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19 and L12 



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toxicity and LI 3 


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(hepatic or renal) near3 toxin or neurotoxin or myotoxin or carcinogen or 


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embryo or rmbryoid adj bod$ or fetus 


27387 


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Search Results - Record(s) 1 through 17 of 17 returned. 



□ 1 . 20030207853 . 20 May 03. 06 Nov 03. Cholesterol and hedgehog signaling. Beachy, Philip A., 
et al. 514/176; 514/1 A61K031/58 A61K031/00. 



□ 2. 20030203885 . 19 May 03. 30 Oct 03. Cholesterol and hedgehog signaling. Beachy, Philip A., et 
al. 514/176; A61K03 1/58. 



□ 3. 20030148510 . 15 Jan 02. 07 Aug 03. Methods of inducing differentiation in stem cells, methods 
of generating tissue using scaffold matrices derived from micro-organs and stem cells, methods of 
producing adult stem cells and methods of continuously generating stem cells by implantation of micro- 
organs as sources of stem cells. Mitrani, Eduardo N.. 435/325; 435/366 C12N005/08. 



□ 4. 20030134413 . 03 Dec 02. 17 Jul 03. Cell production. Rathjen, Peter David, et al. 435/368; 
C12N005/08. 



□ 5. 20030115637 . 23 Oct 02. 19 Jun 03. Embryo sac-specific genes. Dresselhaus, Thomas, et al. 
800/287; 435/183 435/320.1 435/419 435/6 530/370 536/23.6 800/279 A01H001/00 C12N009/00 
C12N015/82 C12Q001/68 C07H021/04 C12P021/02 C07K014/415 C12N005/04. 



□ 6. 20030028909 . 13 May 02. 06 Feb 03. Transgenic zebra fish embryo model for hematopoiesis 
and lymphoproliferative disorders. Uckun, Fatih M., et al. 800/10; 435/7.23 A01K067/00 G01N033/574. 



□ 7. 20020164682 . 03 Jun 98. 07 Nov 02. MAMMALIAN CERBERUS-LIKE PROTEIN AND 
COMPOSITIONS. FOLLETTIE, MAXIMILLIAN, et al. 435/69.1; 424/130.1 435/320.1 435/325 
514/12 530/350 536/23.5 C12P021/06 A61K038/00 A61K039/395 C07K017/00 C07K001/00 
C12N0 15/74 C12N0 15/63 C12N0 15/00 C12N0 15/09 C12N0 15/70 C12N005/00 C07K0 14/00 
C12N005/02 C07H021/04. 



□ 8. 20020102604 . 07 Dec 00. 01 Aug 02. Full-length human cDNAs encoding potentially secreted 
proteins. Milne Edwards, Jean-Baptiste Dumas, et al. 435/7.1; 530/350 536/23.1 G01N033/53 
C07H021/02 C07H021/04 C07K001/00 C07K014/00 C07K017/00. 



□ 9. 20020045607 . 1 1 Sep 01 . 1 8 Apr 02. Cholesterol and hedgehog signaling. Beachy, Philip A., et 
al. 514/176; A61K031/58. 



E 10. 20020025297 . 05 Sep 0 1 . 28 Feb 02. Methods of screening agents for activity using teleosts. 
Serbedzija, George N., et al. 424/9.2; 800/20 800/3 A61K049/00 A01K067/027. 



□ 11. 6656449 . 23 Aug 00; 02 Dec 03. Methods of screening agents for activity using teleosts. 
Serbedzija; George, et al. 424/9.2; 424/9.1 424/9.34 424/9.6. A61K049/00 A61B005/055 A61B010/00. 



□ 12. 6299858 . 22 Feb 99; 09 Oct 01 . Methods of screening agents for activity using teleosts. 
Serbedzija; George N., et al. 424/9.2; 424/9.1 424/9.6. A61K049/00 A61B005/055 A61B010/00. 



□ 13. 6288048 . 12 Feb 99; 1 1 Sep 01 . Cholesterol and hedgehog signaling. Beachy; Philip A., et al. 



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514/176; 435/962 436/63 436/71 436/86 436/87 436/92 514/278. A61K031/58. 

□ 14. 6262025 . 07 Apr 98; 17 Jul 01 . Nucleotide and protein sequences of vertebrate delta genes and 
methods based thereon. Ish-Horowicz; David, et al. 514/12; 530/300 530/350. C07K014/00. 

□ 15. 6004924 . 06 Mar 96; 21 Dec 99. Protein sequences of serrate gene products. Ish-Horowicz; 
David, et al. 514/2; 514/13 514/15 530/300 530/326 530/328 530/350. A01N037/18 A61K037/00 
C07K014/00. 

□ 16 : 5935852 . 03 Jul 97; 10 Aug 99. DNA molecules encoding mammalian cerberus-like proteins. 
Follettie; Maximillian, et al. 435/325; 435/252.3 435/252.33 435/254.11 435/320.1 435/357 435/358 
435/366 536/23.1 536/23.5 536/24.31. C12N015/11 C12N015/85 C12N001/21 C07H021/04. 

□ 17. 5869282 . 07 Mar 95; 09 Feb 99. Nucleotide and protein sequences of the serrate gene and 
methods based thereon. Ish-Horowicz; David, et al. 435/69.1; 435/252.3 435/320.1 435/325 530/300 
530/350 536/23.1 536/24.3. C12P021/00 C12N015/00 C07H017/00 C07K014/00. 



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toxicity and 19 


13 


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3 


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toxicity and 13 


6750 


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67087 


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pattern) 




Li 


embryo or rmbryoid adj bod$ or fetus 


27387 


Li 



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Search Results - Record(s) 1 through 13 of 13 returned. 

□ 1. 20030148510 . 15 Jan 02. 07 Aug 03. Methods of inducing differentiation in stem cells, methods 
of generating tissue using scaffold matrices derived from micro-organs and stem cells, methods of 
producing adult stem cells and methods of continuously generating stem cells by implantation of micro- 
organs as sources of stem cells. Mitrani, Eduardo N.. 435/325; 435/366 C12N005/08. 

□ 2. 20030140372 . 19 Aug 02. 24 Jul 03. Genes for desaturases to alter lipid profiles in corn. Shen, 
Jennie Bih-Jien. 800/281; 435/190 435/320.1 435/419 435/69.1 536/23.2 800/320.1 A01H005/00 
C12N015/82 C07H021/04 C12N009/04 C12P021/02 C12N005/04. 



□ 3. 20030027783 . 17 May 02. 06 Feb 03. Inhibiting gene expression with dsRNA. Zernicka-Goetz, 
Magdalena, et al. 514/44; 424/93.2 435/6 A61K048/00 C12Q001/68. 



□ 4. 20030017549 . 24 Jan 02. 23 Jan 03. Methods and compositions for expressing polynucleotides 
specifically in smooth muscle cells in vivo. Owens, Gary K., et al. 435/69.7; 435/183 435/320.1 435/325 
530/350 530/351 536/23.5 C12P021/02 C12N005/06 C07H021/04 C12N009/00 C07K014/52. 



□ 5. 20020114784 . 04 Jan 02. 22 Aug 02. Composition and method for in vivo and in vitro 
attenuation of gene expression using double stranded RNA. Li, Yin-Xiong, et al. 424/93.2; 435/455 
435/456 A61K048/00 C12N015/86. 



□ 6. 20020102724 . 17 Aug 01.01 Aug 02. Novel hematopoietic genes and polypeptides. Hidaka, 
Michihiro, et al. 435/320.1; 424/130.1 435/419 435/6 435/69.1 435/7.1 435/7.4 530/350 536/23.6 
536/24.1 536/24.3 800/13 800/278 C12Q001/68 G01N033/573 C07H021/04 C12P021/06 C12N015/82 
C12N015/09 C12N015/29 C07K001/00 C07K014/00 C12N005/04 C07K016/00. 



□ 7. 20020102604 . 07 Dec 00. 01 Aug 02. Full-length human cDNAs encoding potentially secreted 
proteins. Milne Edwards, Jean-Baptiste Dumas, et al. 435/7.1; 530/350 536/23.1 G01N033/53 
C07H021/02 C07H021/04 C07K001/00 C07K014/00 C07K017/00. 



□ 8. 20020025297 . 05 Sep 01 . 28 Feb 02. Methods of screening agents for activity using teleosts. 
Serbedzija, George N., et al. 424/9.2; 800/20 800/3 A61K049/00 A01K067/027. 



□ 9. 6656449 . 23 Aug 00; 02 Dec 03. Methods of screening agents for activity using teleosts. 
Serbedzija; George, et al. 424/9.2; 424/9.1 424/9.34 424/9.6. A61K049/00 A61B005/055 A61B010/00. 



13 10. 6586217 . 18 Dec 98; 01 Jul 03. Mammalian selenophosphate synthetase. Guimaraes; M. Jorge, 
et al. 435/194; 435/183 435/252.3 435/325 435/6 435/69.1 435/91.2 514/44 536/23.1 536/23.2 536/24.3 
536/24.31 536/24.33. C12N015/12 C12N015/54 C12N009/12. 



□ 11. 6548290 . 1 1 Jun 98; 15 Apr 03. Geminin gene and protein. McGarry; Thomas J., et al. 
435/252.3; 435/320.1 435/325 536/23.2 536/23.5. C12N015/00. 



13 12. 6299858 . 22 Feb 99; 09 Oct 01 . Methods of screening agents for activity using teleosts. 
Serbedzija; George N., et al. 424/9.2; 424/9.1 424/9.6. A61K049/00 A61B005/055 A61B010/00. 



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□ 13. 6060590 . 31 Mar 98; 09 May 00. Chitinase related proteins and methods of use. Bryant; Peter 
J, et al. 530/399; 530/350. C07K014/435 C07K014/475. 



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Search Results - Record(s) 1 through 3 of 3 returned. 



D 1 . 20030073637 . 01 Oct 02. 17 Apr 03. Method for stimulating connective tissue growth or wound 
healing. Uutela, Marko, et al. 514/12; 435/320.1 435/455 514/44 A61K048/00 A61K038/18 
C12N0 15/85. 



□ 2. 20020164710 . 04 Mar 02. 07 Nov 02. Platelet-derived growth factor D, DNA coding therefor, 
and uses thereof. Eriksson, Ulf, et al. 435/69.1; 435/320.1 435/325 530/350 530/399 536/23.5 
C07K014/49 C07H021/04 C12P021/02 C12N005/06. 



□ 3. 20020136726 . 20 Nov 01 . 26 Sep 02. Artery smooth muscle- and vein smooth muscle-specific 
proteins and uses therefor. Anderson, David J., et al. 424/146.1; A61K039/395. 




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(FILE 'HOME' ENTERED AT 14:29:41 ON 18 DEC 2003) 



FILE 'MEDLINE, CAPLUS , BIOSIS, SCISEARCH' ENTERED AT 14:31:13 ON 18 DEC 
2003 



LI 


784358 


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EMBRYO OR EMBRYOID (W) BOD? OR FETUS 


L2 


7391 


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MOLECULAR (5A) PROFILE 


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1292275 


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(GENE OR PROTEIN) (5A) (EXPRESSION OR PATTERN) 


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910 


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TROGLITAZONE OR ERYTHROMYCIN 


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(HEPATIC OR RENAL) (3A) TOXIN OR NEUROTOXIN OR MYOTOXIN 


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407061 


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TERATOGENIC OR CARCINOGEN OR COSMETICS OR AGRICULTUR? (3A) (CHE 


L12 


24 


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159 


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DUP REM L12 (0 DUPLICATES REMOVED) 


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DUP REM LI 3 (43 DUPLICATES REMOVED) 



=> d bib ab 19 



L9 ANSWER 1 OF 1 CAPLUS COPYRIGHT 2 003 ACS on STN 
AN 2000:402043 CAPLUS 
DN 133:26835 

TI Toxicity typing using embryoid bodies 

IN Snodgrass, H. Ralph 
PA Vistagen, Inc., USA 
SO PCT Int. Appl., 56 pp. 

CODEN: PIXXD2 
DT Patent 
LA English 
FAN.CNT 1 

PATENT NO. KIND DATE APPLICATION NO. DATE 



PI WO 2000034525 Al 20000615 WO 1999-US29384 19991209 



W: AE , 


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AB This invention provides methods and systems for identifying and typing 
toxicity of chem. compns . , as well as for screening new compns . 
for toxicity. The invention involves detecting alterations in 
gene or protein expression and hence 
establishing mol . profiles in isolated mammalian 
embryoid bodies contacted with various chem. compns. of 
known and unknown toxicities, and correlating the mol. 
profiles with toxicities of the chem. compns. 





RE . CNT 



8 



THERE ARE 8 CITED REFERENCES AVAILABLE FOR THIS RECORD 
ALL CITATIONS AVAILABLE IN THE RE FORMAT 



=> d 1-24 au ti so ab 114 

L14 ANSWER 1 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Perrone-Bizzozero, N. I. [Reprint Author]; Yang, Y. [Reprint Author]; 

Caldeira, J. [Reprint Author] ; Caldwell, K. K. [Reprint Author] ; 

Valenzuela, C. F. [Reprint Author] ; Savage, D. D. [Reprint Author] 
TI Fetal alcohol exposure alters the expression of several 

plasticity-associated genes in the hippocampus of adult rat 

offspring. 

SO Alcoholism Clinical and Experimental Research, (May 2003) Vol. 27, No. 5 
Supplement, pp. 124A. print. 

Meeting Info.: Scientific Meeting of the Research Society on Alcoholism 
and the 12th Congress of the International Society for Biomedical Research 
on Alcoholism. Fort Lauderdale, FL, USA. June 21-25, 2003. Research 
Society on Alcoholism; International Society for Biomedical Research on 
Alcoholism . 

CODEN: ACRSDM. ISSN: 0145-6008. 

L14 ANSWER 2 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Brambila, Eduardo; Liu, Jie; Morgan, Daniel L.; Beliles, Robert P.; 

Waalkes, Michael P. [Reprint author] 
TI Effect of mercury vapor exposure on metallothionein and glutathione 

S-transf erase gene expression in the kidney of 

nonpregnant, pregnant, and neonatal rats. 
SO Journal of Toxicology and Environmental Health Part A, (September 13, 

2002) Vol. 65, No. 17, pp. 1273-1288. print. 

ISSN: 1528-7394. 

AB Elemental mercury (HgO) is a ubiquitous toxic pollutant. Exposure to HgO 
vapor typically is by inhalation, and the kidney is the primary target 
organ. Glutathione (GSH) and metallothionein (MT) appear to mitigate 
mercury toxicity. However, little is known about GSH or MT 
regulation after HgO vapor exposure, particularly during pregnancy, a time 
of high sensitivity to most metals. Thus, this study sought to determine 
renal mercury accumulation and MT- and GSH-related gene 
expression following HgO vapor exposure in nonpregnant, pregnant, 
and neonatal rats exposed in utero. Groups (n=5) of pregnant rats 
(Long-Evans) were exposed to HgO vapor (4 mg/m3) or air (control) for 2 
h/d from gestational day (GD) 6 to 15, and kidneys from dams and pups were 
removed at various times during and after the onset of exposure. For 
comparative purposes, nonpregnant female rats were exposed to HgO for 10 d 
under the same conditions. Renal mercury, MT protein, and GST activity 
were assayed by standard analytical techniques. Western blot analysis was 
also performed using antibodies against MT and GST-pi. GSH-related 
gene expression was studied by cDNA microarray. HgO 

vapor exposure produced renal accumulation of mercury in nonpregnant, 
pregnant, and neonatal rats. However, the transplacentally exposed 
neonates accumulated approximately 1000-fold less mercury than adults. 
HgO vapor exposure produced a time -dependent increase in renal MT protein 
in nonpregnant and pregnant rats, but not in neonatal rats. Maximum MT 
increases were observed on d 10 (fivefold) in nonpregnant and GD 15 
(threefold) in pregnant rats. Activation of the MT gene by HgO was 
confirmed at the translational level by Western blot analysis and at the 
transcriptional level by Northern blot analysis. Microarray analysis 
revealed a significant upregulation in the renal expression of the GST-pi, 
GST- Ya, and microsomal GST and GST5-5 genes in nonpregnant and pregnant 
rats. Western blot and enzyme assay confirmed the upregulation of GST 
genes after HgO exposure. Thus, in response to HgO vapor exposure, the 
expression of the MT gene and various GST genes is 

activated in nonpregnant and pregnant rats. Activation of these genes 
could be part of a defensive response directed at decreasing renal mercury 




toxicity, and may help divert the metal away from the 
fetus . 

L14 ANSWER 3 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Storch, Alexander [Reprint author] ; Lehmensiek, Vera [Reprint author] ; 

Tan, Eva-Maria [Reprint author] ; Schwarz, Johannes 
TI Expression of mutant alpha- synucleins related to Parkinson's disease 

enhances MPP+ toxicity in HEK-293 cells transfected with the DAT 

gene . 

SO Neurology, (April 9, 2002) Vol. 58, No. 7 Supplement 3, pp. A494-A495. 
print . 

Meeting Info. : 54th Annual Meeting of the American Academy of Neurology. 
Denver, Colorado, USA. April 13-20, 2002. 
CODEN: NEURAL ISSN: 0028-3878. 

L14 ANSWER 4 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 

AU Mengesdorf, Thorsten; Althausen, Sonja; Paschen, Wulf [Reprint author] 

TI Genes associated with pro-apoptotic and protective mechanisms are affected 

differently on exposure of neuronal cell cultures to arsenite. No 

indication for endoplasmic reticulum stress despite activation of grp78 

and gaddl53 expression. 
SO Molecular Brain Research, (15 August, 2002) Vol. 104, No. 2, pp. 227-239. 

print . 

CODEN: MBREE4. ISSN: 016 9-32 8X. 
AB The effect of arsenite exposure on cell viability, protein 
synthesis, energy metabolism and the expression of genes 
coding for cytoplasmic (hsp70) and endoplasmic reticulum (ER; gaddl53, 
grp78, grp94) stress proteins was investigated in primary neuronal cell 
cultures. Furthermore, signs of ER stress were evaluated by investigating 
xbpl mRNA processing. Arsenite levels of 30 and 100 muM induced severe 
cell injury. Protein synthesis was reduced to below 20% of control in 
cultures exposed to 3 0 and 100 muM arsenite for 1 h, and it remained 
markedly suppressed until 24 h of exposure. Arsenite induced a transient 
inhibition of energy metabolism after 1 h of exposure, but energy state 
recovered completely after 3 h. Arsenite exposure affected the 
expression and translation of genes coding for HSP7 0 and 

GRP78, GRP94, GADD153 to different extents. While hsp70 mRNA levels rose 
drastically, approximally 550-fold after 6 h exposure, HSP70 protein 
levels did not change over the first 6 h. On the other hand, gaddl53 mRNA 
levels rose only approximately 14-fold after 6 h exposure, while GADD153 
protein levels were markedly increased after 3 and 6 h exposure. HSP70 
protein levels were markedly increased and GADD153 protein levels 
decreased to almost control levels in cultures left in arsenite solution 
for 24 h, i.e. when only a small fraction of cells had escaped arsenite 
toxicity. Arsenite exposure of neurons thus induced an imbalance 
between pro-apoptotic and survival -activating pathways. Despite the 
marked increase in gaddl53 mRNA levels, we did not observe signs of xbpl 
processing in arsenite exposed cultures, indicating that arsenite did not 
produce ER stress. 

L14 ANSWER 5 OF 24 MEDLINE on STN 

AU Zheng Shuang; Chou Alice H; Jimenez Amie L; Khodadadi Omid; Son Sarah; 

Melega William P; Howard Bruce D 
TI The fetal and neonatal brain protein neuronatin protects PC12 cells 

against certain types of toxic insult. 
SO BRAIN RESEARCH. DEVELOPMENTAL BRAIN RESEARCH, (2 002 Jun 30) 13 6 (2) 

101-10 . 

Journal code: 8908639. ISSN: 0165-3806. 
AB The protein neuronatin is expressed in the nervous system of the 
fetus and neonate at a much higher level than in the adult. Its 
function is unknown. As a result of variable splicing, neuronatin mRNA 
exists in two forms, alpha and beta. Wild type PC12 cells express 
neuronatin-alpha . We have isolated a PC12 variant, called 1.9, that 
retains many of the neuron- like properties of wild type PC12 cells, but it 




does not express neuronatin and it exhibits markedly increased sensitivity 
to the toxic effects of nigericin, rotenone and valinomycin. Pretreatment 
of the 1.9 cells with alpha-methyl tyrosine , which inhibits dopamine 
synthesis, had little effect on the cells' sensitivity to nigericin, 
rotenone or valinomycin indicating that dopamine- induced oxidative stress 
was not involved in the toxicity of these compounds. However, 
flattened cell subvariants of the 1.9 cells, which do not have any 
neuron-specific characteristics, did not exhibit increased sensitivity to 
nigericin indicating that some neuronal characteristic of the 1.9 cells 
contributed to the toxicity of nigericin. After the 

neuronatin-beta gene was transfected into and expressed in the 1.9 cells, 
they regained wild type PC12 levels of resistance to nigericin, rotenone 
and valinomycin. These studies suggest that the function of neuronatin 
during development could be to protect developing cells from toxic insult 
occurring during that period. 

L14 ANSWER 6 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Wessig, J. A. [Reprint Author]; Lewerenz, J. [Reprint Author]; Leypoldt, 

F. [Reprint Author]; Thomsen, S. [Reprint Author]; Methner, A. [Reprint 

Author] 

TI RESISTANCE TO GLUTAMATE MEDIATED OXIDATIVE STRESS LEADS TO INCREASED mRNA 
EXPRESSION OF THE HOMEOBOX TRANSCRIPTION FACTOR PEM . 

SO Society for Neuroscience Abstract Viewer and Itinerary Planner, (2002) 
Vol. 2002, pp. Abstract No. 486.3. http://sfn.scholarone.com. cd-rom. 
Meeting Info. : 32nd Annual Meeting of the Society for Neuroscience. 
Orlando, Florida, USA. November 02-07, 2002. Society for Neuroscience. 

AB Oxidative stress is involved in the pathogenesis of several neurological 
disorders including Alzheimers dementia, Parkinsons disease and stroke. 
It can be studied in the mouse hippocampal cell line Ht22 by adding 
glutamate to the extracellular space, which leads through inhibition of a 
cystine/glutamate antiporter to glutathione depletion and consequently to 
apoptotic cell death by oxidative stress. We selected Ht22 cells 
resistant to glutamate -mediated cell death to screen for regulated genes 
possibly modulating susceptibility to oxidative glutamate toxicity 

Regulated transcripts were identified by subtractive suppression 
hybridisation and northern blotting. This revealed prominent upregulation 
of several gene transcripts including Placental /Embryonal Early Gene 
(PEM) . This homeobox transcription factor has not been implicated in 
oxidative stress or programmed cell death before. Here we show the 
effects of overexpression of PEM on programmed cell death in transiently 
transfected Ht22 cells, tet-inducible HEK293 cells and SFV-transduced rat 
primary cortical cultures. 

L14 ANSWER 7 OF 24 BIOSIS COPYRIGHT 2 0 03 BIOLOGICAL ABSTRACTS INC. on STN 
AU Guerri, Consuelo [Reprint author]; Pascual, Maria; Renau-Piqueras , Jaime 
TI Glia and fetal alcohol syndrome. 

SO Neurotoxicology (Little Rock), (October, 2001) Vol. 22, No. 5, pp. 
593-599. print. 

CODEN: NRTXDN. ISSN: 0161-813X. 
AB Glial cells and their interactions with neurons play vital roles during 

the ontogeny of the nervous system and in the adult brain. Alcohol intake 
during pregnancy can cause mental retardation and neurobehavioral 
disorders as well as fetal alcohol syndrome (FAS) . Clinical and 
experimental evidence indicate that in utero alcohol exposure induces 
structural and functional abnormalities in gliogenesis and in 
glial-neuronal interactions, suggesting a potential role of glial cells on 
ethanol- induced developmental brain abnormalities. In vivo studies have 
shown ethanol-associated alterations in the migration of neurons and 
radial glial as well as in astrogliogenesis and myelin development. In 
astrocytes in primary culture, ethanol has been found to (1) impair cell 
growth and differentiation, (2) decrease the levels of glial fibrillary 
acidic protein or GFAP (an astrocyte marker) and its gene 
expression and (3) interfere with the stimulatory effect of 
trophic factors affecting their release and receptor expression. Evidence 




also suggests that ethanol affects intracellular protein trafficking, 
which may mediate some effects of ethanol on astroglial cells. These 
findings suggest that glial cells are target of ethanol toxicity 
during brain development and may underlie the neurodevelopmental 
abnormalities observed after in utero alcohol exposure and in FAS. 



L14 ANSWER 8 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Kovacs, At ilia D. ; Cebers, Gvido; Cebere, Aleta; Moreira, Tiago; 

Liljequist, Sture [Reprint author] 
TI Cortical and striatal neuronal cultures of the same embryonic origin show 

intrinsic differences in glutamate receptor expression and vulnerability 

to excitotoxicity . 

SO Experimental Neurology, (March, 2001) Vol. 168, No. 1, pp. 47-62. print. 
CODEN: EXNEAC. ISSN: 0014-4886. 

AB Cortical and striatal cultures were prepared from the same embryonic rat 
brains and maintained in identical culture conditions. In this way, the 
intrinsic, genetically imprinted differences determine the responses of 
cortical and striatal neurons in comparative studies. Cortical and 
striatal neurons differed in their sensitivity to glutamate 
receptor-mediated neurotoxicity as measured by the MTT cell viability 
assay. On the 8th day in vitro, striatal cultures were less sensitive to 
N-methyl-D-aspartate (NMDA) -induced toxicity than cortical, 
although both cultures were equally vulnerable to alpha -amino -3 -hydroxy- 5- 
methyl-4-isoxazolepropionate (AMPA) - or kainate- induced toxicity 

The AMPA receptor-mediated cell death in cortical cultures, however, 
was much more dependent on preventing AMPA receptor desensitization than 
in striatal cultures. Furthermore, glutamate- induced neurotoxicity was 
primarily mediated by NMDA receptors in cortical cultures, while blockade 
of either NMDA or AMPA receptors gave almost complete protection against 
glutamate in striatal cultures . To elucidate the molecular mechanisms 
responsible for the observed differences, we analyzed the expression of 
NMDA receptor subunits (NR1, NR2A-C) at the mRNA and the protein level in 
cortical and striatal cultures as well as in standard cerebellar granule 
cell cultures. The lowest expression level of NMDA receptor subunits was 
found in striatal cultures, thereby providing a possible explanation for 
their lower sensitivity to NMDA. Remarkable differences were found 
between the relative rates of mRNA and protein 

expression for NR1 and NR2B in the three cultures, indicative of 
intrinsic differences in the posttranscriptional regulation of NMDA 
receptor subunit expression in cultures from various brain regions. 

L14 ANSWER 9 OF 24 CAPLUS COPYRIGHT 2 003 ACS on STN 
IN Snodgrass, H. Ralph 

TI Toxicity typing using embryoid bodies 
SO PCT Int. Appl., 56 pp. 
CODEN: PIXXD2 

AB This invention provides methods and systems for identifying and typing 
toxicity of chem. compns . , as well as for screening new compns . 
for toxicity. The invention involves detecting alterations in 
gene or protein expression and hence 
establishing mol . profiles in isolated mammalian 
embryoid bodies contacted with various chem. compns. of 
known and unknown toxicities, and correlating the mol. 
profiles with toxicities of the chem. compns. 

L14 ANSWER 10 OF 24 MEDLINE on STN 

AU , Trillo-Pazos G; McFarlane-Abdulla E; Campbell I C; Pilkington G J; Everall 
I P 

TI Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. 

SO BRAIN RESEARCH, (2000 May 12) 864 (2) 315-26. 
Journal code: 0045503. ISSN: 0006-8993. 

AB The expression of HIV-1 negative factor (nef) has been positively 

correlated with HIV disease progression [Z. Hanna, D.G. Kay, N. Rebai, 
A. Guimond, S. Jothy, P. Jocicoeur, Nef harbors a makor determinant of 



pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic 
mice. Cell 95 (1998) 163-175] . Nef expression has been detected in HIV 
infected human brains with neuronal damage [A. Ranki , M . Nyberg, V. 
Ovod, M. Haltia, I. Elovaara, R. Raininko, H. Haapsalo, K. Krohn, 
Abundant expression of HIV Nef and Rev proteins in 

brain astrocytes in associated with dementia, AIDS 9(9) (1995) 1001-1008; 
Y. Saito, L.R. Sharer, M.G. Epstein, J. Michaels, M. Mintz, M. 
Londer, K. Golding, B.M. Blumberg, Overexpression of nef as a marker for 
restricted HIV-1 infection of astrocytes in postmorten paediatric central 
tissues, Neurology 14 (1994) 474-480] . It is postulated that nef may 
contribute to the neuronal damage observed in the brain of those with late 
HIV disease. To test this, the potential toxicity of 
recombinant nef (from HIV-1 IIIB) was compared to the neurotoxin 
human tumour necrosis alpha (TNFalpha) on human brain cells in culture. 
SK-N-SH neuroblastoma, primary human neurons and glial cells were exposed 
to recombinant nef or TNFalpha protein for 3 days or twice over 6 days. 
Cell viability was assessed by Trypan Blue, lactate dehydrogenase (LDH) 
release and MTT assays. Nuclear fragmentation was detected using the 
Hoechst Blue nuclear dye assay. Both nef and TNFalpha (100 ng/ml) caused 
a significant 30% reduction of SK-N-SH cell numbers after 3 days exposure 
(P=0. 001). At this time, exposure to nef caused evident fragmented 
nuclei in these cultures. Human neuronal cultures had a 32 and 33% 
decrease in cell number after 6 days exposure to either nef or TNFalpha, 
respectively (P<0.001). Furthermore, as previously shown [J. He, CM. 
DeCastro, G.R. Vandenbark, J. Busciglio, D. Gabuzda, Astrocyte 
apoptosis induced by HIV-1 transactivation of the c-kit protoonocogene, 
Proc. Natl. Acad. Sci. 94 (1997) 3954-3959], a 3-day exposure to nef 
significantly reduced human glial cell number by 25% (P=0.001) . 
Recombinant nef and TNFalpha compromise human neurons in culture. Thus, 
like other virotoxins, it is shown for the first time that nef may also 
contribute to neuronal damage that has been reported in dementia in late 
HIV disease. 

L14 ANSWER 11 OF 24 MEDLINE on STN 

AU Llansola M; Minana M D; Montoliu C; Saez R; Corbalan R; Manzo L; Felipo V 

TI Prenatal exposure to aluminum reduces expression of neuronal nitric oxide 
synthase and of soluble guanylate cyclase and impairs glutamatergic 
neurotransmission in rat cerebellum. 

SO JOURNAL OF NEUROCHEMISTRY, (1999 Aug) 73 (2) 712-8. 
Journal code: 2985190R. ISSN: 0022-3042. 

AB Exposure to aluminum (Al) produces neurotoxic effects in humans. However, 
the molecular mechanism of Al neurotoxicity remains unknown. Al 
interferes with glutamatergic neurotransmission and impairs the neuronal 
glutamate-nitric oxide-cyclic GMP (cGMP) pathway, especially in rats 
prenatally exposed to Al . The aim of this work was to assess whether Al 
interferes with processes associated with activation of NMDA receptors and 
to study the molecular basis for the Al- induced impairment of the 
glutamate-nitric oxide-cGMP pathway. We used primary cultures of 
cerebellar neurons prepared from control rats or from rats prenatally 
exposed to Al . Prenatal exposure to Al prevented glutamate- induced 
proteolysis of the microtubule-associated protein-2, disaggregation of 
microtubules, and neuronal death, indicating an impairment of NMDA 
receptor-associated signal transduction pathways. Prenatal exposure to Al 
reduced significantly the content of nitric oxide synthase and guanylate 
cyclase and increased the content of calmodulin both in cultured neurons 
and in the whole cerebellum. This effect was selective for proteins of 
the glutamate-nitric oxide-cGMP pathway as the content of 
mitogen-activated protein kinase and the synthesis of most proteins were 
not affected by prenatal exposure to Al . The alterations in the 
expression of proteins of the glutamate-nitric 

oxide-cGMP pathway could be responsible for some of the neurotoxic effects 
of Al. 



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AU Petersen A; Brundin P 

TI Effects of ciliary neurotrophic factor on excitotoxicity and 

calcium-ionophore A23 187 -induced cell death in cultured embryonic striatal 
neurons . 

SO EXPERIMENTAL NEUROLOGY, (1999 Dec) 160 (2) 402-12. 
.Journal code: 0370712. ISSN: 0014-4886. 

AB Ciliary neurotrophic factor (CNTF) has a protective effect on the striatum 
in animal models of Huntington's disease. However, the mechanism through 
which it exerts its effect is not clear. In this study, we show that 
there is a concentration-dependent direct protective effect of CNTF 
against N-methyl-D-aspartate-mediated excitotoxicity on striatal neurons 
in vitro. The CNTF has to be added more than half an hour before the 
insult for the effect to occur and its effect is eliminated by the 
presence of the protein synthesis inhibitor cycloheximide . This suggests 
that the protective mechanism of CNTF does not involve acute interference 
with the glutamate receptors, but probably requires gene/ 
protein expression. We have also shown that the effect 
of CNTF against glutamate -induced excitotoxicity is dependent on the 
concentration of glutamate with a protective effect more evident at a low 
grade excitotoxic insult. Finally, we saw no effect of CNTF on calcium 
ionophore A2 3 18 7 -induced toxicity in striatal cultures, 

indicating that the growth factor does not promote survival by enhancing 
general defenses against raised intracellular levels of calcium. 



L14 ANSWER 13 OF 24 MEDLINE on STN 

AU Takashima H; Tsu j ihata M; Kishikawa M; Freed W J 

TI Bromocriptine protects dopaminergic neurons from levodopa- induced 
toxicity by stimulating D (2 ) receptors . 

SO EXPERIMENTAL NEUROLOGY, (1999 Sep) 159 (1) 98-104. 
Journal code: 0370712. ISSN: 0014-4886. 

AB Neuroprotective properties of bromocriptine, a D(2) receptor agonist, were 
investigated using the in vitro neurotoxicity of levodopa for dopaminergic 
neurons from rat embryonic ventral mesencephalon. Levodopa, when added to 
the culture medium, showed toxicity which was specific for 
dopaminergic neurons. Bromocriptine was found to protect dopaminergic 
neurons from levodopa toxicity. Another D(2) agonist, 

2- (N-phenethyl-N-propyl-amino-5-hydroxytetralin, showed similar protective 
effects. The neuroprotective effect of bromocriptine was inhibited by 
supplementation of the culture medium with sulpiride, a D(2) antagonist, 
or by D(2) receptor knockdown with an ant i sense oligonucleotide. 
Dopaminergic neurons treated with levodopa showed an increase in free 
radicals. These data suggest that neuroprotective properties of 
bromocriptine seen in this cellular model of neurotoxicity are dependent 
on dopamine D(2) autoreceptor binding and that levodopa toxicity 
may be related to increased free radical generation in dopaminergic 
neurons . 

Copyright 1999 Academic Press. 
L14 ANSWER 14 OF 24 MEDLINE on STN 

AU Meucci O; Fatatis A; Simen A A; Bushell T J; Gray P W; Miller R J 
TI Chemokines regulate hippocampal neuronal signaling and gpl20 
neurotoxicity. 

SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF 
AMERICA, (1998 Nov 24) 95 (24) 14500-5. 
Journal code: 7505876. ISSN: 0027-8424. 

AB The HIV-1 envelope protein gpl20 induces apoptosis in hippocampal neurons. 
Because chemokine receptors act as cellular receptors for HIV-1, we 
examined rat hippocampal neurons for the presence of functional chemokine 
receptors. Fura-2-based Ca imaging showed that numerous chemokines, 
including SDF-lalpha, RANTES, and fractalkine, affect neuronal Ca 
signaling, suggesting that hippocampal neurons possess a wide variety of 
chemokine receptors. Chemokines also blocked the frequency of spontaneous 
glutamatergic excitatory postsynaptic currents recorded from these neurons 
and reduced voltage -dependent Ca currents in the same neurons. Reverse 



transcription-PCR demonstrated the expression of CCR1, CCR4, CCR5, 
CCR9/10, CXCR2, CXCR4 , and CX3CR1, as well as the chemokine fractalkine in 
these neurons. Both fractalkine and macrophage -derived chemokine (MDC) 
produced a time -dependent activation of extracellular response kinases 
(ERK)-l/2, whereas no activation of c-JUN NH2 -terminal protein kinase 
(JNK) /stress-activated protein kinase, or p38 was evident. Furthermore, 
these two chemokines, as well as SDF-lalpha, activated the Ca- and 
cAMP- dependent transcription factor CREB. Several chemokines were able 
also to block gpl2 0- induced apoptosis of hippocampal neurons, both in the 
presence and absence of the glial feeder layer. These data suggest that 
chemokine receptors may directly mediate gpl2 0 neurotoxicity. 

L14 ANSWER 15 OF 24 MEDLINE on STN 

AU Seidel B; Keilhoff G; Reinheckel T; Wolf G 

TI Differentially expressed genes in hippocampal cell cultures in response to 
an excitotoxic insult by quinolinic acid. 

SO BRAIN RESEARCH. MOLECULAR BRAIN RESEARCH, (1998 Oct 1) 60 (2) 296-300. 
Journal code: 8908640. ISSN: 0169-328X. 

AB The NMDA-type glutamate receptor agonist quinolinic acid (QA) , which 

causes tissue lesions in the rat brain as well as cell loss in neuronal 
cultures, is widely used in models of glutamate excitotoxicity . The aim 
of this study was to evaluate the alterations in gene 
expression in a primary hippocampal cell culture after exposure to 
QA. By means of differential mRNA display, we were able to pinpoint as 
many as 23 bands which appeared to be upregulated after a 6-h treatment 
with quinolinic acid. The differential expression of 13 cDNAs could be 
confirmed by dot blot and/or Northern analysis. Of the cDNAs, the pll2 
regulatory subunit of the 26S proteasome, a PDGF-associated protein and 
the glia-derived protease nexin PN-1 could be identified. The results 
provide emphasis to the participation of proteolysis and protease 
inhibition in neurodegenerative processes. 
Copyright 1998 Elsevier Science B.V. 

L14 ANSWER 16 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 

AU Bales, Kelly R./ Du, Yansheng; Dodel, Richard C; Yan, Guang-Mei; 
Hamilton-Byrd, Elizabeth; Paul, Steven M. [Reprint author] 

TI The NF-kappaB/Rel family of proteins mediates A beta-induced neurotoxicity 
and glial activation. 

SO Molecular Brain Research, (June 1, 1998) Vol. 57, No. 1, pp. 63-72. print. 
CODEN: MBREE4. ISSN: 0169-328X. 

AB The beta-amyloid peptide (Abeta) is deposited in neuritic plaques which 
are characteristic features of Alzheimer's disease (AD). Prominent 
neurodegeneration and glial activation occurs around these plaques leading 
to the hypothesis that Abeta may play a causative role in the neuronal 
loss and the inflammatory response associated with AD. Here we show that 
Abeta-induced toxicity of cultured fetal rat cortical neurons is 
associated with internucleosomal DNA fragmentation beginning just 6 h 
after neurons are exposed to Abeta. Additionally, constitutive NF-kappaB 
activity readily measured in fetal rat cortical neurons decreases in a 
concentration- and time -dependent fashion following exposure to Abeta, but 
there is no corresponding decrease in NF-kappaB mRNA or protein (p65) . An 
upregulation of both IkappaBalpha protein and mRNA which occurs in 
cortical neurons exposed to Abeta may be responsible for retaining 
NF-kappaB in the cytoplasm accounting for the observed decrease in 
activated NF-kappaB. The latter is supported by the observation that 
pretreatment of cortical cultures with an antisense oligonucleotide to 
IkappaBalpha mRNA is neuroprotective. In contrast to cortical neurons, 
exposure of rat primary astroglial cultures to Abeta results in a 
concentration- and time -dependent activation of NF-kappaB with subsequent 
upregulation of IL-lbeta and IL-6. Our data suggest that A beta-induced 
neurotoxicity as well as astrocyte activation may be medicated by the 
NF-kappaB/Rel family of proteins, and thus alterations in 
NF-kappaB-directed gene expression may contribute to 

both the neurodegeneration and inflammatory response which occur in AD. 




4EI 



L14 



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MEDLINE on STN 



AU Samdani A F; Newcamp C; Re sink A; Facchinetti F; Hoffman B E; Dawson V L; 
Dawson T M 

TI Differential susceptibility to neurotoxicity mediated by neurotrophins and 
neuronal nitric oxide synthase. 

SO JOURNAL OF NEUROSCIENCE , (1997 Jun 15) 17 (12) 4633-41. 
Journal code: 8102140. ISSN: 0270-6474. 

AB NMDA neurotoxicity, which is mediated, in part, by formation of nitric 

oxide (NO) via activation of neuronal NO synthase (nNOS) , is modulated by 
neurotrophins. nNOS expression in rat and mouse primary neuronal cultures 
grown on a glial feeder layer is significantly less than that of neurons 
grown on a polyornithine (Poly-O) matrix. Neurotrophins markedly increase 
the number of nNOS neurons, nNOS protein, and NOS catalytic activity and 
enhance NMDA neurotoxicity via NO-dependent mechanisms when neurons are 
grown on glial feeder layers. In contrast, when rat or mouse primary 
cortical neurons are grown on a Poly-0 matrix, neurotrophins have no 
influence on nNOS neuronal number or NOS catalytic activity and reduce 
NMDA neurotoxicity. Primary neuronal cultures from mice lacking nNOS 
grown on a glial feeder layer fail to respond to neurotrophin-mediated 
enhancement of neurotoxicity. Together, these results indicate that nNOS 
expression and NMDA NO-mediated neurotoxicity are dependent, in part, on 
the culture paradigm, and neurotrophins regulate the susceptibility to 
NMDA neurotoxicity via modulation of nNOS. Furthermore, these results 
support the idea that NMDA neurotoxicity in culture is critically 
dependent on the developmental state of the neurons being assessed and 
suggest that, when cortical neurons are cultured on a glial feeder layer, 
they do not reach nearly as mature a phenotype as when grown on a Poly-0 
matrix. 

L14 ANSWER 18 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 
AU Valles, S./ Pitarch, J.; Renau-Piqueras , J.; Guerri, C. [Reprint author] 
TI Ethanol exposure affects glial fibrillary acidic protein 

gene expression and transcription during rat brain 

development . 

SO Journal of Neurochemistry, (Dec, 1997) Vol. 69, No. 6, pp. 2484-2493. 
print. 

CODEN: J0NRA9. ISSN: 0022-3042. 
AB Exposure to ethanol during fetal development reduces the 

astroglial-specif ic marker glial fibrillary acidic protein (GFAP) and its 
mRNA levels in brains of fetal rats and in radial glia in primary culture, 
affecting the proliferation and differentiation of astrocytes. The 
objectives of this study were to evaluate the possible effect of ethanol 
on GFAP mRNA levels in astrocytes and to investigate the molecular 
mechanism (s) involved in ethanol -induced changes in GFAP expression by 
analyzing the GFAP transcription rate, GFAP mRNA stability, and GFAP DNA 
methylation. We show here that prenatal exposure to ethanol reduces 
significantly GFAP immunoreactivity and its mRNA levels in both astrocytes 
in primary culture and brains of pups from alcohol-fed mothers. Runoff 
experiments from nuclei of astrocytes indicate that ethanol exposure 
decreases GFAP transcription rate significantly and reduces GFAP mRNA 
stability slightly. DNA methylation analysis indicates that prenatal 
ethanol exposure induces a hype rme thy la ted state of the GFAP DNA in fetal 
brains. Methylation-mediated repression of GFAP transcription could be a 
mechanism involved in ethanol -induced reduction of GFAP expression. 
Ethanol -induced alterations in GFAP expression and astroglial development 
may underlie the CNS dysfunctions observed after prenatal alcohol 
exposure . 

L14 ANSWER 19 OF 24 MEDLINE on STN 

AU Williamson L C; Halpern J L; Montecucco C; Brown J E; Neale E A 
TI Clostridial neurotoxins and substrate proteolysis in intact 

neurons: botulinum neurotoxin C acts on synaptosomal -associated 

protein of 25 kDa . 



SO JOURNAL OF BIOLOGICAL CHEMISTRY, (1996 Mar 29) 271 (13) 7694-9. 
Journal code: 2985121R. ISSN: 0021-9258. 

AB Clostridial neurotoxins are zinc endopeptidases that block 

neurotransmission and have been shown to cleave, in vitro, specific 
proteins involved in synaptic vesicle docking and/or fusion. We have used 
immunohistochemistry and immunoblotting to demonstrate alterations in 
toxin substrates in intact neurons under conditions of toxin- induced 
blockade of neurotransmitter release. Vesicle-associated membrane 
protein, which colocalizes with synaptophysin, is not detectable in 
tetanus toxin-blocked cultures. Syntaxin, also concentrated in synaptic 
sites, is cleaved by botulinum neurotoxin C. Similarly, the 
carboxyl terminus of the synaptosomal-associated protein of 25 kDa 
(SNAP-25) is not detectable in botulinum neurotoxin A-treated 
cultures. Unexpectedly, tetanus toxin exposure causes an increase in 
SNAP-25 immunofluorescence, reflecting increased accessibility of 
antibodies to antigenic sites rather than increased expression 
of the protein. Furthermore, botulinum neurotoxin C 

causes a marked loss of the carboxyl terminus of SNAP-2 5 when the toxin is 
added to living cultures, whereas it has no action on SNAP-25 in vitro 
preparations. This study is the first to demonstrate in functioning 
neurons that the physiologic response to these toxins is correlated with 
the proteolysis of their respective substrates. Furthermore, the data 
demonstrate that botulinum neurotoxin C, in addition to cleaving 
syntaxin, exerts a secondary effect on SNAP-25. 

L14 ANSWER 20 OF 24 BIOSIS COPYRIGHT 2003 BIOLOGICAL ABSTRACTS INC. on STN 

AU Valles, S . ; Sancho-Tello , M . ; Minana, R.; Climent, E . ; Renau-Piqueras , J.; 
Guerri, C. [Reprint author] 

TI Glial fibrillary acid protein expression in rat brain 

and in radial glia culture is delayed by prenatal ethanol exposure. 

SO Journal of Neurochemistry , (1996) Vol. 67, No. 6, pp. 2425-2433. 
CODEN: JONRA9. ISSN: 0022-3042. 

AB The alterations in astrocyte proliferation and differentiation induced by 
prenatal exposure to alcohol (PEA) suggest that ethanol exposure affects 
the radial glial cells, the main astrocytic precursors. We have 
investigated the effects of ethanol on the early stages of 
astrogliogenesis by analyzing the developmental pattern of vimentin and 
glial fibrillary acidic protein (GFAP) immunoreactivity and their mRNA 
levels during embryonic/ fetal brain development and in radial glia in 
primary culture. GFAP appeared late in gestation and at day 5 of culture 
of radial glia, whereas GFAP mRNA was first detected on fetal day 15 and 
increased in content on fetal day 21. In contrast, the levels of vimentin 
and its mRNA were high at fetal day 15 but decreased on day 21. Alcohol 
exposure delays the appearance of GFAP and its mRNA and significantly 
decreases the GFAP expression in fetal brain and in primary culture of 
radial glia. In addition, some morphological alterations were observed in 
PEA glial cells in culture. These results demonstrate that astroglial 
precursor cells are damaged by prenatal exposure to ethanol and suggest 
that abnormalities in the astrogliogenesis may underlie the disruption in 
neuronal migration and other CNS alterations observed after prenatal 
ethanol exposure . 

L14 ANSWER 21 OF 24 MEDLINE on STN 

AU Prehn J H; Bindokas V P; Jordan J; Galindo M F; Ghadge G D; Roos R P; 

Boise L H; Thompson C B; Krajewski S; Reed J C; Miller R J 
TI Protective effect of transforming growth factor-beta 1 on beta-amyloid 

neurotoxicity in rat hippocampal neurons. 
SO MOLECULAR PHARMACOLOGY, (1996 Feb) 49 (2) 319-28. 

Journal code: 0035623. ISSN: 0026-895X. 
AB Neurodegeneration associated with Alzheimer's disease is believed to 

involve toxicity to beta-amyloid (A beta) and related peptides. 

Treatment of cultured rat hippocampal neurons with A beta 1-40 (1 microM) 

or the active fragment A beta 25-35 (1 microM) for 5 days led to a 

approximately 40-50% decrease in neuronal viability. The hydrophilic 



antioxidant ascorbic acid (3 00 microM) and the lipophilic antioxidant 
2-mercaptoethanol (10 microM) both protected significantly against A beta 
neurotoxicity. Despite the protective effects of these antioxidants, both 
acute and chronic treatments with A beta 25-35 did not increase production 
of superoxide anions, as monitored with the fluorescent probe 
hydroethidine . Similarly, overexpression of Cu/Zn- superoxide dismutase 
using adenovirus -mediated gene transfer did not protect against A beta 
neurotoxicity. A beta neurotoxicity, however, was prevented in cultures 
infected with a recombinant, replication-defective adenovirus 
overexpressing the Ca2+ binding protein calbindin D28k. Transforming 
growth factor-beta 1 (TGF-beta 1) has been shown to protect neurons 
against both Ca(2+)- and free radical -mediated neuronal degeneration. We 
found that A beta neurotoxicity was significantly attenuated by single 
treatments with TGF-beta 1 (0.1-10 ng/ml) and prevented by repetitive 
treatments (10 ng/ml/day) . The protective effects of TGF-beta 1 were 
associated with a preservation of mitochondrial potential and function, as 
determined with rhodamine- 12 3 -based microf luorimetry . Because both 
increased oxidative stress and pathophysiological Ca2+ fluxes can impair 
mitochondrial function, preservation of mitochondrial potential by 
TGF-beta 1 could be directly associated with its protection against A beta 
neurotoxicity. The ability of TGF-beta 1 to increase the 
expression of the anti-apoptotic proteins Bcl-2 and 
Bcl-XL is discussed in this context. 

L14 ANSWER 22 OF 24 MEDLINE on STN 

AU Forloni G; Bugiani 0; Tagliavini F; Salmona M 

TI Apoptosis -mediated neurotoxicity induced by beta-amyloid and PrP 
fragments . 

SO MOLECULAR AND CHEMICAL NEUROPATHOLOGY, (1996 May-Aug) 28 (1-3) 163-71. 
Journal code: 8910358. ISSN: 1044-7393. 

AB The neurotoxic activity of beta-amyloid (beta A) and prion protein (PrP) 
fragments contributed to the hypothesis concerning a causal role of 
amyloid deposits in Alzheimer disease (AD) and in prion-related 
encephalopathies. In this study, we investigated some aspects of the 
molecular mechanisms associated with neurotoxic activity of synthetic 
peptides homologous to beta A (beta 25-35) or PrP (PrP106-126) fragments. 
Chronic (5-7 d) exposure to both peptides induced neuronal death by 
apoptosis, as suggested by biochemical and morphological analysis. The 
apoptotic mechanism was confirmed by ultrastructural examination. The 
intracellular cascade of events activated by peptides was investigated by 
Northern blot and PCR analysis of expression of early 
genes (c-fos, c-jun, c-myc) and other proteins (p53, SGP-2 bcl-2, 
HSP70, Ich-1) potentially involved in apoptosis. With the exception of 
bcl-2 mRNA decrease and a slight increase of SGP-2 in PrP106-126-treated 
cells, no consistent alterations of these mRNA expressions were found in 
neuronal cells exposed to beta 25-35 or PrP106-126. Furthermore, we 
synthesized amidated homologs of both peptides with low amyloidogenic 
activity to test directly the relationship between amyloid fibrils and 
cell death. The neurotoxicity exhibited by PrP106- 126-NH2 was similar to 
that observed with original peptide, whereas the amidation of beta 25-35 
partially reduced the neurotoxicity of this peptide. 

L14 ANSWER 23 OF 24 MEDLINE on STN 

AU Cheng B; Christakos S; Mattson M P 

TI Tumor necrosis factors protect neurons against metabolic-excitotoxic 
insults and promote maintenance of calcium homeostasis. 

SO NEURON, (1994 Jan) 12 (1) 139-53. 

Journal code: 8809320. ISSN: 0896-6273. 

AB Emerging data indicate that neurotrophic factors and cytokines utilize 

similar signal transduction mechanisms. Although neurotrophic factors can 
protect CNS neurons against a variety of insults, the role of cytokines in 
the injury response is unclear. We now report that TNF beta and TNF alpha 
(1-100 ng/ml) can protect cultured embryonic rat hippocampal, septal, and 
cortical neurons against glucose deprivation- induced injury and excitatory 



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amino acid toxicity. The elevation of intracellular calcium 
concentration ([Ca2+]i) induced by glucose deprivation, glutamate, NMD A, 
or AM PA was attenuated in neurons pretreated with TNF beta. The mechanism 
whereby TNFs stabilize [Ca2+]i may involve regulation of the 
expression of proteins involved in maintaining [Ca2+] i 
homeostasis, since both TNF beta and TNF alpha caused a 4- to 8 -fold 
increase in the number of neurons expressing the calcium-binding protein 
calbindin-D2 8Jc. These data suggest a neuroprotective role for TNFs in the 
brain's response to injury. 

L14 ANSWER 24 OF 24 MEDLINE on STN 

AU Mattson M P; Kumar K N; Wang H; Cheng B; Michaelis E K 

TI Basic FGF regulates the expression of a functional 71 kDa NMDA receptor 
protein that mediates calcium influx and neurotoxicity in hippocampal 
neurons . 

SO JOURNAL OF NEUROSCIENCE , (1993 Nov) 13 (11) 4575-88. 
Journal code: 8102140. ISSN: 0270-6474. 

AB Basic fibroblast growth factor (bFGF) was recently found to modulate the 
outgrowth-regulating effects of glutamate, and protected neurons from 
several brain regions against excitotoxi/ischemic damage. We provide 
evidence that the excitoprotective mechanism of bFGF involves suppression 
of the expression of a 71 kDa NMDA receptor protein (NMDARP-71) . 
NMDARP -71 protein and mRNA levels were reduced in neurons in bFGF-treated 
hippocampal cell cultures. The levels of the NMDARP-71 were not reduced 
by NGF or epidermal growth factor, and bFGF did not reduce the level of 
mRNA for the GluRl kainate/AMPA receptor, demonstrating the specificity of 
the effect of bFGF on the NMDARP -71. The reduction in NMDARP-71 
expression in bFGF-treated neurons was correlated with reduced 
vulnerability to NMDA neurotoxicity. A major role for NMDARP-71 in 
calcium responses to NMDA and excitotoxicity was demonstrated using 
antisense oligonucleotides directed against NMDARP-71. Northern and 
Western blot analysis and immunocytochemistry showed that NMDARP-71 
antisense oligonucleotides caused a selective suppression of NMDARP-71 
mRNA and protein levels during 12-44 hr exposure periods. Elevations in 
intracellular calcium levels normally caused by glutamate and NMDA were 
attenuated in neurons exposed to NMDARP-71 antisense oligonucleotide; 
calcium responses to kainate were relatively unaffected. NMDARP-71 
antisense oligonucleotides protected the neurons against excitotoxicity. 
Thus, NMDARP-71 is a necessary component of an NMDA receptor mediating 
calcium responses and neurotoxicity in hippocampal neurons. Taken 
together, these data identify a mechanism whereby bFGF can modify neuronal 
responses to glutamate, and suggest that regulating the expression of 
excitatory amino acid receptors may provide a means for growth factors to 
influence the plasticity and degeneration of neural circuits. 



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