Effects of selenium-containing compounds on Cu2+/Zn2+-induced neuronal cell death and potential application as therapeutic agents for neurological diseases

A central issue in developing therapies for neurodegenerative diseases involves understanding why adaptive responses to stress or injury fail to prevent synaptic dysfunction and neuronal cell death. Macroautophagy is a major, evolutionarily conserved response to nutrient and bioenergetic stresses, which has the capacity to remove aggregated proteins and damaged organelles such as mitochondria. This has prompted intense interest in autophagy-related therapies for Huntington’s, Alzheimer’s, Parkinson’s, stroke and other neurological diseases. However, excessive or imbalanced induction of autophagic recycling can actively contribute to neuronal atrophy, neurite degeneration and cell death. Oxidative-, aging- and disease-related increases in demand for autophagy, coupled with declining axonal trafficking, lysosomal degradation or biosynthetic efficiencies promote increased susceptibility to a harmful state of autophagic stress. A more complete understanding of dysfunction along the entire spectrum of autophagic recycling, from autophagosome formation through clearance and regeneration of new cellular components, is necessary to restore balance to the system, promote neuronal health and maximize therapeutic potentials.

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Targeting Bid to prevent programmed cell death in neurons

Biochemical Society Transactions ◽

10.1042/bst0341334 ◽

2006 ◽

Vol 34 (6) ◽

pp. 1334-1340 ◽

Cited By ~ 26

Author(s):

C. Culmsee ◽

N. Plesnila

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Tissue Loss ◽

Functional Deficits ◽

Central Nervous System Trauma ◽

Mitochondrial Membrane Permeabilization

Sustained progression of neuronal cell death causes brain tissue loss and subsequent functional deficits following stroke or central nervous system trauma and in neurodegenerative diseases. Despite obvious differences in the pathology of these neurological disorders, the underlying delayed neuronal demise is carried out by a common biochemical cell death programme. Mitochondrial membrane permeabilization and subsequent release of apoptotic factors are key mechanisms during this process. Bcl-2 family proteins, e.g. the pro-apoptotic Bid, Bax or Bad and the antiapoptotic Bcl-2, Bcl-XL, play a crucial role in the regulation of this mitochondrial checkpoint in neurons. In particular, cleavage of cytosolic Bid and subsequent mitochondrial translocation have been detected in many paradigms of neuronal cell death related to acute or chronic neurodegeneration. The current review focuses on the emerging role of Bid as an integrating key regulator of the intrinsic death pathway that amplifies caspase-dependent and caspase-independent execution of neuronal apoptosis. Therefore pharmacological inhibition of Bid provides a promising therapeutic strategy in neurological diseases where programmed cell death is prominent.

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Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43

Journal of Virology ◽

10.1128/jvi.01513-16 ◽

2016 ◽

Vol 91 (1) ◽

Cited By ~ 16

Author(s):

Mathieu Meessen-Pinard ◽

Alain Le Coupanec ◽

Marc Desforges ◽

Pierre J. Talbot

Keyword(s):

Cell Death ◽

Significant Role ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Pivotal Role ◽

Death Process ◽

Potential Implication ◽

Human Coronaviruses

ABSTRACT Human coronaviruses (HCoV) are respiratory pathogens with neuroinvasive, neurotropic, and neurovirulent properties, highlighting the importance of studying the potential implication of these viruses in neurological diseases. The OC43 strain (HCoV-OC43) was reported to induce neuronal cell death, which may participate in neuropathogenesis. Here, we show that HCoV-OC43 harboring two point mutations in the spike glycoprotein (rOC/Us183–241) was more neurovirulent than the wild-type HCoV-OC43 (rOC/ATCC) in mice and induced more cell death in murine and human neuronal cells. To evaluate the role of regulated cell death (RCD) in HCoV-OC43-mediated neural pathogenesis, we determined if knockdown of Bax, a key regulator of apoptosis, or RIP1, a key regulator of necroptosis, altered the percentage of neuronal cell death following HCoV-OC43 infection. We found that Bax-dependent apoptosis did not play a significant role in RCD following infection, as inhibition of Bax expression mediated by RNA interference did not confer cellular protection against the cell death process. On the other hand, we demonstrated that RIP1 and MLKL were involved in neuronal cell death, as RIP1 knockdown and chemical inhibition of MLKL significantly increased cell survival after infection. Taken together, these results indicate that RIP1 and MLKL contribute to necroptotic cell death after HCoV-OC43 infection to limit viral replication. However, this RCD could lead to neuronal loss in the mouse CNS and accentuate the neuroinflammation process, reflecting the severity of neuropathogenesis. IMPORTANCE Because they are naturally neuroinvasive and neurotropic, human coronaviruses are suspected to participate in the development of neurological diseases. Given that the strain OC43 is neurovirulent in mice and induces neuronal cell death, we explored the neuronal response to infection by characterizing the activation of RCD. Our results revealed that classical apoptosis associated with the Bax protein does not play a significant role in HCoV-OC43-induced neuronal cell death and that RIP1 and MLKL, two cellular proteins usually associated with necroptosis (an RCD back-up system when apoptosis is not adequately induced), both play a pivotal role in the process. As necroptosis disrupts cellular membranes and allows the release of damage-associated molecular patterns (DAMP) and possibly induces the production of proinflammatory cytokines, it may represent a proinflammatory cell death mechanism that contributes to excessive neuroinflammation and neurodegeneration and eventually to neurological disorders after a coronavirus infection.

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Mitochondrial pathways of neuronal cell death as therapeutic targets in neurological diseases

Pharmacological Reports ◽

10.1016/s1734-1140(11)70653-3 ◽

2011 ◽

Vol 63 (5) ◽

pp. 1271

Author(s):

Carsten Culmsee

Keyword(s):

Cell Death ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Therapeutic Targets ◽

Neuronal Cell

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MicroRNA-101 Regulates 6-Hydroxydopamine-Induced Cell Death by Targeting Suppressor/Enhancer Lin-12-Like in SH-SY5Y Cells

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.748026 ◽

2021 ◽

Vol 14 ◽

Author(s):

Tomohiro Omura ◽

Luna Nomura ◽

Ran Watanabe ◽

Hiroki Nishiguchi ◽

Kazuhiro Yamamoto ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Ubiquitin Ligase ◽

Untranslated Region ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

6 Hydroxydopamine ◽

Coa Reductase

Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson’s disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3′ untranslated region, and an miR-101 mimic suppressed the 6-OHDA–induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.

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A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms19082178 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2178 ◽

Cited By ~ 8

Author(s):

Jonathan Vinet ◽

Anna-Maria Costa ◽

Manuel Salinas-Navarro ◽

Giuseppina Leo ◽

Lieve Moons ◽

...

Keyword(s):

Cell Death ◽

Status Epilepticus ◽

Optic Nerve ◽

Neurological Diseases ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cell Loss ◽

Optic Nerve Crush ◽

Neuroprotective Effects ◽

Nerve Crush

Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.

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