Increased cortical nuclear factor-κB (NF-κB) DNA binding activity after traumatic brain injury in rats

Yang, Kuo-Hsin; Mu, X. S.; Hayes, Ronald L.

doi:10.1016/0304-3940(95)11919-n

Cited by 78 publications

(58 citation statements)

References 18 publications

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“…The NF-kB pathway plays an important role in the immune system and is generally thought to exacerbate brain damage in ischaemic stroke. In mouse cerebral cortex, the NF-kB inhibitory protein IkBa was induced by OEA treatment ( Figure 4b) and thus would be expected to restrict activity in the NF-kB pathway, inhibition of which has been demonstrated to reduce brain damage in several ischaemic stroke models (Salminen et al, 1995;Yang et al, 1995;Schneider et al, 1999). Consistent with these findings, expression of the NF-kB-regulated COX-2 gene was found to be reduced by OEA treatment.…”

Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidssupporting

confidence: 66%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

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Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidssupporting

confidence: 66%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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“…This is in line with many reports indicating enhanced NF-kB nuclear translocation and DNA binding activity in brain tissue after cerebral ischemia 24 or brain trauma. 25 Since these findings strongly suggested that neuronal death after acute brain injury was associated with enhanced NF-kB activation, a role for NF-kB in neuronal cell death was postulated. 26, 27 We now demonstrate that an increase in NF-kB p65 DNA binding activity does not necessarily correlate with NF-kB transcriptional activity.…”

Section: 12mentioning

confidence: 99%

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity

Plesnila¹,

Baumgarten²,

Retiounskaia³

et al. 2007

Cell Death Differ

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Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53-and NF-jB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-jB transcriptional activity simultaneously declined. Post-traumatic neurodegeneration correlated with the increase in p53 levels and was significantly reduced by the selective p53 inhibitor pifithrin-a (PFT). Strikingly, this protective effect was observed even when PFT treatment was delayed up to 6 h after trauma. Inhibition of p53 activity resulted in the concomitant increase in NF-jB transcriptional activity and upregulation of NF-jB-target proteins, for example X-chromosomal-linked inhibitor of apoptosis (XIAP). It is interesting to note that inhibition of XIAP abolished the neuroprotective effects of PFT in cultured neurons exposed to camptothecin, glutamate, or oxygen glucose deprivation. In conclusion, delayed neuronal cell death after brain trauma is mediated by p53-dependent mechanisms that involve inhibition of NF-jB transcriptional activity. Hence, p53 inhibition provides a promising approach for the treatment of acute brain injury, since it blocks apoptotic pathways and concomitantly triggers survival signaling with a therapeutic window relevant for clinical applications.

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“…25 Increased NF-kB activity may also be associated with Ataxia Teleangectasia. 26 Moreover, NF-kB activity is induced in animal models of neurodegeneration like ischaemia, 27 head trauma, 28 Huntington's disease, 29 and experimental allergic encephalitis. 20 Numerous in vitro studies have demonstrated that diverse neurotoxic and pro-apoptotic stimuli like high concentrations of glutamate, 30 b amyloid, 31 cytokines, 32,33 glycated tau, 34 H 2 O 2 , 35 and glucose deprivation, 36 are potent activators of NF-kB in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

1999

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Apoptosis is now recognized as an important component in many progressive and acute neurodegenerative diseases. Extracellular signals and intracellular mechanisms triggering and regulating apoptosis in neuronal cells are still a matter of investigation. Here we review data from our and other laboratories with the aim to elucidate the nature of some proteins which are known to be involved in cell cycle regulation as well as in promoting degeneration and apoptosis of neurons. The following molecules will be taken into consideration: NF-kB, p53, p21 and MSH2. These proteins are activated by neurotoxic experimental conditions which involve the stimulation of selective receptors for the excitatory aminoacid glutamate. Thus, we hypothesize their contribution to an intracellular pathway responsible for the glutamateinduced neuronal death. Identification of such mechanisms could be relevant for understanding the apoptosis associated with various neurodegenerative diseases as well as for developing novel strategies of pharmacological intervention.

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Increased cortical nuclear factor-κB (NF-κB) DNA binding activity after traumatic brain injury in rats

Cited by 78 publications

References 18 publications

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity

Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathway

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