| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 1996;27:1609-1615.)
© 1996 American Heart Association, Inc.
Articles |
TGF-ß1 Protects Hippocampal Neurons Against Degeneration Caused by Transient Global Ischemia
Dose-Response Relationship and Potential Neuroprotective Mechanisms
the Department of Pharmacology and Toxicology, Philipps-University, Marburg, Germany.
Correspondence to Jochen H.M. Prehn, PhD, Department of Pharmacology and Toxicology, FB 16, Philipps-University, Ketzerbach 63, 35032 Marburg, Germany. E-mail prehn@mailer.uni-marburg.de.
Background and Purpose Transforming growth factor-ß1 (TGF-ß1) has been shown to rescue cultured neurons from excitotoxic and hypoxic cell death and to reduce infarct size after focal cerebral ischemia in mice and rabbits. The present study investigated the effects of TGF-ß1 in a different pathophysiological setting and the delayed neuronal death of hippocampal pyramidal cells after transient global ischemia in rats, and evaluated the potential mechanisms of the neuroprotective activity of TGF-ß1.
Methods Transient forebrain ischemia was induced in male adult Wistar rats with bilateral occlusion of both common carotid arteries combined with systemic hypotension for 10 minutes. Seven days after ischemia, brains were perfusion-fixed and stained for histological evaluation. TGF-ß1 or vehicle was injected intracerebroventricularly (ICV; 0.5, 4, and 50 ng) or intrahippocampally (4 ng) 1 hour before ischemia. For in vitro studies, hippocampal neurons were derived from E17 rat embryos and cultured for 10 to 14 days. Cells were exposed to (1) S-nitrosocysteine (SNOC; 30 µmol/L) to induce nitric oxide–induced oxidative injury and (2) staurosporine (0.03 µmol/L) to induce apoptotic cell death.
Results Transient forebrain ischemia caused extensive degeneration of CA1 hippocampal pyramidal cells in vehicle-treated control animals. Ischemic injury was not significantly reduced after ICV administration of 0.5 ng TGF-ß1 (71±7% damaged neurons versus 84±3% in vehicle-treated controls; n=9 and 11, respectively; P=.07, Mann-Whitney U test). Administration of 4 ng TGF-ß1 reduced the percentage of damaged CA1 pyramidal cells from 71±10% in controls to 52±7% in TGF-ß1–treated animals (n=11 and 12, respectively; P=.04). TGF-ß1 (4 ng) also produced significant protection when injected directly into the hippocampal tissue. In contrast, ICV administration of 50 ng TGF-ß1 failed to show a protective effect in two separate sets of experiments. In vitro, a 24-hour pretreatment of the cultured hippocampal neurons with TGF-ß1 (0.1 to 10 ng/mL) significantly inhibited both nitric oxide and staurosporine neurotoxicity. Posttreatment with TGF-ß1 (10 ng/mL) also inhibited staurosporine neurotoxicity but actually potentiated nitric oxide–induced neuronal injury.
Conclusions We demonstrated that TGF-ß1 in a surprisingly low dose range has the capacity to reduce injury to CA1 hippocampal neurons caused by transient global ischemia in rats. This protective action could well be associated with the antioxidative and antiapoptotic effects of TGF-ß1 demonstrated in vitro.
Editorial Comment
Dose-Response Relationship and Potential Neuroprotective Mechanisms
Duke University Medical Center, Durham, NC
This article has been cited by other articles:
 |
|
 |
|
  L. Qian, S.-J. Wei, D. Zhang, X. Hu, Z. Xu, B. Wilson, J. El-Benna, J.-S. Hong, and P. M. Flood Potent Anti-Inflammatory and Neuroprotective Effects of TGF-{beta}1 Are Mediated through the Inhibition of ERK and p47phox-Ser345 Phosphorylation and Translocation in Microglia J. Immunol., July 1, 2008; 181(1): 660 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Corti, G. Battaglia, G. Molinaro, B. Riozzi, A. Pittaluga, M. Corsi, M. Mugnaini, F. Nicoletti, and V. Bruno The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection J. Neurosci., August 1, 2007; 27(31): 8297 - 8308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Hermonat, D. Li, B. Yang, and J. L. Mehta Mechanism of action and delivery possibilities for TGF{beta}1 in the treatment of myocardial ischemia Cardiovasc Res, May 1, 2007; 74(2): 235 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chung, E. Kim, D. H. Lee, S. Seo, S. Ju, D. Lee, H. Kim, and S. Park Ghrelin Inhibits Apoptosis in Hypothalamic Neuronal Cells during Oxygen-Glucose Deprivation Endocrinology, January 1, 2007; 148(1): 148 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Buckwalter, M. Yamane, B. S. Coleman, B. K. Ormerod, J. T. Chin, T. Palmer, and T. Wyss-Coray Chronically Increased Transforming Growth Factor-{beta}1 Strongly Inhibits Hippocampal Neurogenesis in Aged Mice Am. J. Pathol., July 1, 2006; 169(1): 154 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Chen, P. Kuhn, K. Chaturvedi, N. Boyadjieva, and D. K. Sarkar Ethanol Induces Apoptotic Death of Developing beta-Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-beta1-Linked Apoptotic Signaling Mol. Pharmacol., March 1, 2006; 69(3): 706 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-G. Konig, D. Kogel, A. Rami, and J. H.M. Prehn TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling J. Cell Biol., March 28, 2005; 168(7): 1077 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Culmsee, V. Junker, W. Kremers, S. Thal, N. Plesnila, and J. Krieglstein Combination Therapy in Ischemic Stroke: Synergistic Neuroprotective Effects of Memantine and Clenbuterol Stroke, May 1, 2004; 35(5): 1197 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Zhou, M. Zhao, D. Li, K. Shimazu, K. Sakata, C.-X. Deng, and B. Lu Cerebellar Deficits and Hyperactivity in Mice Lacking Smad4 J. Biol. Chem., October 24, 2003; 278(43): 42313 - 42320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Matucci Cerinic and M. B. Kahaleh Beauty and the Beast. The nitric oxide paradox in systemic sclerosis Rheumatology, August 1, 2002; 41(8): 843 - 847. [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhu, G.-Y. Yang, B. Ahlemeyer, L. Pang, X.-M. Che, C. Culmsee, S. Klumpp, and J. Krieglstein Transforming Growth Factor-beta 1 Increases Bad Phosphorylation and Protects Neurons Against Damage J. Neurosci., May 15, 2002; 22(10): 3898 - 3909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Shum-Tim, C. I. Tchervenkov, A.-M. Jamal, T. Nimeh, C.-Y. Luo, E. Chedrawy, E. Laliberte, A. Philip, C. P. Rose, and J. Lavoie Systemic steroid pretreatment improves cerebral protection after circulatory arrest Ann. Thorac. Surg., November 1, 2001; 72(5): 1465 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. del Zoppo, K. J. Becker, and J. M. Hallenbeck Inflammation After Stroke: Is It Harmful? Arch Neurol, April 1, 2001; 58(4): 669 - 672. [Full Text] [PDF]
|
|
|
|
|
|
L. Pang, W. Ye, X.-M. Che, B. J. Roessler, A. L. Betz, and G.-Y. Yang Reduction of Inflammatory Response in the Mouse Brain With Adenoviral-Mediated Transforming Growth Factor-{beta}1 Expression Stroke, February 1, 2001; 32(2): 544 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Yang, D. S. Zander, and J. L. Mehta Hypoxia-Reoxygenation-Induced Apoptosis in Cultured Adult Rat Myocytes and the Protective Effect of Platelets and Transforming Growth Factor-beta 1 J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 733 - 738. [Abstract] [Full Text]
|
|
|
|
 |
|
 O. Dammann and A. Leviton Brain Damage in Preterm Newborns: Might Enhancement of Developmentally Regulated Endogenous Protection Open a Door for Prevention? Pediatrics, September 1, 1999; 104(3): 541 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Buisson, O. Nicole, F. Docagne, H. Sartelet, E. T. Mackenzie, and D. Vivien Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor ß1 FASEB J, December 1, 1998; 12(15): 1683 - 1691. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. Pantoni, C. Sarti, and D. Inzitari Cytokines and Cell Adhesion Molecules in Cerebral Ischemia : Experimental Bases and Therapeutic Perspectives Arterioscler. Thromb. Vasc. Biol., April 1, 1998; 18(4): 503 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Becker, R. M. McCarron, C. Ruetzler, O. Laban, E. Sternberg, K. C. Flanders, and J. M. Hallenbeck Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia PNAS, September 30, 1997; 94(20): 10873 - 10878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Tsirka, T. H. Bugge, J. L. Degen, and S. Strickland Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin PNAS, September 2, 1997; 94(18): 9779 - 9781. [Abstract] [Full Text] [PDF]
|
|