Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway

Ozawa, Hiroshi; Shioda, Seiji; Dohi, Kenji; Matsumoto, Hiroaki; Mizushima, Hidekatsu; Zhou, Chengji J.; Funahashi, Hiroomi; Nakai, Yasumitsu; Nakajo, Shigeo; Matsumoto, Kiyoshi

doi:10.1016/s0304-3940(99)00034-8

Cited by 100 publications

(60 citation statements)

References 18 publications

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“…Consistent with our findings, it has been reported that activation of JNK and/or p38 MAPK appeared in the heart or kidney exposed to I/R, and in cardiac myocytes subjected to H/R (27)(28)(29)(30)(31)(32)(33). It is highly likely that the pattern and time course of ERK, JNK, and p38 MAPK activation are tissue-specific (29,34,35).…”

Section: Discussionsupporting

confidence: 91%

PKCβ regulates ischemia/reperfusion injury in the lung

Fujita¹,

Asai²,

Andrassy³

et al. 2004

J. Clin. Invest.

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Activation of PKCβII is associated with the response to ischemia/reperfusion (I/R), though its role, either pathogenic or protective, has not been determined. In a murine model of single-lung I/R, evidence linking PKCβ to maladaptive responses is shown in the following studies. Homozygous PKCβ-null mice and WT mice fed the PKCβ inhibitor ruboxistaurin subjected to I/R displayed increased survival compared with controls. In PKCβ-null mice, phosphorylation of extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38 MAPK was suppressed in I/R. Expression of the immediate early gene, early growth response-1 (Egr-1), and its downstream target genes was significantly increased in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this expression was attenuated in PKCβ-null mice or WT mice fed ruboxistaurin. In vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by inhibition of PKCβ, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These findings elucidate key roles for PKCβII activation in I/R by coordinated activation of MAPKs (ERK1/2, JNK) and Egr-1.

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Section: Discussionsupporting

confidence: 91%

PKCβ regulates ischemia/reperfusion injury in the lung

Fujita¹,

Asai²,

Andrassy³

et al. 2004

J. Clin. Invest.

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“…Consistent with a neuroprotective role, GalR2 (unlike GalR1 or GalR3) is known to signal via G q/11 to activate phospholipase C and protein kinase C (33,34) and hence ERK (16). Previous studies have also shown that hippocampal neuroprotection is dependent in part upon activation of ERK (35,36) and ERK KO mice have increased susceptibility to EAE (37). Our data do not exclude the possibility that galanin might also exert immunomodulatory effects.…”

Section: Discussioncontrasting

confidence: 43%

A role for galanin in human and experimental inflammatory demyelination

Wraith¹,

Pope²,

Butzkueven

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The neuropeptide galanin is widely expressed by many differing subsets of neurons in the nervous system. There is a marked upregulation in the levels of the peptide in a variety of nerve injury models and in the basal forebrain of humans with Alzheimer's disease. Here we demonstrate that galanin expression is specifically and markedly upregulated in microglia both in multiple sclerosis (MS) lesions and shadow plaques. Galanin expression is also upregulated in the experimental autoimmune encephalomyelitis (EAE) model of MS, although solely in oligodendrocytes. To study whether the observed increase in expression of galanin in inflammatory demyelination might modulate disease activity, we applied the EAE model to a panel of galanin transgenic lines. Over-expression of galanin in transgenic mice (Gal-OE) abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or galanin receptor-2 (GalR2) increase disease severity. The pronounced effects of altered endogenous galanin or GalR2 expression on EAE disease activity may reflect a direct neuroprotective effect of the neuropeptide via activation of GalR2, similar to that previously described in a number of neuronal injury paradigms. Irrespective of the mechanism(s) by which galanin alters EAE disease activity, our findings imply that galanin/GalR2 agonists may have future therapeutic implications for MS.EAE ͉ GalR2 ͉ Glia ͉ multiple sclerosis T he neuropeptide galanin (1) is widely, but by no means ubiquitously, expressed in the adult brain (2-5), and following injury there is a dramatic increase in the levels of the peptide in many neuronal subpopulations (6-8) and in the basal forebrain of patients with Alzheimer's disease (9, 10). In addition to the neuronal expression of galanin, a small number of reports have shown that the neuropeptide is also expressed by oligodendrocyte or microglial cells following cortical spreading depression (11), transient forebrain ischaemia (12) or colchicine treatment (13,14). Of note, the adult Gal-OE mice used in this study have a marked increase in neuronal galanin expression that is predominantly in the terminal fields of the hippocampus (15). Before the current study there was no evidence that galanin was expressed in non-neuronal cells in these mice.We have previously shown that kainic acid-induced cell death in the CA1 and CA3 regions of the hippocampus is markedly reduced in Gal-OE mice compared to WT controls (15). Similarly, in vitro treatment with staurosporine or glutamate induced significantly less cell death in hippocampal cultures from Gal-OE animals than in WT controls (15). In contrast, Gal-KO mice demonstrated more hippocampal cell death following in vivo and in vitro neuronal damage than WT controls (15). Furthermore the addition of exogenous galanin peptide or the GalR2/3-specific agonist Gal2-11 reduced the amount of cell death when co-administered with either glutamate or staurosporine in WT primary hippocampal cultures (15). We have recently extended these findings by demonstrating that organo...

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“…It has been reported that Src could mediate cell death or cell survival by phosphorylating classical MAP kinase family members, that is, ERK1/2, JNK, and p38 kinase (36,37). These authors have also suggested that the activation of JNK and p38 kinase contributed to apoptosis, while ERK1/2 activation acted as a cell survival factor against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Big Mitogen-Activated Protein Kinase 1 Protects Cultured Rat Aortic Smooth Muscle Cells From Oxidative Damage

et al. 2011

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Abstract. Oxidative stress is considered a major mediator of arteriosclerosis. In vascular smooth muscle cells, oxidative stress-induced cell death (including apoptosis) is probably related to arterial calcification in arteriosclerosis. Big mitogen-activated protein kinase-1 / extracellular signalregulated kinase 5 (BMK1/ERK5) is a newly identified member of the mitogen-activated protein kinases family. Like Src tyrosine kinase, BMK1/ERK5 is known to be sensitive to oxidative stress; however, its pathophysiological significance is poorly understood. In this study, we investigated the involvement of BMK1 and Src in H 2 O 2 -induced cell death using cultured rat aortic smooth muscle cells (RASMCs). Cell apoptosis was evaluated by using the TdT-mediated dUTP nick end labeling (TUNEL) method, and BMK1 and Src activities were determined by Western blotting. The main results are as follows: 1) BMK1 and Src were activated by H 2 O 2 in a time-and concentration-dependent manner in RASMCs; 2) BMK1 activation by H 2 O 2 was attenuated both in Srcknockdown RASMCs and in RASMCs pretreated with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl) pyrazolo [3,4-d]pyrimidine (PP2), a Src family kinases inhibitor; and 3) H 2 O 2 -induced cell death was increased in BMK1-and Src-knockdown RASMCs as well as in PP2-treated RASMCs. These findings suggested that Src and BMK1 may play defensive and resistive roles against oxidative stress-induced death in RASMCs.

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Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen-activated protein kinase signal transduction pathway

Cited by 100 publications

References 18 publications

PKCβ regulates ischemia/reperfusion injury in the lung

PKCβ regulates ischemia/reperfusion injury in the lung

A role for galanin in human and experimental inflammatory demyelination

Big Mitogen-Activated Protein Kinase 1 Protects Cultured Rat Aortic Smooth Muscle Cells From Oxidative Damage

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