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Donald J. Degracia - One of the best experts on this subject based on the ideXlab platform.

  • texture analysis of poly adenylated mrna staining following Global Brain Ischemia and reperfusion
    Computer Methods and Programs in Biomedicine, 2012
    Co-Authors: Jeffrey J Szymanski, Jill T Jamison, Donald J. Degracia
    Abstract:

    Texture analysis provides a means to quantify complex changes in microscope images. We previously showed that cytoplasmic poly-adenylated mRNAs form mRNA granules in post-ischemic neurons and that these granules correlated with protein synthesis inhibition and hence cell death. Here we utilized the texture analysis software MaZda to quantify mRNA granules in photomicrographs of the pyramidal cell layer of rat hippocampal region CA3 around 1h of reperfusion after 10min of normothermic Global cerebral Ischemia. At 1h reperfusion, we observed variations in the texture of mRNA granules amongst samples that were readily quantified by texture analysis. Individual sample variation was consistent with the interpretation that animal-to-animal variations in mRNA granules reflected the time-course of mRNA granule formation. We also used texture analysis to quantify the effect of cycloheximide, given either before or after Brain Ischemia, on mRNA granules. If administered before Ischemia, cycloheximide inhibited mRNA granule formation, but if administered after Ischemia did not prevent mRNA granulation, indicating mRNA granule formation is dependent on dissociation of polysomes. We conclude that texture analysis is an effective means for quantifying the complex morphological changes induced in neurons by Brain Ischemia and reperfusion.

  • persistent redistribution of poly adenylated mrnas correlates with translation arrest and cell death following Global Brain Ischemia and reperfusion
    Neuroscience, 2008
    Co-Authors: Jill T Jamison, Monique Marshall, Foaz Kayali, Jennifer Rudolph, Scot R Kimball, Donald J. Degracia
    Abstract:

    Although persistent translation arrest correlates with the selective vulnerability of post-ischemic hippocampal cornu ammonis 1 (Ammon's horn) (CA1) neurons, the mechanism of persistent translation arrest is not fully understood. Using fluorescent in situ hybridization and immunofluorescence histochemistry, we studied colocalization of polyadenylated mRNAs [poly(A)] with the following mRNA binding factors: eukaryotic initiation factor (eIF) 4G (translation initiation factor), HuR (ARE-containing mRNA stabilizing protein), poly-adenylated mRNA binding protein (PABP), S6 (small ribosomal subunit marker), T cell internal antigen (TIA-1) (stress granule marker), and tristetraprolin (TTP) (processing body marker). We compared staining in vulnerable CA1 and resistant CA3 from 1 to 48 h reperfusion, following 10 min Global Ischemia in the rat. In both CA1 and CA3 neurons, cytoplasmic poly(A) mRNAs redistributed from a homogenous staining pattern seen in controls to granular structures we term mRNA granules. The mRNA granules abated after 16 h reperfusion in CA3, but persisted in CA1 neurons to 48 h reperfusion. Protein synthesis inhibition correlated precisely with the presence of the mRNA granules. In both CA1 and CA3, the mRNA granules colocalized with eIF4G and PABP, but not S6, TIA-1 or TTP, indicating that they were neither stress granules nor processing bodies. Colocalization of HuR in the mRNA granules correlated with translation of 70 kDa inducible heat shock protein, which occurred early in CA3 (8 h) and was delayed in CA1 (36 h). Thus, differential compartmentalization of mRNA away from the 40S subunit correlated with translation arrest in post-ischemic neurons, providing a concise mechanism of persistent translation arrest in post-ischemic CA1.

  • hippocampal cellular stress responses after Global Brain Ischemia and reperfusion
    Antioxidants & Redox Signaling, 2007
    Co-Authors: George Roberts, Mike J Di Loreto, Monique Marshall, Jie Wang, Donald J. Degracia
    Abstract:

    Brain Ischemia and reperfusion (I/R) induce neuronal intracellular stress responses, including the heat-shock response (HSR) and the unfolded protein response (UPR), but the roles of each in neuronal survival or death are not well understood. We assessed the relative expression of UPR (ATF4, CHOP, GRP78, XBP-1) and HSR-related (HSP70 and HSC70) mRNAs and proteins after Brain I/R. We evaluated these in hippocampal CA1 and CA3 after normothermic, transient Global foreBrain Ischemia and up to 42 h of reperfusion. In CA1, chop and xbp-1 mRNA showed maximal 14- and 12-fold increases, and the only protein increase observed was for 30-kDa XBP-1. CA3 showed induction of only xbp-1. GRP78 protein declined in CA1, but increased twofold and then declined in CA3. Transcription of hsp70 was an order of magnitude greater than that of any UPR-induced transcript in either CA1 or CA3. HSP70 translation in CA1 lagged CA3 by ∼24 h. We conclude that (a) in terms of functional end products, the ER stress response after Brain ...

  • dysfunction of the unfolded protein response during Global Brain Ischemia and reperfusion
    Journal of Cerebral Blood Flow and Metabolism, 2003
    Co-Authors: Rita Kumar, Gary S. Krause, Hiderou Yoshida, Kazutoshi Mori, Donald J. Degracia
    Abstract:

    A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane-bound proteins ATF6, IRE1alpha, and PERK. The authors simultaneously examined the activation of ATF6, IRE1alpha, and PERK, as well as components of downstream UPR pathways, in the rat Brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2alpha phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in Brain stem and hippocampus. PERK was degraded in vitro by mu-calpain. Although inactive IRE1alpha was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after Brain Ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.

  • Global Brain Ischemia and reperfusion modifications in eukaryotic initiation factors associated with inhibition of translation initiation
    Journal of Neurochemistry, 2002
    Co-Authors: Donald J. Degracia, Robert W. Neumar, Blaine C. White, Gary S. Krause
    Abstract:

    We used in vitro translation and antibodies against phosphoserine and the eukaryotic initiation factors elF-4E, elF-4G, and elF-2 alpha to examine the effects of Global Brain Ischemia and reperfusion on translation initiation and its regulation in a rat model of 10 min of cardiac arrest followed by resuscitation and 90 min of reperfusion. Translation reactions were performed on postmitochondrial supernatants from Brain homogenates with and without aurintricarboxylic acid to separate incorporation due to run-off from incorporation due to peptide synthesis initiated in vitro. The rate of leucine incorporation due to in vitro-initiated protein synthesis in normal foreBrain homogenates was approximately 0.4 fmol of leucine/min/microgram of protein and was unaffected by 10 min of cardiac arrest, but 90 min of reperfusion reduced this rate 83%. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blots of these homogenates showed that neither 10 min of Global Brain Ischemia nor 90 min of reperfusion induced significant alterations in the quantity or serine phosphorylation of elF-4E. However, we observed in all 90-min-reperfused samples elF-4G fragments that also bound elF-4E. The amount of elF-2 alpha was not altered by Ischemia or reperfusion, and immunoblotting after isoelectric focusing did not detect serine-phosphorylated elF-2 alpha in normal samples or in those obtained after Ischemia without reperfusion. However, serine-phosphorylated elF-2 alpha was uniformly present after 90 min of reperfusion and represented 24 +/- 3% of the elF-2 alpha in these samples. The serine phosphorylation of elF-2 alpha and partial fragmentation of elF-4G observed after 90 min of reperfusion offer an explanation for the inhibition of protein synthesis.

Gary Fiskum - One of the best experts on this subject based on the ideXlab platform.

  • early processing of bid and caspase 6 8 10 14 in the canine Brain during cardiac arrest and resuscitation
    Experimental Neurology, 2004
    Co-Authors: Maryla Krajewska, Jowita Mikolajczyk, Robert E Rosenthal, Thomas Wiesenthal, Henning R Stennicke, Mikihiko Naito, Guy S Salvesen, John C Reed, Gary Fiskum
    Abstract:

    Abstract A clinically relevant model of transient Global Brain Ischemia involving cardiac arrest followed by resuscitation in dogs was utilized to study the expression and proteolytic processing of apoptosis-regulatory proteins. In the hippocampus, an increase in pro-apoptotic Bcl-2 family proteins Bcl-XS and Bak was detected, concomitant with proteolysis of Bcl-XL and Bcl-2, following Ischemia–reperfusion injury. Also, biphasic cleavage of Bid was found in this region of the Brain, with early generation of tBid-p11 within 10 min of cardiac arrest, followed by generation of tBid-p15 within 30-min reperfusion, consistent with activation of this pro-apoptotic protein. In addition, cardiac arrest and resuscitation induced early, reperfusion-dependent proteolytic processing of pro-caspase-6, -8, -10, and -14, which preceded caspase-3 activation. Immunohistochemical analysis using antibodies, which preferentially recognize processed caspase-3, -6, -8, and -10, provided evidence of time-dependent activation of these proteases in both neurons and glia in Ischemia-sensitive regions of the Brain. In conclusion, extremely rapid, cell-selective processing of apoptosis-regulatory proteins occurs in a clinically relevant model of ischemic Brain injury caused by cardiac arrest and resuscitation. The early cleavage of Bid and rapid depletion of 32-kDa pro-caspase-14 from the canine hippocampus after induction of Ischemia suggests the involvement of calpains in the processing of these proteins. Demonstration of in vitro cleavage of recombinant mouse caspase-14 by calpain I in the present study lends support to this hypothesis, further implicating cross-talk between different protease families in the pathophysiology of ischemic neural cell death.

  • Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in Global Brain Ischemia and in excitotoxicity-induced neuronal death.
    Pharmacopsychiatry, 2003
    Co-Authors: Krish Chandrasekaran, Katy Drieu, Zara Mehrabian, Brigitte Spinnewyn, Christos Chinopoulos, Gary Fiskum
    Abstract:

    In this study, we compared the protective effect of bilobalide, a purified terpene lactone component of ginkgo biloba extract EGb 761, (definition see editorial) and EGb 761 against ischemic injury and against glutamate-induced excitotoxic neuronal death. In ischemic injury, we measured neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in vulnerable hippocampal regions of gerbils. At 7 days of reperfusion after 5 min of transient Global Ischemia, a significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before Ischemia progressively protected CA1 neurons from death and from Ischemia-induced reductions in COX III mRNA. In rat cerebellar neuronal cultures, addition of bilobalide or EGb 761 protected in a dose-dependent manner against glutamate-induced excitotoxic neuronal death (effective concentration [EC (50)] = 5 microg/ml (12 microM) for bilobalide and 100 microg/ml for EGb 761. These results suggest that both EGb 761 and bilobalide are protective against Ischemia-induced neuronal death in vivo and glutamate-induced neuronal death in vitro by synergistic mechanisms involving anti-excitotoxicity, inhibition of free radical generation, scavenging of reactive oxygen species, and regulation of mitochondrial gene expression.

  • neuroprotective effects of bilobalide a component of the ginkgo biloba extract egb 761 in gerbil Global Brain Ischemia
    Brain Research, 2001
    Co-Authors: Krish Chandrasekaran, Katy Drieu, Zara Mehrabian, Brigitte Spinnewyn, Gary Fiskum
    Abstract:

    The neuroprotective effect of Ginkgo biloba extract (EGb 761) against ischemic injury has been demonstrated in animal models. In this study, we compared the protective effect of bilobalide, a purified terpene lactone from EGb 761, and EGb 761 against ischemic injury. We measured neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in vulnerable hippocampal regions of gerbils. At 7 days of reperfusion after 5 min of transient Global foreBrain Ischemia, a significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before Ischemia progressively protected CA1 neurons from death and from Ischemia-induced reductions in COX III mRNA. In addition, both bilobalide and EGb 761 protected against Ischemia-induced reductions in COX III mRNA in CA1 neurons prior to their death, at 1 day of reperfusion. These results suggest that oral administration of bilobalide and EGb 761 protect against Ischemia-induced neuron death and reductions in mitochondrial gene expression.

  • distribution of glutamate receptor subunit proteins glur2 4 glur5 6 7 and nmdar1 in the canine and primate cerebral cortex a comparative immunohistochemical analysis
    Brain Research, 1996
    Co-Authors: Patrick R Hof, Robert E Rosenthal, Gary Fiskum, Prabhakar Vissavajjhala, John H Morrison
    Abstract:

    Abstract The distribution of the AMPA, kainate and NMDA glutamate receptor subunit proteins G1uR2(4), G1uR5/6/7 and NMDAR1, respectively, were analyzed in the dog hippocampus and neocortex and compared to macaque monkeys and humans. In the dog hippocampus, these glutamate receptor classes exhibited a comparable distribution with few differences in densities of labeled of neurons in the CA1-CA3 fields and in neuropil staining patterns in the dentate gyrus. In particular, the G1uR5/6/7 subunit proteins were characterized by a more restricted cellular distribution in the CA1-CA3 fields. In the dog neocortex, the G1uR2(4) subunit was found in a higher number of neurons in layers III and V compared to the G1uR5/6/7 or NMDAR1 subunits, which were found predominantly in a population of medium-to-large layer V pyramidal neurons. Layers II and VI were consistently densely labeled with all three receptor classes, especially in the case of the G1uR5/6/7 and NMDARI subunits. All three antibodies used thus far showed an intense labeling of the perikaryon and dendritic segments in the dog cerebral cortex. Apical dendrites could be followed through several layers in some cases, and formed well-stained plexuses in all of the neocortical layers. These patterns were very similar to those observed in the hippocampus and neocortex of both monkey and human, although G1uR2(4), and NMDARI immunoreactivity was visualized in more heterogeneous populations of cortical neurons in the primates than in dogs. Glutamate is the principal excitatory neurotransmitter in the Brain and is involved in the excitotoxic mechanisms occurring in pathologic conditions such as epilepsy and cerebral Ischemia. The dog has been shown to represent a reliable large animal model for several neurologic disorders and is used particularly in investigations of the cerebral repercussions of cardiac arrest. The overall similarity of the staining patterns in dogs and primates observed in the present study suggest that the dog model may be highly valuable for the characterization of potential cellular and synaptic shifts in the distribution and expression of specific glutamate receptor subunits, in the context of other biochemical and morphologic effects of Global Brain Ischemia and reperfusion following cardiac arrest.

Gary S. Krause - One of the best experts on this subject based on the ideXlab platform.

  • insulin activates the pi3k akt survival pathway in vulnerable neurons following Global Brain Ischemia
    Neurological Research, 2009
    Co-Authors: Thomas H Sanderson, Gary S. Krause, Rita Kumar, Alina C Murariudobrin, Andrea B Page, Jonathon M Sullivan
    Abstract:

    AbstractInsulin is neuroprotective following transient Global Brain Ischemia; however, the mechanisms by which insulin exerts its salutary effects remain unclear. Objective: We assessed insulin's effect on the PI3K-Akt survival system and consequent modulation of the pro-apoptotic proteins Bim, Bad and FoxO3a. Methods: We utilized rats subjected to 10 minutes of Global Brain Ischemia, with or without insulin administered at the onset of reperfusion. Results: In sham-operated animals, minimal pAkt immunofluorescence was detected in the CA1. Moreover, at 30 minute reperfusion, there was no change in pAkt in CA1 neurons. Single bolus high-dose insulin treatment resulted in an early increase in pAkt after 30 minutes, preservation of CA1 neurons to 14 days of reperfusion and preservation of spatial learning ability. Insulin treatment increased cytoplasmic and nuclear staining for pAkt in both CA1 and cortex. Insulin-induced Akt phosphorylation was suppressed by the PI3K inhibitor wortmannin. Neither reperfusio...

  • perk is responsible for the increased phosphorylation of eif2α and the severe inhibition of protein synthesis after transient Global Brain Ischemia
    Journal of Neurochemistry, 2005
    Co-Authors: Cheri R Owen, Rita Kumar, Peichuan Zhang, Barbara C Mcgrath, Douglas R Cavener, Gary S. Krause
    Abstract:

    Reperfusion after Global Brain Ischemia results initially in a widespread suppression of protein synthesis in neurons that is due to inhibition of translation initiation as a result of the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2). To address the role of the eIF2alpha kinase RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) in the reperfused Brain, transgenic mice with a targeted disruption of the Perk gene were subjected to 20 min of foreBrain Ischemia followed by 10 min of reperfusion. In wild-type mice, phosphorylated eIF2alpha was detected in the non-ischemic Brain and its levels were elevated threefold after 10 min of reperfusion. Conversely, there was no phosphorylated eIF2alpha detected in the non-ischemic transgenic mice and there was no sizeable rise in phosphorylated eIF2alpha levels in the foreBrain after Ischemia and reperfusion. Moreover, there was a substantial rescue of protein translation in the reperfused transgenic mice. Neither group showed any change in total eIF2alpha, phosphorylated eukaryotic elongation factor 2 or total eukaryotic elongation factor 2 levels. These data demonstrate that PERK is responsible for the large increase in phosphorylated eIF2alpha and the suppression of translation early in reperfusion after transient Global Brain Ischemia.

  • dysfunction of the unfolded protein response during Global Brain Ischemia and reperfusion
    Journal of Cerebral Blood Flow and Metabolism, 2003
    Co-Authors: Rita Kumar, Gary S. Krause, Hiderou Yoshida, Kazutoshi Mori, Donald J. Degracia
    Abstract:

    A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane-bound proteins ATF6, IRE1alpha, and PERK. The authors simultaneously examined the activation of ATF6, IRE1alpha, and PERK, as well as components of downstream UPR pathways, in the rat Brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2alpha phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in Brain stem and hippocampus. PERK was degraded in vitro by mu-calpain. Although inactive IRE1alpha was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after Brain Ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.

  • Global Brain Ischemia and reperfusion modifications in eukaryotic initiation factors associated with inhibition of translation initiation
    Journal of Neurochemistry, 2002
    Co-Authors: Donald J. Degracia, Robert W. Neumar, Blaine C. White, Gary S. Krause
    Abstract:

    We used in vitro translation and antibodies against phosphoserine and the eukaryotic initiation factors elF-4E, elF-4G, and elF-2 alpha to examine the effects of Global Brain Ischemia and reperfusion on translation initiation and its regulation in a rat model of 10 min of cardiac arrest followed by resuscitation and 90 min of reperfusion. Translation reactions were performed on postmitochondrial supernatants from Brain homogenates with and without aurintricarboxylic acid to separate incorporation due to run-off from incorporation due to peptide synthesis initiated in vitro. The rate of leucine incorporation due to in vitro-initiated protein synthesis in normal foreBrain homogenates was approximately 0.4 fmol of leucine/min/microgram of protein and was unaffected by 10 min of cardiac arrest, but 90 min of reperfusion reduced this rate 83%. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blots of these homogenates showed that neither 10 min of Global Brain Ischemia nor 90 min of reperfusion induced significant alterations in the quantity or serine phosphorylation of elF-4E. However, we observed in all 90-min-reperfused samples elF-4G fragments that also bound elF-4E. The amount of elF-2 alpha was not altered by Ischemia or reperfusion, and immunoblotting after isoelectric focusing did not detect serine-phosphorylated elF-2 alpha in normal samples or in those obtained after Ischemia without reperfusion. However, serine-phosphorylated elF-2 alpha was uniformly present after 90 min of reperfusion and represented 24 +/- 3% of the elF-2 alpha in these samples. The serine phosphorylation of elF-2 alpha and partial fragmentation of elF-4G observed after 90 min of reperfusion offer an explanation for the inhibition of protein synthesis.

  • calpain mediates eukaryotic initiation factor 4g degradation during Global Brain Ischemia
    Journal of Cerebral Blood Flow and Metabolism, 1998
    Co-Authors: Robert W. Neumar, Donald J. Degracia, Lynette L. Konkoly, John I. Khoury, Blaine C. White, Gary S. Krause
    Abstract:

    Global Brain Ischemia and reperfusion result in the degradation of the eukaryotic initiation factor (eIF) 4G, which plays a critical role in the attachment of the mRNA to the ribosome. Because eIF-4G is a substrate of calpain, these studies were undertaken to examine whether calpain I activation during Global Brain Ischemia contributes to the degradation of eIF-4G in vivo. Immunoblots with antibodies against calpain I and eIF-4G were prepared from rat Brain postmitochondrial supernatant incubated at 37°C with and without the addition of calcium and the calpain inhibitors calpastatin or MDL-28,170. Addition of calcium alone resulted in calpain I activation (as measured by autolysis of the 80-kDa subunit) and degradation of eIF-4G; this effect was blocked by either 1 μmol/L calpastatin or 10 μmol/L MDL-28,170. In rabbits subjected to 20 minutes of cardiac arrest, immunoblots of Brain postmitochondrial supernatants showed that the percentage of autolyzed calpain I increased from 1.9% ± 1.1% to 15.8% ± 5.0% a...

Jacek Bogucki - One of the best experts on this subject based on the ideXlab platform.

  • Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia
    Journal of Alzheimer's disease : JAD, 2016
    Co-Authors: Ryszard Pluta, Janusz Kocki, Marzena Ułamek-kozioł, Alicja Petniak, Paulina Gil-kulik, Sławomir Januszewski, Jacek Bogucki, Mirosław Jabłoński, Judyta Brzozowska, Wanda Furmaga-jabłońska
    Abstract:

    Brain Ischemia may be causally related with Alzheimer's disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimer's disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min Global Brain Ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postIschemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient Global Brain Ischemia. Finally, the Ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

  • Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete Brain Ischemia due to cardiac arrest
    Pharmacological Reports, 2016
    Co-Authors: Ryszard Pluta, Janusz Kocki, Alicja Petniak, Sławomir Januszewski, Judyta Brzozowska, Marzena Ułamek-kozioł, Anna Bogucka-kocka, Paulina Gil-kulik, Mirosław Jabłoński, Jacek Bogucki
    Abstract:

    Background Brain Ischemia may be causally related with Alzheimer’s disease. Probably, presenilin gene dysregulation may be associated with Alzheimer’s disease neuropathology. Consequently, we have examined quantitative changes in both presenilin 1 and 2 genes in the medial temporal lobe cortex following 10-min Global Brain Ischemia in rats. Methods Global Brain Ischemia was induced by cardiac arrest in female rats that were allowed to survive for 2, 7 and 30 days. The expression of presenilin genes was evaluated in the rat medial temporal lobe cortex with the use of quantitative RT-PCR analysis. Results Presenilin 1 gene expression tended to be downregulated from days 2 to 7 postIschemia but at day 30, there was a reverse tendency. The greatest overexpression of presenilin 2 gene was noted at 2-nd day whilst on day 7, the expression of this gene was only modestly elevated. Eventually, at day 30 expression of presenilin 2 gene was modestly downregulated. Alterations of presenilin 2 gene expression between 2 and 7 days and between 2 and 30 days were statistically significant. Conclusions Thus, presented changes suggest that the significant dysregulation of presenilin 2 gene may be connected with a response of neuronal cells to transient Global Brain Ischemia due to cardiac arrest. Finally, the Ischemia-induced gene dysregulation may play a key role in the late onset of Alzheimer’s-type dementia.

  • dysregulation of amyloid β protein precursor β secretase presenilin 1 and 2 genes in the rat selectively vulnerable ca1 subfield of hippocampus following transient Global Brain Ischemia
    Journal of Alzheimer's Disease, 2015
    Co-Authors: Janusz Kocki, Alicja Petniak, Judyta Brzozowska, Marzena Ulamekkoziol, Anna Boguckakocka, Slawomir Januszewski, Miroslaw Jablonski, Paulina Gilkulik, Wanda Furmagajablonska, Jacek Bogucki
    Abstract:

    The interaction between Brain Ischemia and Alzheimer's disease (AD) has been intensively investigated recently. Nevertheless, we have not yet understood the nature and mechanisms of the ischemic episodes triggering the onset of AD and how they influence its slow progression. The assumed connection between Brain Ischemia and the accumulation of amyloid-β (Aβ) peptide awaits to be clearly explained. In our research, we employed a rat cardiac arrest model to study the changes in gene expression of amyloid-β protein precursor (AβPP) and its cleaving enzymes, β- and γ-secretases (including presenilins) in hippocampal CA1 sector, following transient 10-min Global Brain Ischemia. The quantitative reverse-transcriptase PCR assay demonstrated that the expression of all above genes that contribute to Aβ peptide generation was dysregulated during 30 days in postischemic hippocampal CA1 area. It suggests that studied Aβ peptide generation-related genes can be involved in AβPP metabolism, following Global Brain Ischemia and will be useful to identify the molecular mechanisms underpinning that cerebral Ischemia might be an etiological cause of AD via dysregulation of AβPP and its cleaving enzymes, β- and γ-secretases genes, and subsequently, it may increase Aβ peptide production and promote the gradual and slow development of AD neuropathology. Our data demonstrate that Brain Ischemia activates delayed neuronal death in hippocampus in an AβPP-dependent manner, thus defining a new and important mode of ischemic cell death.

Giora Z Feuerstein - One of the best experts on this subject based on the ideXlab platform.

  • neuroprotective effects of tetrodotoxin as a na channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil Global Brain Ischemia
    Stroke, 1994
    Co-Authors: Paul G. Lysko, Christine L. Webb, Juanli Gu, Giora Z Feuerstein
    Abstract:

    Studies examining the role of tetrodotoxin-sensitive ion channels in hypoxic-ischemic neuronal damage have concluded that sodium influx is an important initiating event. We examined the neuroprotectant effect of tetrodotoxin on both cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to Brain Ischemia.We studied neuroprotective mechanisms using cultured rat cerebellar granule cells exposed to veratridine, which induced cytotoxicity, neurotransmitter release, and calcium influx. Survival of gerbil CA1 neurons was examined by direct neuron counts 7 days after 6 minutes of Global Ischemia with reperfusion.Tetrodotoxin protected cultured neurons in a dose-dependent manner from veratridine-induced toxicity (protective concentration [PC50] = 22 nmol/L). Veratridine induced [3H]aspartate efflux that was sodium dependent, only 25% calcium dependent, and was inhibited by tetrodotoxin (inhibitory concentration [IC50] = 60 nmol/L). Veratridine initiated increases in intracellular calcium th...

  • neuroprotective effects of phenyl t butyl nitrone in gerbil Global Brain Ischemia and in cultured rat cerebellar neurons
    Brain Research, 1992
    Co-Authors: Tianli Yue, Paul G. Lysko, Hungyuan Cheng, Frank C Barone, Giora Z Feuerstein
    Abstract:

    We examined the ability of phenyl-t-butyl-nitrone (PBN), an electron spin trapper, to attenuate Ischemia-induced foreBrain edema and hippocampal CA1 neuronal loss in gerbils, and to protect rat cerebellar neurons in primary culture from glutamate-induced toxicity. PBN, given i.p. at 75 or 150 mg/kg 30 min before Ischemia (5 min occlusion), increased survival (at 7 days) of CA1 neurons from 60 +/- 14 (vehicle-treated, n = 17) to 95 +/- 15 (P less than 0.05, n = 15) and 145 +/- 3 (P less than 0.01, n = 15), respectively. When gerbils were treated with PBN (50 mg/kg, i.p.) immediately and 6 h after reperfusion, followed by b.i.d. for an additional 2 days, CA1 neurons survival improved from 35 +/- 9 (vehicle, n = 20, 6 min occlusion) to 106 +/- 17 (P less than 0.01, n = 13). In gerbils exposed to a more severe Ischemia (10 min), pretreatment with 150 mg/kg PBN increased the survival of CA1 neurons from 6 +/- 6 (vehicle) to 27 +/- 10 (P less than 0.05, n = 11). Pretreatment with PBN, at 150 mg/kg, reduced foreBrain edema (following 15 min Ischemia) by 24.7% (P less than 0.01, n = 16). PBN at 50 mg/kg, i.p. had no hypothermic effect and at 75 or 150 mg/kg caused a transient hypothermia. The presence of PBN in the Brain was confirmed in microdialysis samples and Brain tissue extract using HPLC. In vitro, PBN protected rat cerebellar neurons against 100 microM glutamate-induced toxicity with an EC50 value of 2.7 mM. Our results further support the concept that free radicals contribute to Brain injury following Ischemia and suggest the potential therapeutic application of electron spin trappers in stroke.