Publications by authors named "Martin B Gill"

19 Publications

  • Page 1 of 1

NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease.

Brain 2021 Jun 12. Epub 2021 Jun 12.

Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121 USA.

NPT520-34 is a clinical-stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein (ASYN) clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human ASYN and in an acute lipopolysaccharide (LPS)-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-ASYN (Line 61) transgenic mice for one or three months resulted in reduced ASYN pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In an LPS-challenge model using wild-type mice, a single-dose of NPT520-34 reduced LPS-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology endpoints, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further suggest that NPT520-34 may have two complementary actions: (1) to increase the clearance of neurotoxic protein aggregates and (2) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awab214DOI Listing
June 2021

Structure based design and synthesis of novel Toll-like Receptor 2 (TLR 2) lipid antagonists.

Bioorg Med Chem Lett 2021 05 23;40:127861. Epub 2021 Feb 23.

Neuropore Therapies Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA. Electronic address:

Toll-like receptors (TLRs) play key role in innate immune response to Damage Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs). DAMP/PAMP-mediated activation of TLRs triggers NFκB signaling resulting in pro-inflammatory cytokine release. Using TLR2-Pam2CSK4 agonist co-crystal structure information, we designed and synthesized a novel series of Toll-like Receptor 2 (TLR2) lipid antagonists and identified compounds 14, 15 and 17 with sub-micromolar potency. TLR2 antagonists that we identified are stable for > 1.0 h in both gastric juice and PBS buffer and could be used as research tools.
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http://dx.doi.org/10.1016/j.bmcl.2021.127861DOI Listing
May 2021

The structure of human tau-tubulin kinase 1 both in the apo form and in complex with an inhibitor.

Acta Crystallogr F Struct Biol Commun 2014 Feb 21;70(Pt 2):173-81. Epub 2014 Jan 21.

Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.

Tau-tubulin kinase 1 (TTBK1) is a dual-specificity (serine/threonine and tyrosine) kinase belonging to the casein kinase 1 superfamily. TTBK1 is a neuron-specific kinase that regulates tau phosphorylation. Hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease. Two kinase-domain constructs of TTBK1 were expressed in a baculovirus-infected insect-cell system and purified. The purified TTBK1 kinase-domain proteins were crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data were collected and the structure of TTBK1 was determined by molecular replacement both as an apo structure and in complex with a kinase inhibitor.
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http://dx.doi.org/10.1107/S2053230X14000144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936456PMC
February 2014

AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform.

Eur J Neurosci 2012 Jan 30;35(2):182-94. Epub 2011 Dec 30.

Neuroscience Discovery Research and Clinical Investigation, Eli Lilly and Company, Indianapolis, IN 46285, USA.

Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon-2 (CNIH-2), another AMPA receptor-associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH-2 differentially impacts Type-Ia (γ-2 or γ-3) vs. Type-Ib (γ-4 or γ-8) TARP-containing AMPA receptors. Specifically, with AMPA receptors comprising γ-2, the cerebellar-enriched TARP isoform, CNIH-2 decreases I(KA) /I(Glu) ratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics. By contrast, with AMPA receptors comprising γ-8, the hippocampal-enriched TARP isoform, we find that CNIH-2 slows deactivation kinetics, increases cyclothiazide potency and occludes a novel AMPA receptor kinetic phenomenon, namely resensitization. Additionally, we find that CNIH-2 differentially modulates the glutamate off-kinetics of γ-8-containing, but not γ-2-containing, AMPA receptors in a manner dependent upon the duration of agonist application. Together, these data demonstrate that the modulation of AMPA receptors by CNIH-2 depends upon the TARP isoform composition within the receptor complex.
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http://dx.doi.org/10.1111/j.1460-9568.2011.07948.xDOI Listing
January 2012

Isolation, amino acid sequence and biological activities of novel long-chain polyamine-associated peptide toxins from the sponge Axinyssa aculeata.

Chembiochem 2011 Sep 9;12(14):2191-200. Epub 2011 Aug 9.

Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan.

A novel family of functionalized peptide toxins, aculeines (ACUs), was isolated from the marine sponge Axinyssa aculeate. ACUs are polypeptides with N-terminal residues that are modified by the addition of long-chain polyamines (LCPA). Aculeines were present in the sponge extract as a complex mixture with differing polyamine chain lengths and peptide structures. ACU-A and B, which were purified in this study, share a common polypeptide chain but differ in their N-terminal residue modifications. The amino acid sequence of the polypeptide portion of ACU-A and B was deduced from 3' and 5' RACE, and supported by Edman degradation and mass spectral analysis of peptide fragments. ACU induced convulsions upon intracerebroventricular (i.c.v.) injection in mice, and disrupted neuronal membrane integrity in electrophysiological assays. ACU also lysed erythrocytes with a potency that differed between animal species. Here we describe the isolation, amino acid sequence, and biological activity of this new group of cytotoxic sponge peptides.
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http://dx.doi.org/10.1002/cbic.201100329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533443PMC
September 2011

Cornichon-2 modulates AMPA receptor-transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology.

J Neurosci 2011 May;31(18):6928-38

Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

Neuronal AMPA receptor complexes comprise a tetramer of GluA pore-forming subunits as well as accessory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon-2/3 (CNIH-2/3). The mechanisms that control AMPA receptor complex assembly remain unclear. AMPA receptor responses in neurons differ from those in cell lines transfected with GluA plus TARPs γ-8 or γ-7, which show unusual resensitization kinetics and non-native AMPA receptor pharmacologies. Using tandem GluA/TARP constructs to constrain stoichiometry, we show here that these peculiar kinetic and pharmacological signatures occur in channels with four TARP subunits per complex. Reducing the number of TARPs per complex produces AMPA receptors with neuron-like kinetics and pharmacologies, suggesting a neuronal mechanism controls GluA/TARP assembly. Importantly, we find that coexpression of CNIH-2 with GluA/TARP complexes reduces TARP stoichiometry within AMPA receptors. In both rat and mouse hippocampal neurons, CNIH-2 also associates with AMPA receptors on the neuronal surface in a γ-8-dependent manner to dictate receptor pharmacology. In the cerebellum, however, CNIH-2 expressed in Purkinje neurons does not reach the neuronal surface. In concordance, stargazer Purkinje neurons, which express CNIH-2 and γ-7, display AMPA receptor kinetics/pharmacologies that can only be recapitulated recombinantly by a low γ-7/GluA stoichiometry. Together, these data suggest that CNIH-2 modulates neuronal AMPA receptor auxiliary subunit assembly by regulating the number of TARPs within an AMPA receptor complex to modulate receptor gating and pharmacology.
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http://dx.doi.org/10.1523/JNEUROSCI.6271-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562416PMC
May 2011

Transmembrane AMPA receptor regulatory proteins and cornichon-2 allosterically regulate AMPA receptor antagonists and potentiators.

J Biol Chem 2011 Apr 22;286(15):13134-42. Epub 2011 Feb 22.

Discovery Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.

AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [(3)H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [(3)H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [(3)H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [(3)H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
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http://dx.doi.org/10.1074/jbc.M110.212522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075660PMC
April 2011

Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.

Neuron 2010 Dec;68(6):1082-96

Department of Neuroscience, Eli Lilly and Company, Indianapolis, IN 46285, USA.

Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7, and γ-8, but not γ-2, γ-3, or γ-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates γ-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, γ-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in γ-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic γ-8-containing AMPA receptors. Thus, γ-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.
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http://dx.doi.org/10.1016/j.neuron.2010.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034222PMC
December 2010

An emerging role for TARPs in neuropsychiatric disorders.

Neuropsychopharmacology 2011 Jan;36(1):362-3

Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, IN, USA.

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http://dx.doi.org/10.1038/npp.2010.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055496PMC
January 2011

Novel N-methylated 8-oxoisoguanines from Pacific sponges with diverse neuroactivities.

J Med Chem 2010 Aug;53(16):6089-99

Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan.

Marine organisms have yielded a variety of metabolites with neuropharmacological applications. Here we describe the isolation and pharmacological characterization of four novel, neurologically active purines 1-4, isolated from Haplosclerida sponges collected in the Republic of Palau. The structures were determined by analyses of spectral and X-ray data. Compound 1 induced convulsions upon intracerebroventricular injection into mice, with a CD50 value of 2.4 nmol/mouse. Purines 2-4 were active in mouse bioassays at higher doses. The seizurogenic activity of 1 was correlated with inhibition of neuronal GABAergic transmission, with only a modest impact on excitatory signaling, in electrophysiological recordings from hippocampal neurons. Despite having a purine template structure, the inhibitory activity of 1 was not prevented by a nonselective adenosine receptor antagonist. Thus, 1 represents a novel substituted purine that elicits convulsions through its actions on inhibitory neurotransmission. These 8-oxoisoguanine analogs comprise a new family of compounds closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants.
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http://dx.doi.org/10.1021/jm100490mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241477PMC
August 2010

Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues.

European J Org Chem 2009 Nov;2009(32):5531-5548

Graduate School of Nanobioscience, Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels-Alder reaction as a key step, promoted by the Hoveyda-Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene ["Ru"= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway.
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http://dx.doi.org/10.1002/ejoc.200900580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872180PMC
November 2009

Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs.

Bioorg Med Chem 2010 Jun 21;18(11):3795-804. Epub 2010 Apr 21.

Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan.

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a-6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps. In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization.
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http://dx.doi.org/10.1016/j.bmc.2010.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901232PMC
June 2010

TARPs differentially decorate AMPA receptors to specify neuropharmacology.

Trends Neurosci 2010 May 8;33(5):241-8. Epub 2010 Mar 8.

Department of Neuroscience, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510, USA.

Transmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel. Although initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent research demonstrated that it also regulates AMPA receptor kinetics and synaptic waveforms. Recent studies have identified a diverse collection of TARP isoforms--types Ia, Ib II--that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. These TARP isoforms are heterogeneously expressed in specific neuronal populations and can differentially sculpt synaptic transmission and plasticity. Whole-genome analyses also link multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorder. TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.tins.2010.02.004DOI Listing
May 2010

Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.

Hippocampus 2010 Sep;20(9):1072-82

Department of Psychiatry and Behavioral Sciences and The Asher Center for the Study and Treatment of Depressive Disorders, Chicago, Illinois, USA.

Activation of NMDA receptors (NMDAR) in the hippocampus is essential for the formation of contextual and trace memory. However, the role of individual NMDAR subunits in the molecular mechanisms contributing to these memory processes is not known. Here we demonstrate, using intrahippocampal injection of subunit-selective compounds, that the NR2A-preferring antagonist impaired contextual and trace fear conditioning as well as learning-induced increase of the nuclear protein c-Fos. The NR2B-specific antagonist, on the other hand, selectively blocked trace fear conditioning without affecting c-Fos levels. Studies with cultured primary hippocampal neurons, further showed that synaptic and extrasynaptic NR2A and NR2B differentially regulate the extracellular signal-regulated kinase 1 and 2/mitogen- and stress-activated protein kinase 1 (ERK1/2/MSK1)/c-Fos pathway. Activation of the synaptic population of NMDAR induced cytosolic, cytoskeletal, and perinuclear phosphorylation of ERK1/2 (pERK1/2). The nuclear propagation of pERK1/2 signals, revealed by upregulation of the downstream nuclear targets pMSK1 and c-Fos, was blocked by a preferential NR2A but not by a specific NR2B antagonist. Conversely, activation of total (synaptic and extrasynaptic) NMDAR engaged receptors with NR2B subunits, and resulted in membrane retention of pERK1/2 without inducing pMSK1 and c-Fos. Stimulation of extrasynaptic NMDAR alone was consistently ineffective at activating ERK signaling. The discrete contribution of synaptic and total NR2A- and NR2B-containing NMDAR to nuclear transmission vs. membrane retention of ERK signaling may underlie their specific roles in the formation of contextual and trace fear memory.
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http://dx.doi.org/10.1002/hipo.20705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891656PMC
September 2010

Regioselective Domino Metathesis of 7-Oxanorbornenes and Its Application to the Synthesis of Biologically Active Glutamate Analogues.

European J Org Chem 2008 Nov;2008(31):5215-5220

Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 981-8555, Japan, , E-mail:

A highly regioselective domino metathesis reaction of 7-oxanorbornene was developed that employed an intramolecular association of an amide carbonyl group to a ruthenium metal centre. By using this reaction, twelve glutamate analogues inspired by dysiherbaine were efficiently synthesized over 12-14 steps; one of the analogues exhibited bioactivity consistent with central nervous system depression.
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http://dx.doi.org/10.1002/ejoc.200800704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717718PMC
November 2008

Glutamate binding and conformational flexibility of ligand-binding domains are critical early determinants of efficient kainate receptor biogenesis.

J Biol Chem 2009 May 2;284(21):14503-12. Epub 2009 Apr 2.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

Intracellular glutamate binding within the endoplasmic reticulum (ER) is thought to be necessary for plasma membrane expression of ionotropic glutamate receptors. Here we determined the importance of glutamate binding to folding and assembly of soluble ligand-binding domains (LBDs), as well as full-length receptors, by comparing the secretion of a soluble GluR6-S1S2 protein versus the plasma membrane localization of GluR6 kainate receptors following mutagenesis of the LBD. The mutations were designed to either eliminate glutamate binding, thereby trapping the bilobate LBD in an "open" conformation, or "lock" the LBD in a closed conformation with an engineered interdomain disulfide bridge. Analysis of plasma membrane localization, medium secretion of soluble LBD proteins, and measures of folding efficiency suggested that loss of glutamate binding affinity significantly impacted subunit protein folding and assembly. In contrast, receptors with conformationally restricted LBDs also exhibited decreased PM expression and altered oligomeric receptor assembly but did not exhibit any deficits in subunit folding. Secretion of the closed LBD protein was enhanced compared with wild-type GluR6-S1S2. Our results suggest that glutamate acts as a chaperone molecule for appropriate folding of nascent receptors and that relaxation of LBDs from fully closed states during oligomerization represents a critical transition that necessarily engages other determinants within receptor dimers. Glutamate receptor LBDs therefore must access multiple conformations for efficient biogenesis.
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http://dx.doi.org/10.1074/jbc.M900510200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682899PMC
May 2009

Bax shuttling after rotenone treatment of neuronal primary cultures: effects on cell death phenotypes.

J Neurosci Res 2009 Jul;87(9):2047-65

Department of Neuroscience and Cell Biology, University of Texas-Medical Branch, Galveston, TX 77555-1072, USA.

Neonatal (P7) brain hypoxia-ischemia (HI) induces intracellular Bax protein shifts to the nucleus, mitochondria, and endoplasmic reticulum (ER), where it triggers the activation of the respective cell death signaling cascades. When compared with HI-treated rat pups, 100% O(2) resuscitation of HI-treated rat pups increases HI-induced ER Bax levels, ER-mediated cell death signaling, and resultant lesion volume and inflammation due to increased necrotic-like cell death. To better characterize the role of Bax intracellular shuttling ER cell death signaling and necrotic-like cell death, we used rotenone-treated P5 neuronal cortical cultures to increase ER Bax levels and subsequent cell death signaling. We treated P5 primary cortical neurons with 25 microM and 100 microM rotenone as an apoptotic or necrotic-like stimulus, respectively, and measured intracellular organelle Bax levels and the subsequent activation of ER/mitochondrial cell death signaling. The 25 microM rotenone treatment promptly increased nuclear Bax levels followed by a later increase in mitochondrial Bax levels and caspase-mediated cleavage of alpha-fodrin. The 100 microM rotenone treatment also resulted in an early increase in nuclear Bax levels followed by a subsequent increase in ER Bax levels and calpain-mediated cleavage of alpha-fodrin. After pretreatment with the immunosuppressive and neuroprotective FK506, there was a delay in Bax intracellular shifts and cell death signaling for both the 25 and 100 microM rotenone treatments. These results suggest that the different outcomes of apoptotic-like vs. necrotic-like cell death resulting from the treatment of neuronal cultures with rotenone at 25 and 100 microM rotenone reflect changes in the intracellular trafficking of Bax among different organelles.
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http://dx.doi.org/10.1002/jnr.22019DOI Listing
July 2009

Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects.

J Neurosci Res 2008 Dec;86(16):3584-604

Department of Neuroscience and Cell Biology, University of Texas-Medical Branch, Galveston, TX 77555-1072, USA.

Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O(2) resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O(2) (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1beta) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O(2) resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O(2) treatment for neonatal HI should be reevaluated.
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http://dx.doi.org/10.1002/jnr.21795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585158PMC
December 2008

Hypoxia ischemia-mediated cell death in neonatal rat brain.

Neurochem Res 2008 Dec 12;33(12):2379-89. Epub 2008 Apr 12.

Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1072, USA.

The examination of Bcl-2-associated X protein (Bax) protein's role in the activation of cognate nuclear, mitochondrial and ER cell death signaling cascades and the resulting effects on cell death phenotype in the brain after neonatal hypoxia-ischemia (HI) requires an understanding of neonatal HI insult and progression, as well as, its dysfunctional outcomes. In addition, knowledge of key concepts of oxidative stress, a major injurious component of HI, and the different cell death phenotypes (i.e. apoptosis and necrosis) will aid the design of appropriate useful experimental paradigms. Here we discuss organelle cell death signaling cascades in the context of the different cell death phenotypes associated with animal models of neonatal hypoxia ischemia and tissue culture models used in the study of hypoxia ischemia, focusing on the intracellular shifts of the Bcl-2 associated X protein (Bax) in the hypoxic brain.
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http://dx.doi.org/10.1007/s11064-008-9649-1DOI Listing
December 2008
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