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Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

ABSTRACT: Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recently identified BH3-only protein Bcl-2-modifying factor (Bmf) normally interacts with the cytoskeleton, but upon certain cellular stresses, such as loss of extracellular matrix adhesion or energy crisis, Bmf relocalizes to mitochondria, where it can promote Bax activation and mitochondrial dysfunction. Although Bmf has been widely reported in the hematopoietic system to exert a proapoptotic effect, no studies have been undertaken in models of neurological disorders. To examine whether Bmf is important for seizure-induced neuronal death, we studied Bmf induction after prolonged seizures induced by intra-amygdala kainic acid (KA) in mice, and examined the effect of Bmf-deficiency on seizures and damage caused by SE. Seizures triggered an early (1-8?h) transcriptional activation and accumulation of Bax in the cell death-susceptible hippocampal CA3 subfield. Bmf mRNA was biphasically upregulated beginning at 1?h after SE and returning to normal by 8?h, while again being found elevated in the hippocampus of epileptic mice. Bmf upregulation was prevented by Compound C, an inhibitor of adenosine monophosphate-activated protein kinase, indicating Bmf expression may be induced in response to bioenergetic stress. Bmf-deficient mice showed normal sensitivity to the convulsant effects of KA, but, surprisingly, displayed significantly more neuronal death in the hippocampal CA1 and CA3 subfields after SE. These are the first studies investigating Bmf in a model of neurologic injury, and suggest that Bmf may protect neurons against seizure-induced neuronal death in vivo.

SUBMITTER: Moran C

PROVIDER: S-EPMC3668628 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

Moran C C Sanz-Rodriguez A A Jimenez-Pacheco A A Martinez-Villareal J J McKiernan R C RC Jimenez-Mateos E M EM Mooney C C Woods I I Prehn J H M JH Henshall D C DC Engel T T

Cell death & disease 20130425

Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recen ...[more]

PMID: 23618904

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Project description:AIMS:The abundance of beta 3-adrenergic receptors (?3-ARs) is upregulated in diseased human myocardium. We previously showed that cardiac-specific expression of ?3-AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in the anti-hypertrophic effect of ?3-AR. METHODS AND RESULTS:In vitro hypertrophic responses to phenylephrine (PE) were analysed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human ?3-AR (AdVh?3). We confirmed results in mice with cardiomyocyte-specific moderate expression of human ?3-AR (?3-TG) and wild-type (WT) littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. We observed a colocalization of ?3-AR with the AMP-activated protein kinase (AMPK) both in neonatal rat and in adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172-AMPK (/2, P = 0.0487) and phosphorylation of Ser79-acetyl-CoA carboxylase (ACC) (/2.6, P = 0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (×2.5, P = 0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice but restored to basal levels in ?3-AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti-hypertrophic effect of ?3-AR in response to PE in NRVM. Concomitant with hypertrophy, autophagy was decreased by PE, as measured by microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio (/2.6, P = 0.0010) and p62 abundance (×3, P = 0.0016) in NRVM or by TAC in WT mice (LC3-II/LC3-I ratio: /5.4, P = 0.0159), but preserved in human ?3-AR expressing cells and mice, together with reduced hypertrophy. CONCLUSIONS:Cardiac-specific moderate expression of ?3-AR inhibits the hypertrophic response in part through AMPK activation followed by inhibition of protein synthesis and preservation of autophagy. Activation of the cardiac ?3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling.

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Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

Publications

Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.

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