<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd"> <html> <head> <title>UTas ePrints - Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury</title> <script type="text/javascript" src="http://eprints.utas.edu.au/javascript/auto.js"><!-- padder --></script> <style type="text/css" media="screen">@import url(http://eprints.utas.edu.au/style/auto.css);</style> <style type="text/css" media="print">@import url(http://eprints.utas.edu.au/style/print.css);</style> <link rel="icon" href="/images/eprints/favicon.ico" type="image/x-icon" /> <link rel="shortcut icon" href="/images/eprints/favicon.ico" type="image/x-icon" /> <link rel="Top" href="http://eprints.utas.edu.au/" /> <link rel="Search" href="http://eprints.utas.edu.au/cgi/search" /> <meta content="Chung, R.S." name="eprints.creators_name" /> <meta content="Vickers, J.C." name="eprints.creators_name" /> <meta content="Chuah, Meng Inn" name="eprints.creators_name" /> <meta content="West, A.K." name="eprints.creators_name" /> <meta content="rschung@utas.edu.au" name="eprints.creators_id" /> <meta content="" name="eprints.creators_id" /> <meta content="Inn.Chuah@utas.edu.au" name="eprints.creators_id" /> <meta content="awest@utas.edu.au" name="eprints.creators_id" /> <meta content="article" name="eprints.type" /> <meta content="2007-10-16 01:51:05" name="eprints.datestamp" /> <meta content="2008-01-08 15:30:00" name="eprints.lastmod" /> <meta content="show" name="eprints.metadata_visibility" /> <meta content="Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury" name="eprints.title" /> <meta content="pub" name="eprints.ispublished" /> <meta content="320000" name="eprints.subjects" /> <meta content="270000" name="eprints.subjects" /> <meta content="restricted" name="eprints.full_text_status" /> <meta content="metallothionein; reactive sprouting; neurite sprouting; neurite growth; cortical brain injury; wound healing" name="eprints.keywords" /> <meta content="Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties. To investigate the effect of another MT isoform, human MT-IIA, on neurite growth, we used rat cortical neuron cultures. MT-IIA promoted a significant increase in the rate of initial neurite elongation of individually plated neurons. We also investigated the effect of MT-IIA on the neuronal response to axonal transection in vitro. MT-IIA promoted reactive axonal growth after injury, and, by 18 hr after transection, MT-IIA had promoted axonal growth across the injury tract. Exogenous application of MT-IIA after cortical brain injury promoted wound healing, as observed by a significant decrease in cellular degradation at 4 d after injury. Furthermore, MT-IIA-treated rats exhibited numerous SMI-312-immunoreactive axonal processes within the injury tract. This was in contrast to vehicle-treated animals, in which few axonal sprouts were observed. By 7 d after injury, MT-IIA treatment resulted in a total closing over of the injury tract by microglia, astrocytes, and reactive axonal processes. However, although some reactive axonal processes were observed within the injury tract of vehicle-treated rats, the tract itself was almost never entirely enclosed. These results are discussed in relation to a possible physiological role of metallothioneins in the brain, as well as in a therapeutic" name="eprints.abstract" /> <meta content="2003" name="eprints.date" /> <meta content="published" name="eprints.date_type" /> <meta content="Journal of Neuroscience" name="eprints.publication" /> <meta content="23" name="eprints.volume" /> <meta content="3336-3342" name="eprints.pagerange" /> <meta content="TRUE" name="eprints.refereed" /> <meta content="0270-6474" name="eprints.issn" /> <meta content="Abdel-Mageed AB, Agrawal KC (1998) Activation of nuclear factor kappaB: potential role in metallothionein-mediated mitogenic response. Cancer Res 58:2335–2338. Adlard PA, West AK, Vickers JC (1998) Increased density of metallothionein I/II-immunopositive cortical glial cells in the early stages of Alzheimer’s disease. Neurobiol Dis 5:349–356. Aschner M, Cherian MG, Klaassen CD, Palmiter RD, Erickson JC, Bush AI (1997) Metallothioneins in brain—the role in physiology and pathology. Toxicol Appl Pharmacol 142:229–242. Blaauwgeers HG, Anwar Chand M, van den Berg FM, Vianney de Jong JM, Troost D (1996) Expression of different metallothionein messenger ribonucleic acids in motor cortex, spinal cord and liver from patients with amyotrophic lateral sclerosis. J Neurol Sci 142:39–44. Bremner L, Mehra RK, Sato M (1987) Metallothionein in blood, bile and urine. Toxicol 108:129–140. Campagne MV, Thibodeaux H, van Bruggen N, Cairns B, Gerlai R, Palmer JT, Williams SP, Lowe DG (1999) Evidence for a protective role of metallothionein-1 in focal cerebral ischemia. Proc Natl Acad Sci USA 96:12870–12875. Carmel JB, Galante A, Soteropoulos P, Tolias P, Recce M, Young W, Hart RP (2001) Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss. Physiol Genomics 7:201–213. Chung RS, Holloway AF, Eckhardt BL, Harris JA, Vickers JC, Chuah MI, West AK (2002a) Sheep have an unusual variant of the brain specific metallothionein, MT-III. Biochem J 365:323–328. Chung RS, Vickers JC, Chuah MI, Eckhardt BL, West AK (2002b) Metallothionein-III inhibits initial neurite formation in developing neurons as well as post-injury, regenerative neurite sprouting. Exp Neurol 178:1–12. Dickson TC, Adlard PA, Vickers JC (2000) Sequence of cellular changes following localized axotomy to cortical neurons in glia-free culture. J Neurotrauma 17:1095–1103. Erickson JC, Sewell AK, Jensen LT, Winge DR, Palmiter RD (1994) Enhanced neurotrophic activity in Alzheimer’s disease cortex is not associated with down-regulation of metallothionein-III (GIF). Brain Res 649:297–304. Garvey JS (1984) Metallothionein: structure/antigenicity and detection/ quantitation in normal physiological fluids. Environ Health Prosp 54:117–127. Giralt M, Penkowa M, Lago N, Molinero A, Hidalgo J (2002) Metallothionein- 12 protect the CNS after a focal brain injury. Exp Neurol 173:114–128. Goedart M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer’s disease: identification as the microtubuleassociated protein tau. Proc Natl Acad Sci USA 85:4051–4055. Hamer DH (1986) Metallothionein. Annu Rev Biochem 55:913–951. Hidalgo J, Giralt M, Garvey JS, Armario A (1988) Physiological role of glucocorticoids on rat serum and liver metallothionein basal and stress conditions. Am J Physiol 254:E71–E78. Hidalgo J, Aschner M, Zatta P, VasakM (2001) Roles of the metallothionein family of proteins in the central nervous system. Brain Res Bull 55:133–145. Hoffman PN, ClevelandDW (1988) Neurofilament and tubulin expression recapitulates the developmental program during axonal regeneration: induction of a specific beta-tubulin isotype. Proc Natl Acad Sci USA 85:4530–4533. Kagi JH, Schaffer A (1988) Biochemistry of Metallothionein. Biochemistry 27:8509–8515. Karlsson JE, Rosengren LE, Haglid KG (1987) A rapid HPLC method to separate the triplet proteins of neurofilament. J Neurochem 49:1375–1378. Kelly EJ, Quaife CJ, Froelick GJ, Palmiter RD (1996) Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice. J Nutr 120:403–409. King CE, Jacobs I, Dickson TC, Vickers JC (1997) Physical damage to rat cortical axons mimics early Alzheimer’s neuronal pathology. NeuroReport 8:1663–1665. King CE, Canty AJ, Vickers JC (2001) Alterations in neurofilaments associated with reactive brain changes and axonal sprouting following acute physical injury to the rat neocortex. Neuropathol Appl Neurobiol 27:115–126. Lee MK, ClevelandDW (1996) Neuronal intermediate filaments. Annu Rev Neurosci 19:187–217. Lee MK, Tuttle JB, Rebhun LI, Cleveland DW, Frankfurter A (1990) The expression and posttranslational modification of a neuron-specific betatubulin isotype during chick embryogenesis. Cell Motil Cytoskeleton 17:118–132. Palmiter RD (1998) The elusive function of metallothioneins. Proc Natl Acad Sci USA 95:8428–8430. Palmiter RD, Findley SD, Whitmore TE, Durnam DM (1992) MT-III, a brain specific member of the metallothionein gene family. Proc Natl Acad Sci USA 89:6333–6337. Penkowa M, Hidalgo J (2000) Metallothionein III expression and their role in experimental autoimmune encephalomyelitis. Glia 32:247–263. Penkowa M, Hidalgo J (2001) Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF- and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE). Exp Neurol 170:1–14. Penkowa M, Carrasco J, Giralt M, Moos T, Hidalgo J (1999a) CNS wound healing is severely depressed in metallothionein I- and II-deficient mice. J Neurosci 19:2535–2545. Penkowa M, Giralt M, Moos T, Thomsen PS, Hernandez J, Hidalgo J (1999b) Impaired inflammatory response to glial cell death in genetically metallothionein-I- and -II-deficient mice. Exp Neurol 156:149–164. Penkowa M, Carrasco J, Giralt M, Molinero A, Hernandez J, Campbell IL, Hidalgo J (2000) Altered central nervous system cytokine-growth factor expression profiles and angiogenesis in metallothionein-III deficient mice. J Cereb Blood Flow Metab 20:1174–1189. Penkowa M, Giralt M, Camats J, Hidalgo J (2002) Metallothionein 12 protect the CNS during neuroglial degeneration induced by 6-aminonicotinamide. J Comp Neurol 444:174–189. Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP, Palmiter RD (1994) Induction of a new metallothionein isoform (MTIV) occurs during differentiation of stratified squamous epithelia. Biochemistry 33:7250–7259. Romero-Isart N, Jensen LT, Zerbe O, Winge DR, VasakM (2002) Engineering of metallothionein-3 neuroinhibitory activity into the inactive isoform metallothionein-1. J Biol Chem 277:37023–37028. Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radic Biol Med 14:325–337. Sewell AK, Erickson JC, Palmiter RD, Winge DR (1995) Bioactivity of metallothionein-3 correlates with its novel domain sequence rather than metal binding properties. Biochemistry 34:4740–4747. Trayhurn P, Duncan JS, Wood AM, Beattie JH (2000) Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture. Horm Metab Res 32:542–547. Trendelenburg G, Prass K, Priller J, Kapinya K, Polley A, Muselmann C, Ruscher K, Kannbley U, Schmitt AO, Castell S, Wiegand F, Meisel A, Rosenthal A, Dirnagl U (2002) Serial analysis of gene expression identifies metallothionein-II as major neuroprotective gene in mouse focal cerebral ischemia. J Neurosci 22:5879–5888. Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991) The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein. Neuron 7:337–347. Uchida Y, Gomi F, Masumizu T, Miura Y (2002) Growth inhibitory factor prevents neurite extension and death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging. J Biol Chem 277:32353–32359. Ulfig N, Nickel J, Bohl J (1998) Monoclonal antibodies SMI 311 and SMI 312 as tools to investigate the maturation of nerve cells and axonal patterns in human fetal brain. Cell Tissue Res 291:433–443. Vasak M, Hasler DW (2000) Metallothioneins: new structural and functional insights. Curr Opin Chem Biol 4:177–183" name="eprints.referencetext" /> <meta content="Chung, R.S. and Vickers, J.C. and Chuah, Meng Inn and West, A.K. (2003) Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury. Journal of Neuroscience, 23 . pp. 3336-3342. ISSN 0270-6474" name="eprints.citation" /> <meta content="http://eprints.utas.edu.au/2229/1/Chung_etal._J.Neurosci.pdf" name="eprints.document_url" /> <link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /> <meta content="Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury" name="DC.title" /> <meta content="Chung, R.S." name="DC.creator" /> <meta content="Vickers, J.C." name="DC.creator" /> <meta content="Chuah, Meng Inn" name="DC.creator" /> <meta content="West, A.K." name="DC.creator" /> <meta content="320000 Medical and Health Sciences" name="DC.subject" /> <meta content="270000 Biological Sciences" name="DC.subject" /> <meta content="Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties. To investigate the effect of another MT isoform, human MT-IIA, on neurite growth, we used rat cortical neuron cultures. MT-IIA promoted a significant increase in the rate of initial neurite elongation of individually plated neurons. We also investigated the effect of MT-IIA on the neuronal response to axonal transection in vitro. MT-IIA promoted reactive axonal growth after injury, and, by 18 hr after transection, MT-IIA had promoted axonal growth across the injury tract. Exogenous application of MT-IIA after cortical brain injury promoted wound healing, as observed by a significant decrease in cellular degradation at 4 d after injury. Furthermore, MT-IIA-treated rats exhibited numerous SMI-312-immunoreactive axonal processes within the injury tract. This was in contrast to vehicle-treated animals, in which few axonal sprouts were observed. By 7 d after injury, MT-IIA treatment resulted in a total closing over of the injury tract by microglia, astrocytes, and reactive axonal processes. However, although some reactive axonal processes were observed within the injury tract of vehicle-treated rats, the tract itself was almost never entirely enclosed. These results are discussed in relation to a possible physiological role of metallothioneins in the brain, as well as in a therapeutic" name="DC.description" /> <meta content="2003" name="DC.date" /> <meta content="Article" name="DC.type" /> <meta content="PeerReviewed" name="DC.type" /> <meta content="application/pdf" name="DC.format" /> <meta content="http://eprints.utas.edu.au/2229/1/Chung_etal._J.Neurosci.pdf" name="DC.identifier" /> <meta content="Chung, R.S. and Vickers, J.C. and Chuah, Meng Inn and West, A.K. (2003) Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury. 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border: solid 1px #ccc; padding: 3px"><tr> <td align="left"><a href="http://eprints.utas.edu.au/cgi/users/home">Login</a> | <a href="http://eprints.utas.edu.au/cgi/register">Create Account</a></td> <td align="right" style="white-space: nowrap"> <form method="get" accept-charset="utf-8" action="http://eprints.utas.edu.au/cgi/search" style="display:inline"> <input class="ep_tm_searchbarbox" size="20" type="text" name="q" /> <input class="ep_tm_searchbarbutton" value="Search" type="submit" name="_action_search" /> <input type="hidden" name="_order" value="bytitle" /> <input type="hidden" name="basic_srchtype" value="ALL" /> <input type="hidden" name="_satisfyall" value="ALL" /> </form> </td> </tr></table></td></tr> <tr> <td class="toplinks"><!-- InstanceBeginEditable name="content" --> <div align="center"> <table width="720" class="ep_tm_main"><tr><td align="left"> <h1 class="ep_tm_pagetitle">Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury</h1> <p style="margin-bottom: 1em" class="not_ep_block"><span class="person_name">Chung, R.S.</span> and <span class="person_name">Vickers, J.C.</span> and <span class="person_name">Chuah, Meng Inn</span> and <span class="person_name">West, A.K.</span> (2003) <xhtml:em>Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury.</xhtml:em> Journal of Neuroscience, 23 . pp. 3336-3342. ISSN 0270-6474</p><p style="margin-bottom: 1em" class="not_ep_block"></p><table style="margin-bottom: 1em" class="not_ep_block"><tr><td valign="top" style="text-align:center"><a href="http://eprints.utas.edu.au/2229/1/Chung_etal._J.Neurosci.pdf"><img alt="[img]" src="http://eprints.utas.edu.au/style/images/fileicons/application_pdf.png" class="ep_doc_icon" border="0" /></a></td><td valign="top"><a href="http://eprints.utas.edu.au/2229/1/Chung_etal._J.Neurosci.pdf"><span class="ep_document_citation">PDF</span></a> - Full text restricted - Requires a PDF viewer<br />580Kb</td><td><form method="get" accept-charset="utf-8" action="http://eprints.utas.edu.au/cgi/request_doc"><input accept-charset="utf-8" value="2799" name="docid" type="hidden" /><div class=""><input value="Request a copy" name="_action_null" class="ep_form_action_button" onclick="return EPJS_button_pushed( '_action_null' )" type="submit" /> </div></form></td></tr></table><div class="not_ep_block"><h2>Abstract</h2><p style="padding-bottom: 16px; text-align: left; margin: 1em auto 0em auto">Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties. To investigate the effect of another MT isoform, human MT-IIA, on neurite growth, we used rat cortical neuron cultures. MT-IIA promoted a significant increase in the rate of initial neurite elongation of individually plated neurons. We also investigated the effect of MT-IIA on the neuronal response to axonal transection in vitro. MT-IIA promoted reactive axonal growth after injury, and, by 18 hr after transection, MT-IIA had promoted axonal growth across the injury tract. Exogenous application of MT-IIA after cortical brain injury promoted wound healing, as observed by a significant decrease in cellular degradation at 4 d after injury. Furthermore, MT-IIA-treated rats exhibited numerous SMI-312-immunoreactive axonal processes within the injury tract. This was in contrast to vehicle-treated animals, in which few axonal sprouts were observed. By 7 d after injury, MT-IIA treatment resulted in a total closing over of the injury tract by microglia, astrocytes, and reactive axonal processes. However, although some reactive axonal processes were observed within the injury tract of vehicle-treated rats, the tract itself was almost never entirely enclosed. These results are discussed in relation to a possible physiological role of metallothioneins in the brain, as well as in a therapeutic</p></div><table style="margin-bottom: 1em" cellpadding="3" class="not_ep_block" border="0"><tr><th valign="top" class="ep_row">Item Type:</th><td valign="top" class="ep_row">Article</td></tr><tr><th valign="top" class="ep_row">Keywords:</th><td valign="top" class="ep_row">metallothionein; reactive sprouting; neurite sprouting; neurite growth; cortical brain injury; wound healing</td></tr><tr><th valign="top" class="ep_row">Subjects:</th><td valign="top" class="ep_row"><a href="http://eprints.utas.edu.au/view/subjects/320000.html">320000 Medical and Health Sciences</a><br /><a href="http://eprints.utas.edu.au/view/subjects/270000.html">270000 Biological Sciences</a></td></tr><tr><th valign="top" class="ep_row">ID Code:</th><td valign="top" class="ep_row">2229</td></tr><tr><th valign="top" class="ep_row">Deposited By:</th><td valign="top" class="ep_row"><span class="ep_name_citation"><span class="person_name">A/Prof MI Chuah</span></span></td></tr><tr><th valign="top" class="ep_row">Deposited On:</th><td valign="top" class="ep_row">16 Oct 2007 12:51</td></tr><tr><th valign="top" class="ep_row">Last Modified:</th><td valign="top" class="ep_row">09 Jan 2008 02:30</td></tr><tr><th valign="top" class="ep_row">ePrint Statistics:</th><td valign="top" class="ep_row"><a target="ePrintStats" href="/es/index.php?action=show_detail_eprint;id=2229;">View statistics for this ePrint</a></td></tr></table><p align="right">Repository Staff Only: <a href="http://eprints.utas.edu.au/cgi/users/home?screen=EPrint::View&eprintid=2229">item control page</a></p> </td></tr></table> </div> <!-- InstanceEndEditable --></td> </tr> <tr> <td><!-- #BeginLibraryItem "/Library/footer_eprints.lbi" --> <table width="795" border="0" align="left" cellpadding="0" class="footer"> <tr valign="top"> <td colspan="2"><div align="center"><a href="http://www.utas.edu.au">UTAS home</a> | <a href="http://www.utas.edu.au/library/">Library home</a> | <a href="/">ePrints home</a> | <a href="/contact.html">contact</a> | <a href="/information.html">about</a> | <a href="/view/">browse</a> | <a href="/perl/search/simple">search</a> | <a href="/perl/register">register</a> | <a href="/perl/users/home">user area</a> | <a href="/help/">help</a></div><br /></td> </tr> <tr><td colspan="2"><p><img src="/images/eprints/footerline.gif" width="100%" height="4" /></p></td></tr> <tr valign="top"> <td width="68%" class="footer">Authorised by the University Librarian<br /> © University of Tasmania ABN 30 764 374 782<br /> <a href="http://www.utas.edu.au/cricos/">CRICOS Provider Code 00586B</a> | <a href="http://www.utas.edu.au/copyright/copyright_disclaimers.html">Copyright & Disclaimers</a> | <a href="http://www.utas.edu.au/accessibility/index.html">Accessibility</a> | <a href="http://eprints.utas.edu.au/feedback/">Site Feedback</a> </td> <td width="32%"><div align="right"> <p align="right" class="NoPrint"><a href="http://www.utas.edu.au/"><img src="http://www.utas.edu.au/shared/logos/unioftasstrip.gif" alt="University of Tasmania Home Page" width="260" height="16" border="0" align="right" /></a></p> <p align="right" class="NoPrint"><a href="http://www.utas.edu.au/"><br /> </a></p> </div></td> </tr> <tr valign="top"> <td><p> </p></td> <td><div align="right"><span class="NoPrint"><a href="http://www.eprints.org/software/"><img src="/images/eprintslogo.gif" alt="ePrints logo" width="77" height="29" border="0" align="bottom" /></a></span></div></td> </tr> </table> <!-- #EndLibraryItem --> <div align="center"></div></td> </tr> </table> </body> </html>