Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats.
In previous studies, we showed that basic fibroblast growth factor (bFGF) reduced infarct volume when infused intravenously in animal models of focal cerebral ischemia. In the current study, we examined the potential mechanism of infarct reduction by bFGF, especially effects on apoptosis within the ischemic brain. We found that bFGF decreased DNA fragmentation in the ischemic hemisphere, as assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) histochemical methods combined with morphological criteria. bFGF also prevented reduction of immunoreactivity of the anti-apoptotic protein Bcl-2 in the ischemic hemisphere, but did not alter immunoreactivity of the pro-apoptotic proteins Bax, Caspase-1, or Caspase-3. These changes in TUNEL histochemistry and Bcl-2 immunoreactivity were especially prominent in cortex at the borders ('penumbra') of infarcts, spared by bFGF treatment. We conclude that the infarct-reducing effects of bFGF may be due, in part, to prevention of downregulation of Bcl-2 expression and decreased apoptosis in the ischemic brain.
CNS Growth Factor Research Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 02114, Boston, MA, USA.
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016222:Fibroblast Growth Factor 2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1