Effects of hepatocyte growth factor on phosphorylation of extracellular signal-regulated kinase and hippocampal cell death in rats with transient forebrain ischemia

Niimura, Makiko; Takagi, Norio; Takagi, Keiko; Funakoshi, Hiroshi; Nakamura, Toshikazu; Takeo, Satoshi

doi:10.1016/j.ejphar.2006.01.037

Cited by 24 publications

(19 citation statements)

References 34 publications

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“…Several downstream signaling proteins activated by growth factor receptors, such as Akt, calcium/calmodulin-dependent protein kinase II (CaMKII), p44/42 mitogen activated protein kinase (MAPK), and glycogen synthase kinase-3β (GSK-3β), are crucial regulators of dendritic growth and development [12][13][14][15][16]. Recently Akt has been implicated in signaling downstream of c-Met [17,18].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway

Lim

Walikonis

2008

Cellular Signalling

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During central nervous system development, growth factors and their associated receptor protein tyrosine kinases regulate many neuronal functions such as neurite extension and dendrite maturation. Hepatocyte growth factor (HGF) and its receptor, c-Met, can promote formation of neurites and enhance elaboration of dendrites in mature neurons, but their effects on the early stages of dendrite maturation in hippocampal neurons and the signaling pathways by which they promote dendrite formation have not been studied. Exogenous HGF treatment effectively enhanced the phosphorylation and activation of c-Met in cultured hippocampal neurons at 4 days in vitro. HGF treatment increased the number of dendrites and promoted dendrite elongation in these neurons. Consistent with these results, HGF activated Akt, which phosphorylates glycogen synthase kinase-3β (GSK-3β) to inactivate it, and reduced phosphorylation of microtubule-associated protein 2 (MAP2), which can promote microtubule polymerization and dendrite elongation when dephosphorylated. Conversely, pharmacological inhibition of c-Met with its specific inhibitor, PHA-665752, or genetic knock-down of c-Met with short hairpin RNAs (shRNAs) suppressed HGFinduced phosphorylation of Akt and GSK-3β, increased phosphorylation of MAP2, and reduced dendrite number and length in cultured hippocampal neurons. Moreover, suppressing c-Met with PHA-665752 or by shRNA decreased MAP2 expression. Inhibiting Akt activity with the phosphoinositide-3-kinase inhibitor LY294002 or Akt inhibitor X suppressed HGF-induced phosphorylation of GSK-3β, increased MAP2 phosphorylation, and blocked the ability of HGF to enhance dendritic length. These observations indicate that HGF and c-Met can regulate the early stages of dendrite maturation via activation of the Akt/GSK-3β pathway.

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Section: Introductionmentioning

confidence: 99%

Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway

Lim

Walikonis

2008

Cellular Signalling

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“…hHGF, also known as scatter factor, has been isolated and purified from rat platelets [33]. However, in many investigations, hHGF decreased brain I/R injury via an ERK-dependent pathway, reduced heart I/R injury via the regulation of cell apoptosis and alleviated kidney I/R injury via the inhibition of apoptotic cell death [5-7]. In this study, we found that in rats, both hHGF and hHGF/PEG-b-P(ELG-g-PLL) protected the brain and kidney against I/R injury by decreasing oxidative stress damage and protected the heart against I/R injury by reducing CK and LDH release.…”

Section: Discussionmentioning

confidence: 99%

“…Recent research has shown that hHGF can attenuate brain, heart and kidney ischemia/reperfusion (I/R) injury [5-7]. However, the half-life of hHGF is very short, and hHGF that enters the body is metabolized and rapidly cleared from tissues [8].…”

Section: Introductionmentioning

confidence: 99%

Poly (Ethylene Glycol)-<b><i>Block</i></b>-Brush Poly (L-Lysine) Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy

Tong¹,

Zhang²

2017

Kidney Blood Press Res

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Background/Aims: The aim of this study was to assess the effect of human hepatocyte growth factor (hHGF)-loaded poly (ethylene glycol)-b-brush poly (l-lysine) (PEG-b-P(ELG-g-PLL)) copolymer on ischemia/reperfusion (I/R) injury to different organs. Methods: The isoelectric point (pI) of hHGF is 5.5, and hHGF combined with PEG-b-P(ELG-g-PLL) copolymer via electrostatic interactions at pH 7.4. The synthesized PEG-b-P(ELG-g-PLL) copolymer was analyzed using ¹H nuclear magnetic resonance (¹H NMR) and gel permeation chromatography (GPC). The hHGF/PEG-b-P(ELG-g-PLL) complex was evaluated using a nanoparticle size instrument and transmission electron microscopy (TEM). In addition, vivo performance of hHGF/PEG-b-P(ELG-g-PLL) complex was evaluated using plasma hHGF concentration and different organs ischemia reperfusion injury in rats. Results: An in vitro investigation showed that PEG-b-P(ELG-g-PLL) could serve as a potential hHGF nanocarrier with efficient encapsulation and sustained release. An additional in vivo investigation revealed that the hHGF/PEG-b-P(ELG-g-PLL) complex could prolong increases in plasma hHGF concentration and protect different organs (the brain, heart and kidney) against I/R injury. Conclusion: Poly (ethylene glycol)-block-brush poly (l-lysine) copolymer as an efficient nanocarrier for human hepatocyte growth factor with enhanced bioavailability and anti-ischemia reperfusion injury efficacy.

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“…In terms of the dose of HGF, 5.0, 10.0 and 30.0 lg were checked in our preliminary experiment (Miyazawa et al, 1998;Niimura et al, 2006), and the effect of 30.0 lg in 9 ll of vehicle was the best. The dose of GDNF was chosen based on our previous report (Abe et al, 1997).…”

Section: Hgf or Gdnf Treatment In Vivomentioning

confidence: 99%

Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion

Shang

Deguchi

Ohta

et al. 2010

J of Neuroscience Research

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Hepatocyte growth factor (HGF) and glial cell line-derived neurotrophic factor (GDNF) are strong neurotrophic factors. However, their potentials in neurogenesis, angiogenesis, synaptogenesis, and antifibrosis have not been compared. Therefore, we investigated these effects of HGF and GDNF in cerebral ischemia in the rat. Wistar rats were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO). Immediately after reperfusion, HGF or GDNF was given by topical application. BrdU was injected intraperitoneally twice daily 1, 2, and 3 days after tMCAO. On 14 day, we histologically evaluated infarct volume, antiapoptotic effect, neurogenesis, angiogenesis, synaptogenesis, and antifibrosis. Both HGF and GDNF significantly reduced infarct size and the number of TUNEL-positive cells, but only HGF significantly increased the number of BrdU-positive cells in the subventricular zone, and 5'-bromo-2'-deoxyuridine -positive cells differentiated into mature neurons on the ischemic side. Enhancement of angiogenesis and synaptogenesis at the ischemic boundary zone was also observed only in HGF-treated rats. HGF significantly decreased the glial scar formation and scar thickness of the brain pia mater after tMCAO, but GDNF did not. Our study shows that both HGF and GDNF had significant neurotrophic effects, but only HGF can promote the neurogenesis, angiogenesis, and synaptogenesis and inhibit fibrotic change in brains after tMCAO.

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Effects of hepatocyte growth factor on phosphorylation of extracellular signal-regulated kinase and hippocampal cell death in rats with transient forebrain ischemia

Cited by 24 publications

References 34 publications

Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway

Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway

Poly (Ethylene Glycol)-<b><i>Block</i></b>-Brush Poly (L-Lysine) Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy

Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion

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