Basic Fibroblast Growth Factor Increases Regional Cerebral Blood Flow and Reduces Infarct Size After Experimental Ischemia in a Rat Model

Tanaka, Ryusui; Miyasaka, Yoshio; Yada, Kenzoh; Ohwada, Takashi; Kameya, Toru

doi:10.1161/01.str.26.11.2154

Cited by 66 publications

(41 citation statements)

References 27 publications

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“…We previously could not demonstrate a significant in vivo decrease in ischemic lesion volumes with basic fibroblast growth factor with a similar study protocol, 44 whereas we could demonstrate a significant effect of the agent at postmortem as several studies had demonstrated before. [45][46][47][48] Using a glycine site antagonist, we obtained a significant postmortem reduction in ischemic lesion size, while in the same study DWI did not show an in vivo effect during a 3.5-hour MRI protocol. 49 With the same drug and with a similar study protocol, others have shown an in vivo lesion reduction by DWI at 6 hours after MCAO, 50 suggesting a late effect.…”

Section: Tatlisumak Et Al April 1998 855mentioning

confidence: 53%

A Novel Endothelin Antagonist, A-127722, Attenuates Ischemic Lesion Size in Rats With Temporary Middle Cerebral Artery Occlusion

Tatlısumak

Carano²,

Takano³

et al. 1998

Stroke

145

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Background and Purpose-Endothelins (ETs) are potent vasoconstrictors. Plasma ET levels increase during acute brain ischemia and may worsen the ischemic damage. Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for evaluation of acute cerebral ischemia. We studied the effects of A-127722, a novel ET A -selective ET antagonist, on cerebral ischemic lesion size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion development with DWI, and on the cerebral circulation using PI. Methods-Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (nϭ10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before initiation of treatment and repeated frequently thereafter up to 4 hours after MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. Results-Physiological parameters, body weight, neurological scores, and premature mortality (2 versus 2) did not differ between the two groups. No hypotension, abnormal behavior, or other adverse effects were seen. TTC-derived %HLV was 25.3Ϯ5.6% for controls and 16.2Ϯ9.6% for treated animals (36% reduction, PϽ.02). Six animals in each group had successful reperfusion as shown by PI. Among these animals, %HLV was 23.2Ϯ3.1% for controls and 9.3Ϯ4.4% for treated animals (60% reduction, Pϭ.0001). The beneficial effect of A-127722 was limited to animals in which successful reperfusion was demonstrated. No difference in PI-detected perfusion deficit size was observed between the groups. DWI did not demonstrate significant in vivo lesion size differences. Conclusions-A-127722 significantly reduced ischemic lesion size in rats without observable adverse effects. It is not clear whether the effect was due to vasodilatation of collateral arterioles not detectable by PI or whether A-127722 has neuroprotective properties that are independent of vascular effects. (Stroke. 1998;29:850-858.)

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Section: Tatlisumak Et Al April 1998 855mentioning

confidence: 53%

A Novel Endothelin Antagonist, A-127722, Attenuates Ischemic Lesion Size in Rats With Temporary Middle Cerebral Artery Occlusion

Tatlısumak

Carano²,

Takano³

et al. 1998

Stroke

145

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“…This may require further investigation because another growth factor, bFGF, has been shown to dilate collaterals in the peri-ischemic zone, even at doses not promoting systemic hypotension, thus increasing blood flow to the penumbral regions. 30 In conclusion, intravenous administration of G-CSF achieved a significant neuroprotective effect in cell culture and after focal cerebral ischemia and was associated with increased STAT3 expression. These effects were probably mediated by interaction with G-CSFR.…”

Section: Physiological Parameter Of G-csf Treated Animals and Controlsmentioning

confidence: 82%

Neuroprotective Effect of Granulocyte Colony–Stimulating Factor After Focal Cerebral Ischemia

Schäbitz

Kollmar

Schwaninger

et al. 2003

Stroke

375

310

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Background and Purpose-The potential neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF) after glutamate-induced excitotoxicity in cell culture and after focal cerebral ischemia in rats was studied. We hypothesized the existence of the G-CSF receptor (G-CSFR) as a main G-CSF effector on neurons, and immunohistochemistry, immunoblotting, and polymerase chain reaction were performed. The G-CSFR-mediated action was studied by activation of signal transducer(s) and activator(s) of transcription-3 (STAT3) in the periphery of the infarction. Methods-Neuroprotection of various G-CSF concentrations on glutamate-induced excitotoxicity was studied in cell culture. In vivo, ischemia was induced by use of a suture occlusion model of the middle cerebral artery (90-minute occlusion) in the rat. Thirty minutes after the induction of ischemia, the animals (nϭ12 per group) received G-CSF at 60 g/kg body wt IV for 90 minutes or vehicle (saline). Infarct volume was calculated on the basis of 2,3,5-triphenyltetrazolium chloride staining 24 hours after ischemia. Expression of the G-CSFR was studied by immunohistochemistry and verified by reverse transcription-polymerase chain reaction and immunoblotting. Expression of STAT3 was determined by immunohistochemistry. Results-In cell culture, G-CSF exhibited a significant neuroprotective effect after glutamate-induced excitotoxicity (PϽ0.05). A G-CSF concentration of 10 ng/mL was maximally effective, resulting in a nearly complete protection. In vivo, G-CSF reduced infarct volume to 47% (132.0Ϯ112.7 mm 3 versus 278.9Ϯ91.6 mm 3 [PϽ0.05] in the control group). Immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction revealed the existence of G-CSFRs in neurons and glial cells. Animals treated with G-CSF significantly upregulated STAT3 in the periphery of the infarction compared with control animals (PϽ0.05). Conclusions-G-CSF

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“…For example, in a focal ischemia model in the rat, intravenous administration of bFGF reduced the infarct size. 1,12,22) In models of middle cerebral artery occlusion in rat, treatment with bFGF demonstrated a decrease in infarct size. 22) However, the mechanism of infarct reduction by bFGF remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, reduction in infarct size was accompanied by an increased rCBF in the peri-infarct area. 22) Furthermore, bFGF has a potent neurotrophic function 25) and this may cause the therapeutic effect on cerebral infarction. This protective effect may be independent of rCBF increase.…”

Section: Discussionmentioning

confidence: 99%

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Vasodilatory Effect of Basic Fibroblast Growth Factor in Isolated Rat Cerebral Arterioles: Mechanisms Involving Nitric Oxide and Membrane Hyperpolarization.

Kajita

Takayasu²,

Yoshida³

et al. 2001

Neurol. Med. Chir.(Tokyo)

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Basic fibroblast growth factor (bFGF), a potent mitogen, acutely dilates cerebral blood vessels and may be effective in reducing cerebral infarction. However, the vasodilatory mechanism, which may involve nitric oxide (NO), is not completely understood. This study investigated whether membrane hyperpolarization is also involved in this mechanism. Membrane potential (MP) of smooth muscle cells and vessel diameter of isolated intracerebral arterioles were simultaneously measured following extraluminal application of bFGF in rats. The involvement of NO and adenosine triphosphate-sensitive potassium (K ATP ) channels in bFGF-induced vasodilation and membrane hyperpolarization was evaluated using specific inhibitors, N G -monomethyl-L-arginine (L-NMMA, 10 -4 M) and glibenclamide (GB, 10 -5 M), respectively. The resting MP was recorded at a mean value of -31.9 ± 4.5 mV. bFGF (1 to 1000 ng/ml) produced significant vasodilation and hyperpolarization. Treatment with L-NMMA caused vasoconstriction and significantly attenuated bFGF-induced vasodilation without affecting membrane hyperpolarization. In the presence of GB, the membrane potential was significantly depolarized but the vessel diameter was only marginally reduced, so bFGF-induced membrane hyperpolarization was inhibited while arteriolar dilation was attenuated. These results suggest that bFGF-induced vasodilation is mediated by a mechanism involving both NO and membrane hyperpolarization, and that membrane hyperpolarization is caused by the activation of K ATP channels.

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Basic Fibroblast Growth Factor Increases Regional Cerebral Blood Flow and Reduces Infarct Size After Experimental Ischemia in a Rat Model

Abstract: The present study suggested that intracarotid administration of bFGF (100 ng) can reduce infarct size after MCA occlusion. It was speculated that the increased CBF in the penumbral areas of MCA may contribute to contraction of infarct size.

Cited by 66 publications

References 27 publications

A Novel Endothelin Antagonist, A-127722, Attenuates Ischemic Lesion Size in Rats With Temporary Middle Cerebral Artery Occlusion

A Novel Endothelin Antagonist, A-127722, Attenuates Ischemic Lesion Size in Rats With Temporary Middle Cerebral Artery Occlusion

Neuroprotective Effect of Granulocyte Colony–Stimulating Factor After Focal Cerebral Ischemia

Vasodilatory Effect of Basic Fibroblast Growth Factor in Isolated Rat Cerebral Arterioles: Mechanisms Involving Nitric Oxide and Membrane Hyperpolarization.

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