Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia (original) (raw)
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Experimental Neurobiology, 2015
Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor β (TGF-β) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuro pathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippo campus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treat ment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treat ment resulted in the decrease of the IκB-α degradation and increase of the phosphorylation level of RelA/p65. These results indi cate that GDF15 has a potential link to NF-κB activation, making GDF15 a valuable target for modulating inflammatory conditions.
Protective Effects of Glial Cell Line-Derived Neurotrophic Factor in Ischemic Brain Injury
Annals of The New York Academy of Sciences, 2002
A BSTRACT : Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor- (TGF- ) superfamily, has been shown to have trophic activity on dopaminergic neurons. Recent studies indicate that GDNF can protect the cerebral hemispheres from damage induced by middle cerebral arterial ligation. We found that such neuroprotective effects are mediated through specific GDNF receptor alpha-1 (GFR ␣ 1). Animals with a deficiency in GFR ␣ -1 have less GDNF-induced neuroprotection. Ischemia also enhances nitric oxide synthase (NOS) activity, which can be attenuated by GDNF. These.data suggest that GDNF can protect against ischemic injury through a GFR ␣ -1/NOS mechanism. We also found that the receptor for GDNF, GFR ␣ 1, and its signaling moiety c-Ret were upregulated, starting immediately after ischemia. This upregulation suggests that activation of an endogenous neuroprotective mechanism occurs so that responsiveness of GDNF can be enhanced at very early stages during ischemia.
AbstractöGene expression for glial cell line-derived neurotrophic factor (GDNF) family ligands and receptors was analyzed with in situ hybridization after two focal ischemic insults of di¡erent severities. Focal ischemia was induced in rats by either 30 min or 2 h of middle cerebral artery occlusion (MCAO), causing damage to the striatum only, or involving also the parietal cortex, respectively. We found modest, transient elevation of GDNF mRNA in the dentate granule cell layer. In addition, the number of GDNF mRNA-expressing cells increased in the cortex and striatum after 2 h or 30 min of MCAO, respectively. No changes of neurturin or persephin mRNA expression were detected. Both c-Ret and GFRK1 mRNA levels were markedly increased in the ipsilateral cortex outside the ischemic lesion at 6^24 h after the 2-h insult, whereas GFRK2 expression was decreased in cortical areas both within and outside the lesion. Similar increases of c-Ret and GFRK1 mRNA levels were detected in the striatum, and to a lesser extent, in the cortex following 30 min of MCAO. The 2-h insult also gave rise to transient increases of c-Ret and GFRK1 mRNA in hippocampal subregions. Thirty minutes and 2 h of MCAO lead to elevated c-Ret, and GFRK1 or GFRK2 mRNA expression, respectively, in the ipsilateral ventroposterolateral thalamic nucleus. Both insults induced increased levels of GFRK1 mRNA in the subventricular zone of the lateral ventricle.
Molecular Brain Research, 1996
Although transforming growth factor-[~ is known to be multifunctional in many physiological systems, its role in the brain is undergoing elucidation. The situation is made more complex by the presence of multiple isoforms, which may be differentially regulated and have various activities in each particular cell type. Because neurons are dependent on neurotrophic factors for survival, we utilized a rat model of transient forebrain ischemia (TFI) to test the hypothesis that TGF-[3 isoforms are important in the hippocampal response to injury. Northern blot analysis demonstrated a differential and temporal alteration in TGF-[3 isoform expression following TFI. In-situ hybridization experiments revealed that at day 1 following TFI, there was a strong neuronal increase in the TGF[3-1 transcript but a reciprocal decrease in TGF-[32 and -[33 transcript levels. Immunohistochemical analysis of all three TGF-[3s demonstrated at day 1 following TFI a loss of the immunoreactive proteins in the vulnerable CA-1 hippocampal neurons, but protein preservation in the CA-2-4 neurons which are more resistant to the ischemic insult. At 3-5 days following TFI, significant extraneuronal changes in TGF-[3 isoform expression were also detected. Double-staining experiments with antibody to glial fibrillary acidic protein (GFAP) as a marker for astrocytes, and lectin isolectin B4 Griffonia simplicifolia for microglia, demonstrated increased expression of all TGF-[3 isoforms in astrocytes but not microglia. Taken together, these results suggest that the TGF-[3 peptides in neurons and astrocytes are important endogenous mediators in the CNS response to ischemic injury.
Molecular Brain Research, 1996
Basic fibroblast growth factor (bFGF) is a polypeptide with potent trophic effects on brain neurons, glia, and endothelial cells. In the current study, we used Northern blotting, in situ hybridization, and immunohistochemical techniques to examine bFGF expression in brain following local infarction due to permanent occlusion of the proximal middle cerebral artery in mature Sprague-Dawley rats. We found a four-fold increase in bFGF mRNA in tissue surrounding focal infarcts at 1 day after ischemia. In situ hybridization showed that this increase was found throughout several structures in the ipsilateral hemisphere, including frontoparietal, temporal, and cingulate cortex, as well as in caudoputamen, globus pallidus, septal nuclei, nucleus accumbens, and olfactory tubercle. Increased bFGF mRNA expression was associated with cells having the distinct morphological appearance of astroglia in these structures. Immunohistochemistry showed an increase in the size and number of bFGF-immunoreactive (IR) nuclei in these same structures, as well as a shift from nuclear to nuclear plus cytoplasmic localization of immunoreactivity, beginning at 1 day, and peaking at 3 days after ischemia. Double immunostaining identified bFGF-IR cells as astroglia in these structures. (An exception was the piriform cortex, in which both increased bFGF mRNA levels and increased bFGF-IR was found in neurons at 1 day after ischemia.) Overall, the peak of increased bFGF expression preceded the peak in expression of the astroglial marker GFAP within the ipsilateral hemisphere. Increased bFGF expression may play an important role in the glial, neuronal, and vascular changes occurring after focal infarction.
Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia
Molecular Brain Research, 1997
. Basic fibroblast growth factor bFGF is a biologically active polypeptide with mitogenic, angiogenic, and neurotrophic properties. In the present study, we examined the temporal and spatial expression profiles of bFGF mRNA and protein concentration in a focal cerebral Ž . Ž . ischemia model induced by transient occlusion of the right middle cerebral artery MCA and both common carotid arteries CCAs .
Molecular Brain Research, 2001
Chronic bilateral common carotid artery occlusion (BCCAO) induces moderate ischemia (oligemia) in the rat forebrain in the absence of overt neuronal damage. In situ hybridization for brain-derived neurotrophic factor (BDNF) mRNA was used to search for a molecular response to moderate ischemia. BDNF mRNA was significantly increased in the hippocampal granule cells at 6 h of occlusion (ANOVA, Tukey test P,0.05). At 1, 7 and 14 days BDNF mRNA levels returned to control levels. The frequency of BDNF gene expression at 6 h was 83%, which was significantly higher than the 7% incidence of histological injury in the hippocampus (Fisher's exact test, P,0.002). Cerebral blood flow was reduced to 75% of control levels in the hippocampus after 1 week of BCCAO when measured with the autoradiographic method. Measurements of tissue flow with a microprobe for laser Doppler flow excluded decreases into the ischemic range during the period when elevated gene expression was observed. Prolonged moderate ischemia (oligemia) is a sufficient stimulus for BDNF gene expression in the hippocampus. These molecular studies provide direct evidence for an involvement of the hippocampus in the BCCAO model.
Experimental Neurology, 2004
FGF-2, a potent multifunctional and neurotrophic growth factor, is widely expressed in the brain and upregulated in cerebral ischemia. Previous studies have shown that intraventricularly or systemically administered FGF-2 reduces the size of cerebral infarcts. Whether endogenous FGF-2 is beneficial for the outcome of cerebral ischemia has not been investigated. We have used mice with a null mutation of the fgf2 gene to explore the relevance of endogenous FGF-2 in brain ischemia. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCAO). We found a 75% increase in infarct volume in fgf2 knock-out mice versus wild type littermates (P < 0.05). This difference in the extent of ischemic damage was observed after 24 h, and correlated with decreased viability in fgf2 mutant mice following MCA occlusion. Increased infarct volume in fgf2 null mice was associated with a loss of induction in hippocampal BDNF and trkB mRNA expression. These findings indicate that signaling through trkB may contribute to ameliorating brain damage following ischemia and that bdnf and trkB may be target genes of FGF-2. Together, our data provide the first evidence that endogenous FGF-2 is important in coping with ischemic brain damage suggesting fgf2 as one crucial target gene for new therapeutic strategies in brain ischemia.
Induction of transforming growth factor beta receptors following focal ischemia in the rat brain
PloS one, 2014
Transforming growth factor-βs (TGF-βs) regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI) and II receptors (TGF-βRII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII). TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were indu...
J Cerebr Blood Flow Metabol, 2001
Growth factors promote cell growth and survival and protect the brain from developing injury after ischemia. In this article, the authors examined whether transforming growth factor-␣ (TGF-␣) was protective in transient focal ischemia and whether alteration of cerebral circulation was involved. Rats received intraventricular TGF-␣ (50 ng, either split into 2 doses given 30 minutes before and 30 minutes after middle cerebral artery occlusion (MCAO), or 1 dose given 30 minutes after MCAO) or vehicle. Rats were subjected to 1-hour intraluminal MCAO and cerebral blood flow was recorded continuously by laser-Doppler flowmetry. Infarct volume was measured 1 and 4 days later. The effects of TGF-␣ on arterial tone were assessed in isolated rabbit basilar and common carotid arteries. Transforming growth factor-␣ before and after ischemia re-duced infarct volume by 70% at 1 day and 50% at 4 days. Transforming growth factor-␣ given only after ischemia also did reduce infarct volume by 70% at 1 day and 80% at 4 days. The protective effect was more marked in cortex than in striatum. Transforming growth factor-␣ did not change cortical microvascular perfusion and did not modify arterial passive tone nor agonist-induced active tone. It can be concluded that TGF-␣ reduces infarct volume, even when the factor is exclusively administered at reperfusion, and that this effect is not mediated by changes in microvascular perfusion or cerebral arteries. It is therefore suggested that TGF-␣ has a protective effect against neuronal cell death after transient focal ischemia.