BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

Nagy, Gábor; Szarka, András; Lotz, G.; Dóczi, Judit; Wunderlich, Lívius; Kiss, András; Jemnitz, Katalin; Veres, Zsuzsa; Bánhegyi, Gábor; Schaff, Zsuzsa; Sümegi, Balázs; Mandl, József

doi:10.1016/j.taap.2009.11.017

Cited by 63 publications

(70 citation statements)

References 25 publications

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“…In addition, our data implicate disruption of mitochondrial function as a pathological mechanism contributing to the death of neurons in FD and place FD alongside more prevalent neurodegenerative disorders characterized by mitochondrial dysfunction (34,47). BGP-15 has been shown to improve metabolic function in rodent models of several human degenerative diseases (18,22,23,(26)(27)(28) and has been given to more than 400 patients in human clinical trials with no severe adverse drug-related events (62). The data reported here suggest that this drug, or compounds like it, may be effective in slowing or preventing the progressive loss of neurons in FD patients.…”

Section: Discussionmentioning

confidence: 77%

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BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

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

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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Section: Discussionmentioning

confidence: 77%

“…BGP-15 is a hydroxylamine derivative that has been shown to exert cyto-and neuroprotective effects in mammalian models of injury, stress, and disease (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These improvements in cellular function have been correlated with the activation of several intracellular pathways.…”

mentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

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

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“…In a rat model of type II diabetes, BGP-15 increases mitochondrial area in muscle and improves insulin sensitivity (Henstridge et al, 2014), and in a model of acetaminophen-induced liver toxicity, BGP-15 induces phosphorylated eIF2α and restores mitochondrial depolarization . The observation that BGP-15 had no effect on mitochondrial replication in oocyte complexes from lean mice was not unexpected because this class of compounds has no discernible effects in the absence of cellular stress (Chung et al, 2008;Nagy et al, 2010;Crul et al, 2013). Our findings that BGP-15 (as well as the laboratory reagent salubrinal) is able to reverse mitochondrial dysfunction in oocytes clearly demonstrate that obesity-induced, and probably other, mitochondrial deficits in oocytes can be alleviated by using interventions before conception to improve embryo and fetal development.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

et al. 2015

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Over-nutrition in females causes altered fetal growth during pregnancy and permanently programs the metabolism of offspring; however, the temporal and mechanistic origins of these changes, and whether they are reversible, are unknown. We now show that, in obese female mice, cumulus-oocyte complexes exhibit endoplasmic reticulum (ER) stress, high levels of intracellular lipid, spindle abnormalities and reduced PTX3 extracellular matrix protein production. Ovulated oocytes from obese mice contain normal levels of mitochondrial (mt) DNA but have reduced mitochondrial membrane potential and high levels of autophagy compared with oocytes from lean mice. After in vitro fertilization, the oocytes of obese female mice demonstrate reduced developmental potential and form blastocysts with reduced levels of mtDNA. Blastocysts transferred to normal weight surrogates that were then analyzed at E14.5 showed that oocytes from obese mice gave rise to fetuses that were heavier than controls and had reduced liver and kidney mtDNA content per cell, indicating that maternal obesity before conception had altered the transmission of mitochondria to offspring. Treatment of the obese females with the ER stress inhibitor salubrinal or the chaperone inducer BGP-15 before ovulation increased the amount of the mitochondrial replication factors TFAM and DRP1, and mtDNA content in oocytes. Salubrinal and BGP-15 also completely restored oocyte quality, embryo development and the mtDNA content of fetal tissue to levels equivalent to those derived from lean mice. These results demonstrate that obesity before conception imparts a legacy of mitochondrial loss in offspring that is caused by ER stress and is reversible during the final stages of oocyte development and maturation.

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“…Chemicals and drugs usually activate extrinsic caspase pathway, leading to increase in caspase 3 and later caspase 8 activities, and to poly (adenosine diphosphate-ADP-ribose) polymerase (PARP) cleavage. It has been suggested that the mode of death for acetaminophen's liver toxicity is caspase-independent apoptosis, initiated by activation of PARP-1 [13][14][15]. The widely used antidepressant, sertraline was shown to cause to apoptosis and mitochondrial dysfunction in primary rat hepatocytes and human HepG2 cells [16].…”

Section: Apoptosismentioning

confidence: 99%

“…Excessive and prolonged ER stress finally leads to apoptosis or necrotic cell death [27]. However, ER stress may also occur after a cascade of events, such as GSH depletion and oxidative stress [28].…”

Section: Endoplasmic Reticulum (Er) Stressmentioning

confidence: 99%

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

Erkekoğlu¹

2015

MOJT

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Despite recent advances in drug development technologies, some drugs continue to be withdrawn from the market because of their late hepatotoxic effects. Drugs can cause liver toxicity through several molecular mechanisms, most of which need to be clarified by further research. Newly found drug-induced liver injury (DILI)-mechanisms like endoplasmic reticulum stress should also be considered while evaluating drug toxicity. New drugs launched in the market should be tested particularly for hepatotoxicity by using hepatic cell cultures and animal models continuously. Future research should target patients in the post-marketing phase in order to provide more evidence grounds to the clinical safety of potential drugs of high propensity of DILI. This review aims to draw the attention to the issue of cellular and molecular aspects of liver toxicity induced by drugs and address DILI as a potential clinical problem that needs further investigation.

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BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

Cited by 63 publications

References 25 publications

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

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