dressel A, Becker K (2013) Severe stroke induces long-lasting alterations of high-mobility group box 1. Stroke. 44: 246-248.
 
[88]  Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ (1999) Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 274: 17406-17409.
 
[89]  Seong SY, Matzinger P (2004) Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 4: 469-478.
 
[90]  Shen F, Hu Z, Goswami J, Gaffen SL (2006) Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem. 281: 24138-24148.
 
[91]  Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A (2012) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med. 18: 911-917.
 
[92]  Siddappa AJ, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK (2002) Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res. 68: 761-775.
 
[93]  Skrzypiec AE, Shah RS, Schiavon E, Baker E, Skene N, Pawlak R, Mucha M (2013) Stress-induced lipocalin-2 controls dendritic spine formation and neuronal activity in the amygdala. PLoS One. 8: e61046.
 
[94]  Sloviter RS, Zappone CA, Harvey BD, Frotscher M (2006) Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats. J Comp Neurol. 494: 944-960.
 
[95]  Srinivasan G, Aitken JD, Zhang B, Carvalho FA, Chassaing B, Shashidharamurthy R, Borregaard N, Jones DP, Gewirtz AT, Vijay-Kumar M (2012) Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis. J Immunol. 189: 1911-1919.
 
[96]  Sroga JM, Jones TB, Kigerl KA, McGaughy VM, Popovich PG (2003) Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J Comp Neurol. 462: 223-240.
 
[97]  Streit WJ (2006) Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci. 29: 506-510.
 
[98]  Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation. 1: 14.
 
[99]  Sunil VR, Patel KJ, Nilsen-Hamilton M, Heck DE, Laskin JD, Laskin DL (2007) Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Exp Mol Pathol. 83: 177-187.
 
[100]  Tan BK, Adya R, Shan X, Syed F, Lewandowski KC, O'Hare JP, Randeva HS (2009) Ex vivo and in vivo regulation of lipocalin-2, a novel adipokine, by insulin. Diabetes Care. 32: 129-131.
 
[101]  Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol. 208: 1-25.
 
[102]  Triebel S, Blaser J, Reinke H, Tschesche H (1992) A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase. FEBS Lett. 314: 386-388.
 
[103]  van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis. 11: 91-99.
 
[104]  Velez-Pardo C, Jimenez Del Rio M, Verschueren H, Ebinger G, Vauquelin G (1997) Dopamine and iron induce apoptosis in PC12 cells. Pharmacol Toxicol. 80: 76-84.
 
[105]  Venkatesha S, Hanai J, Seth P, Karumanchi SA, Sukhatme VP (2006) Lipocalin 2 antagonizes the proangiogenic action of ras in transformed cells. Mol Cancer Res. 4: 821-829.
 
[106]  Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med. 13: 1042-1049.
 
[107]  Wallis LI, Paley MN, Graham JM, Grunewald RA, Wignall EL, Joy HM, Griffiths PD (2008) MRI assessment of basal ganglia iron deposition in Parkinson's disease. J Magn Reson Imaging. 28: 1061-1067.
 
[108]  Wang D, Zhu D, Wei XE, Li YH, Li WB (2013a) Using susceptibility-weighted images to quantify iron deposition differences in amnestic mild cognitive impairment and Alzheimer's disease. Neurol India. 61: 26-34.
 
[109]  Wang G, Weng Y-C, X.Han, Chou W-H (2013b) Lipocalin 2 is a detrimental factor induced after stroke-reperfusion injury. Paper presented at the Society for Neuroscience, San Diego, Sunday, Nov 10, 2013
 
[110]  Wang Q, Du F, Qian ZM, Ge XH, Zhu L, Yung WH, Yang L, Ke Y (2008) Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain. Endocrinology. 149: 3920-3925.
 
[111]  Wang YC, Lin S, Yang QW (2011) Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation. 8: 134.
 
[112]  Wessling-Resnick M (2010) Iron homeostasis and the inflammatory response. Annu Rev Nutr. 30: 105-122.
 
[113]  Woo JS, Kim KM, Kang JS, Zodpe P, Chae SW, Hwang SJ, Lee HM (2007) Expression of neutrophil gelatinase-associated lipocalin in human salivary glands. Ann Otol Rhinol Laryngol. 116: 599-603.
 
[114]  Yan L, Borregaard N, Kjeldsen L, Moses MA (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem. 276: 37258-37265.
 
[115]  Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA (2009) Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A. 106: 3913-3918.
 
[116]  Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell. 10: 1045-1056.
 
[117]  Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci. 32: 6391-6410.
 
[118]  Zhang JG, Czabotar PE, Policheni AN, Caminschi I, Wan SS, Kitsoulis S, Tullett KM, Robin AY, Brammananth R, van Delft MF, Lu J, O'Reilly LA, Josefsson EC, Kile BT, Chin WJ, Mintern JD, Olshina MA, Wong W, Baum J, Wright MD, Huang DC, Mohandas N, Coppel RL, Colman PM, Nicola NA, Shortman K, Lahoud MH (2012) The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity. 36: 646-657.
 
[119]  Zhang SJ, Li XW, Wang Y, Wei D, Jiang W (2010) [Expression of IL-1 mRNA in the dentate gyrus of adult rats following lithium-pilocarione-induced seizures]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 26: 288-290.
 
[120]  Zhao P, Stephens JM (2013) STAT1, NF-kappaB and ERKs play a role in the induction of lipocalin-2 expression in adipocytes. Mol Metab. 2: 161-170.
 
[121]  Zurolo E, Iyer A, Maroso M, Carbonell C, Anink JJ, Ravizza T, Fluiter K, Spliet WG, van Rijen PC, Vezzani A, Aronica E (2011) Activation of Toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. Brain. 134: 1015-1032.
 
Show Less References

Article

Alcohol Abuse and Seizures: an Overview of Clinical Notions and Pathogenetic Theories

1Doctoral School, Faculty of Medical and Technical Sciences, University of Medicine in Tirana, Albania

2Biomedical and Experimental Department, Faculty of Medicine, University of Medicine in Tirana, Albania


International Journal of Clinical and Experimental Neurology. 2014, 2(1), 4-7
DOI: 10.12691/ijcen-2-1-2
Copyright © 2014 Science and Education Publishing

Cite this paper:
Gjon Preçi, Gentian Vyshka. Alcohol Abuse and Seizures: an Overview of Clinical Notions and Pathogenetic Theories. International Journal of Clinical and Experimental Neurology. 2014; 2(1):4-7. doi: 10.12691/ijcen-2-1-2.

Correspondence to: Gentian  Vyshka, Biomedical and Experimental Department, Faculty of Medicine, University of Medicine in Tirana, Albania. Email: gvyshka@yahoo.com

Abstract

Alcohol abuse is a major causative factor of different neurological disorders, among which seizures and epilepsy have an important burden of disease. Through discussing different pathogenetic mechanisms, scholars have tried to define and describe the diversity of clinical pictures and occurrences that might elicit a convulsive disorder in the alcoholics. An overview of the history of the diagnostic and classificatory attempts is made in the present paper, and distinctions between acute intoxication and withdrawal syndromes are summarized. The influences of ethanol on the cellular level and on the synaptic processes are succinctly mentioned. The authors are focused predominantly in three particularities of the alcohol-related seizures, namely the so-called alcoholic epilepsy, withdrawal seizures, and subacute encephalopathy with seizures in chronic alcoholism (SESA syndrome). Several sources are quoted, and the paper contains a brief overview on the efficacy of benzodiazepines and other antiepileptic drugs in the treatment of this variety of clinical events.

Keywords

References

[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[
[[1]  Nikaj A, Vyshka G. A historical approach to alcohol abuse. International Journal of Clinical Toxicology. 2013; 1 (2): 52-55.
 
[[2]  Rogawski MA. Update on the neurobiology of alcohol withdrawal seizures. Epilepsy Curr. 2005 Nov-Dec; 5 (6): 225-30.
 
[[3]  Zorumski CF, Mennerick S, Izumi Y. Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol. 2014 Feb; 48 (1): 1-17.
 
[[4]  Hendricson AW, Maldve RE, Salinas AG, Theile JW, Zhang TA, Diaz LM, Morrisett RA. Aberrant synaptic activation of N-methyl-D-aspartate receptors underlies ethanol withdrawal hyperexcitability. J Pharmacol Exp Ther. 2007 Apr; 321 (1): 60-72.
 
[[5]  Echevarria MG. On alcoholic epilepsy. J Merit Sci 1881; 26: 489.
 
Show More References
[6]  Victor M, Brausch C. The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia. 1967 Mar; 8 (1): 1-20.
 
[7]  Devetag F, Mandich G, Zaiotti G, Toffolo GG. Alcoholic epilepsy: review of a series and proposed classification and etiopathogenesis. Ital J Neurol Sci. 1983 Sep; 4 (3): 275-84.
 
[8]  Weber M, Bouly S. Alcoolisme et épilepsie. La Lettre du Neurologue. 2002; 6 (4): 124-127.
 
[9]  Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr, Swartz MN. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993 Jan 7; 328 (1): 21-8.
 
[10]  Lennox W. Alcohol and Epilepsy. Q J Stud Alcohol. 1941; 2: 1-11.
 
[11]  Carrington CD, Ellinwood EH Jr, Krishnan RR. Effects of single and repeated alcohol withdrawal on kindling. Biol Psychiatry. 1984 Apr; 19 (4): 525-37.
 
[12]  Espir ML, Rose FC. Alcohol, seizures and epilepsy. J R Soc Med. 1987 Sep; 80 (9): 542-3.
 
[13]  Yamane H, Katoh N. Alcoholic epilepsy. A definition and a description of other convulsions related to alcoholism. Eur Neurol. 1981; 20 (1): 17-24.
 
[14]  Tartara A, Manni R, Mazzella G. Epileptic seizures and alcoholism. Clinical and pathogenetic aspects. Acta Neurol Belg. 1983 Mar-Apr; 83 (2): 88-94.
 
[15]  Bråthen G. The classification and clinical diagnosis of alcohol-related seizures. [Norwegian] Prisforedrag: Klassifikasjon og diagnostikk av alkoholrelaterte epileptiske anfall. Norsk Epilepsiselskaps høstmøte. NTNU. 2001.
 
[16]  Rathlev NK, Ulrich AS, Delanty N, D'Onofrio G. Alcohol-related seizures. J Emerg Med. 2006 Aug; 31(2): 157-63.
 
[17]  Hughes JR. Alcohol withdrawal seizures. Epilepsy Behav. 2009 Jun; 15 (2): 92-7.
 
[18]  Fisch BJ, Hauser WA, Brust JC, Gupta GS, Lubin R, Tawfik G, Hyacinthe JC. The EEG response to diffuse and patterned photic stimulation during acute untreated alcohol withdrawal. Neurology. 1989 Mar; 39 (3): 434-6.
 
[19]  Ropper AH, Brown RH. Adams and Victor’s Principles of Neurology. Eighth edition, McGraw-Hill, Medical Publishing Division. 2005; 1009-1010.
 
[20]  Rhinehart JW. Factors determining "rum fits". Am J Psychiatry. 1961 Sep; 118: 251-2.
 
[21]  Strande vom W. Chicago in tears and smiles. [Translated from German from Gutermann RE]. Cleveland, Ohio: Press of Lauer & Mattill. 1893; 37-38.
 
[22]  Andrew C, Fein G. Induced theta oscillations as biomarkers for alcoholism. Clin Neurophysiol. 2010 Mar; 121 (3): 350-8.
 
[23]  Niedermeyer E, Freund G, Krumholz A. Subacute encephalopathy with seizures in alcoholics: a clinical-electroencephalographic study. Clin Electroencephalogr. 1981 Jul; 12 (3): 113-29.
 
[24]  Janati A, Chesser MZ, Husain MM. Periodic lateralized epileptiform discharges (PLEDs): a possible role for metabolic factors in pathogenesis. Clin Electroencephalogr. 1986 Jan; 17 (1): 36-43.
 
[25]  Itoh N, Matsui N, Matsui S. Periodic lateralized epileptiform discharges in EEG during recovery from hyponatremia: a case report. Clin Electroencephalogr. 1994 Oct; 25 (4): 164-9.
 
[26]  Westmoreland BF. Periodic lateralized epileptiform discharges after evacuation of subdural hematomas. J Clin Neurophysiol. 2001 Jan; 18 (1): 20-4.
 
[27]  Boroojerdi B, Hungs M, Biniek R, Noth J. Subacute encephalopathy with epileptic seizures in a patient with chronic alcoholism (SESA syndrome). Nervenarzt. 1998 Feb; 69 (2): 162-5.
 
[28]  LaRoche SM, Shivdat-Nanhoe R. Subacute encephalopathy and seizures in alcoholics (SESA) presenting with non-convulsive status epilepticus. Seizure. 2011 Jul; 20 (6): 505-8.
 
[29]  Fernández-Torre JL, Kaplan PW. Subacute encephalopathy with seizures in alcoholics (SESA syndrome) revisited. Seizure. 2014 May; 23 (5): 393-6.
 
[30]  Schuchardt V. Der Alkoholiker als Intensivpatient – Erfahrungen einer Neurologischen Intensivstation. Intensivmed. 1988; 25: 55-62.
 
[31]  Leach JP, Mohanraj R, Borland W. Alcohol and drugs in epilepsy: pathophysiology, presentation, possibilities, and prevention. Epilepsia. 2012 Sep; 53 Suppl 4: 48-57.
 
[32]  Hillbom M, Pieninkeroinen I, Leone M. Seizures in alcohol-dependent patients: epidemiology, pathophysiology and management. CNS Drugs. 2003; 17 (14): 1013-30.
 
[33]  Bartolomei F. Epilepsy and alcohol. Epileptic Disord 2006; 8 (S1): S72-8.
 
[34]  Samokhvalov AV, Irving H, Mohapatra S, Rehm J. Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis. Epilepsia. 2010 Jul; 51 (7): 1177-84.
 
[35]  Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia. 2001 Oct; 42 (10): 1266-72.
 
[36]  Lutz UC, Batra A, Kolb W, Machicao F, Maurer S, Köhnke MD. Methylenetetrahydrofolate reductase C677T-polymorphism and its association with alcohol withdrawal seizure. Alcohol Clin Exp Res. 2006 Dec; 30(12): 1966-71.
 
[37]  Soyka M, Schmidt P, Franz M, Barth T, de Groot M, Kienast T, Reinert T, Richter C, Sander G. Treatment of alcohol withdrawal syndrome with a combination of tiapride/carbamazepine: results of a pooled analysis in 540 patients. Eur Arch Psychiatry Clin Neurosci. 2006 Oct; 256 (7): 395-401.
 
[38]  Menken M, Buonpane N, Perly R. Alcoholic epilepsy. Effects of treatment on convulsions following the cessation of drinking. J Med Soc N J. 1977 Nov; 74 (11): 947-9.
 
[39]  Kattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: A systematic review. Ind Psychiatry J. 2013 Jul; 22 (2): 100-8.
 
[40]  DeMuro JP. Alcohol withdrawal syndromes in the critically ill. OA Alcohol 2013 Feb 01; 1 (1): 1.
 
[41]  Melson J, Kane M, Mooney R, McWilliams J, Horton T. Improving alcohol withdrawal outcomes in acute care. Perm J. 2014 Spring; 18 (2): e141-5.
 
Show Less References

Article

Gender Differences in Trail Making Test Performance in a Nonclinical Sample of Adults

1Department of Psychology, Islamic Azad University, Isfahan Science and Research Branch, Isfahan, Iran


International Journal of Clinical and Experimental Neurology. 2014, 2(1), 1-3
DOI: 10.12691/ijcen-2-1-1
Copyright © 2014 Science and Education Publishing

Cite this paper:
Elham Foroozandeh. Gender Differences in Trail Making Test Performance in a Nonclinical Sample of Adults. International Journal of Clinical and Experimental Neurology. 2014; 2(1):1-3. doi: 10.12691/ijcen-2-1-1.

Correspondence to: Elham  Foroozandeh, Department of Psychology, Islamic Azad University, Isfahan Science and Research Branch, Isfahan, Iran. Email: elham_for@yahoo.com

Abstract

Trail making test (TMT) is one of the neuropsychological task to evaluate mental flexibility, visual search, motor speed and executive functions in neurological patients. Attention and speed are two mental functions necessary to complete the task in a short time with the least of errors. It is suggested that age and education have respectively positive and negative relationships with the time of performance of the task by neuropsychological patients. In this study it is hypothesized that (a) there is a positive relationship between education and motor speed in normal adults (b) there is a negative relationship can be seen between age and motor speed in normal adults and (c) normal men and women have not different motor speed in part A and part B of TMT. In order to do this study, 285 normal adults (men=112) were selected and their motor speed and errors were measured in part A and B. The results showed that (a) there was a negative, but not statistically significant, relationship between education and motor speed in groups, (b) there was a negative relationship between age and motor speed in part B only in male group, and (c) there was no differences between men and women in errors of part A and B, and there was no differences between them in motor speed in part A, but there was a significant difference in time of performance of part B. The results are discussed based on evidences of harder tasks in part B of TMT and gender differences in mental functions.

Keywords

References

[[[[[[[[[[[[[
[[1]  Lezak, M.D, Neuropsychological assessment (3rd ed.), Oxford University Press, New York, 1995.
 
[[2]  Jarvis, P.E. and Barth, J.T., The Halstead- Reitan Neuropsychological Battery: A guide to interpretation and clinical applications, FL: Psychological Assessment Resources, Odessa, 1994.
 
[[3]  Gaudino E. A., Geisler M.W. and Squires N. K., “Construct validity in the trail making test: What makes part B harder?”, Journal of Clinical and Experimental Neuropsychology, 17 (4). 529-535. 1995.
 
[[4]  Spreen, O., and Strauss, E, A compendium of neuropsychological tests: Administration, norms and commentary (2nd ed.), Oxford University Press, New York, 1998.
 
[[5]  Reitan, R. M, “Trail Making Test Results for Normal and Brain-Damaged Children”, Perceptual and Motor Skills, 33. 575-581. 1971.
 
Show More References
[6]  Giovagnoli A.R., Del Pesce, M., Mascheroni S., Simoncelli M., Laiacona M. And Capitani E, “Trail making test: normative values from 287 normal adult controls”, The Italian Journal of Neurological Sciences, 17 (4). 305-309. 1996.
 
[7]  Tombaugh, T. N, “Trail Making Test A and B: Normative data stratified by age and education”, Archives of Clinical Neuropsychology, 19. 203-214. 2004.
 
[8]  Janowsky, J. S, “Thinking with your gonads: testosterone and cognition”, TRENDS in Cognitive Sciences, 10 (2). 77-82. 2006.
 
[9]  Finley, S. and Kritzer, M, “Immunoreactivity for intracellular androgen receptors in identified subpopulations of neurons, astrocytes and oligodendrocytes in primate prefrontal cortex”, Journal of Neurobiology, 40. 446-457. 1999.
 
[10]  Beyenburg, S., Watzka M., Clusmann, H., Blümcke, I., Bidlingmaier, F., Elger, C.E. and Stoffel-Wagner, B., “Androgen receptor mRNA expression in the human hippocampus”. Neuroscience Letters, 294. 25-28. 2000.
 
[11]  Sarrieau, A. Mitchell, J.B., Lal S., Olivier A., Quirion R. and Meaney M.J. “Androgen binding sites in human temporal cortex”. Neuroendocrinology, 51. 713-716. 1990.
 
[12]  Abdelgadir, S.E., Roselli, C.E., Choate, J.V., and Resko, J.A. “Androgen receptor messenger ribonucleic acid in brains and pituitaries of male rhesus monkeys: studies on distribution, hormonal control, and relationship to luteinizing hormone secretion”. Biology of Reproduction, 60. 1251-1256. 1999.
 
[13]  Mitrushina, M.N., Boone, K. L., and D’ Elia, L. Handbook of normative data for neuropsychological assessment, Oxford University Press, New York, 1999.
 
[14]  Barrett-Connor, E., Goodman-Gruen D., and Patay, B. “Endogenous sex hormones and cognitive function in older men”, The Journal of Clinical Endocrinology& Metabolism, 84. 3681-3685. 1999.
 
[15]  Moffat, S.D., Zonderman, A.B., Metter E. J., Blackman M. R., S. Harman M. and Resnick S.M. “Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men”, The Journal of Clinical Endocrinology& Metabolism, 87. 5001-5007. 2002.
 
[16]  Barrett-Connor, E. and Goodman-Gruen, D. “Cognitive function and endogenous sex hormones in older women”, Journal of the American Geriatrics Society, 47, 1289-1293. 1999.
 
[17]  Muller, M., Aleman, A., Grobbee, D. E., de HaanE. H.F. and van der Schouw, Y. T. “Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level?”, Neurology, 64. 866-871. 2005.
 
[18]  Fontani, G. Lodi L., Felici, A., Corradeschi, F. And Lupo, C. “Attentional, emotional and hormonal data in subjects of different ages”, European Journal of Applied Physiology, 92. 452-461. 2004.
 
Show Less References
comments powered by Disqus