Differential Vulnerability of the CA1 and CA3 Subfields of the Hippocampus to Superoxide and Hydroxyl Radicals In Vitro

Wilde, Geraint J. C.; Pringle, Ashley K.; Wright, Peter; Iannotti, Fausto

doi:10.1046/j.1471-4159.1997.69020883.x

Cited by 135 publications

(99 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The acidosis following cerebral ischemia with enhancement of glial edema, protein denaturization, and depletion of energy generation creates an optimal milieu for free radical formation. 29,30) Oxidative stress is one trigger of apoptotic cell death, and treatment of cells with a variety of different exogenous antioxidants blocks apoptosis. 31) The mechanisms by which oxygen radicals are produced in apoptotic cells are still not clear, but disruptions in mitochondrial function may play a role.…”

Section: Fig 1 Representative Brain Infarctions After 1-h Ischemia/mentioning

confidence: 99%

Gastrodia elata Blume and an Active Component, p-Hydroxybenzyl Alcohol Reduce Focal Ischemic Brain Injury through Antioxidant Related Gene Expressions

Kim

Lee

et al. 2005

Biological & Pharmaceutical Bulletin

103

View full text Add to dashboard Cite

Ischaemic stroke is a leading cause of death and long-lasting disability. Gastrodia elata blume (GEB) is a Chinese herb that is widely used to treat convulsive disorders, such as epilepsy, and p-hydroxybenzyl alcohol (HBA) is the active ingredient in GEB. The present study was conducted to evaluate the effects of GEB and HBA on the brain damage and transcriptional levels of Protein disulfide isomerase (PDI) and 1-Cys peroxiredoxin (1-Cys Prx) genes known to play a role in antioxidant systems after transient focal ischemia in the rat brain. Focal ischemia was induced in rats by middle cerebral artery occlusion (MCAO). All animals underwent ischemia for 1 h, followed by 24 h of reperfusion. Coronal brain slices were stained with 2,3,5-triphenyltetrazolium chloride or total RNA was extracted for the analysis of gene expression. Histopathologic analysis revealed a significant ( pϽ0.05) decrease in infarct size in the ipsilateral brain with GEB extracts or HBA. Moreover, the levels of PDI and 1-Cys Prx transcription were significantly increased in the GEB extract-or HBA-treated group compared with the untreated group (pϽ0.05). This study therefore indicated that GEB and HBA provide neuroprotection by preventing brain damage through the increased expression of genes encoding antioxidant proteins after transient focal cerebral ischemia and may be effective as neuroprotective agents at the cellular and molecular levels in the brain.

show abstract

Section: Fig 1 Representative Brain Infarctions After 1-h Ischemia/mentioning

confidence: 99%

Gastrodia elata Blume and an Active Component, p-Hydroxybenzyl Alcohol Reduce Focal Ischemic Brain Injury through Antioxidant Related Gene Expressions

Kim

Lee

et al. 2005

Biological & Pharmaceutical Bulletin

103

View full text Add to dashboard Cite

show abstract

“…However, the mechanisms underlying this heterogeneous sensitivity are not well understood. Regional variability in hypoxic sensitivity has been reported in the brain during conditions of oxygen deprivation such as hypoxic ischemia, malonate-induced mitochondrial metabolic disruption (2), and during oxidant stress following ischemia (4). As an example of selective vulnerability within a well defined brain structure, the hippocampus contains two regions that clearly differ in their susceptibility to hypoxia.…”

Section: Expression Of Constitutively Active Akt In Pc-12 Cells Inducmentioning

confidence: 99%

“…However, the mechanisms underlying this heterogeneous sensitivity are not well understood. Heterotopic differences in hypoxic sensitivity are now well established in the brain during conditions of oxygen deprivation such as hypoxic ischemia and the oxidant stress that follows reperfusion or malonate-induced mitochondrial metabolic disruption (1)(2)(3)(4). Previous studies from our laboratory have identified significant differences in the hypoxic susceptibility of the CA1 and CA3 hippocampal regions, with CA1 vulnerability being particularly prominent in response to intermittent mild hypoxic episodes (5-7).…”

mentioning

confidence: 97%

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Klein

Barati

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hypoxia is a common environmental stress that influences signaling pathways and cell function. Previous studies from our laboratory have identified significant differences in cellular responses to sustained or intermittent hypoxia with the latter proving more cytotoxic. We hypothesized that differences in susceptibility of neurons to intermittent (IH) and sustained hypoxia (SH) are mediated by altered Akt signaling. SH, but not IH, induced a significant increase in Akt activation in rat CA1 hippocampal region extracts compared with room air controls. Most mammalian neurons are sensitive to hypoxia to a varying degree. However, the mechanisms underlying this heterogeneous sensitivity are not well understood. Heterotopic differences in hypoxic sensitivity are now well established in the brain during conditions of oxygen deprivation such as hypoxic ischemia and the oxidant stress that follows reperfusion or malonate-induced mitochondrial metabolic disruption (1-4). Previous studies from our laboratory have identified significant differences in the hypoxic susceptibility of the CA1 and CA3 hippocampal regions, with CA1 vulnerability being particularly prominent in response to intermittent mild hypoxic episodes (5-7). These findings suggest that the CA3 region is relatively resistant to hypoxia when compared with the CA1 region, and CA1 regional vulnerability to hypoxia varies depending on the mode, severity, and duration of the hypoxic insult (8 -10). The mechanisms underlying the greater susceptibility of the CA1 region to intermittent hypoxia (IH) 1 than to sustained hypoxia (SH) are unknown. We have recently shown in PC-12 cells that different signaling pathways are involved in sustained and intermittent hypoxia-induced cell death. Identifying these pathways may contribute to our understanding of differential brain susceptibility to sustained and intermittent hypoxia (11). In the present study, we found that in rat CA1, SH but not IH induces significant increase in Akt activation compared with room air (RA) control, suggesting that differences in Akt signaling maybe implicated in the differences in hypoxia sensitivity in IH versus SH. Proteomic analysis of Akt immunoprecipitates from RA, SH, and IH CA1 samples was performed to identify differences in the assembly of Akt-binding partners among different conditions. These studies demonstrated that SH but not IH increased expression and association of endoplasmic reticulum (ER)-proteasome interacting protein, velosin-containing protein 97 (VCP) with Akt, compared with RA-exposed animals. Additionally, VCP was identified as an Akt substrate in vitro and in vivo thereby potentially implicating the VCP-Akt complex in the regulation of protein quality control during SH.VCP is a member of the AAA (ATPases associated with various cellular activities) family and is divided into N (residues 1-187), D1 (residues 209 -460), D2 (residues 481-761), and C (residues 742-806) domains, and two linkers, N-D1 linker (residues 188 -208) and D1-D2 linker (residues 461-

show abstract

“…Indeed, periods of hypoxia that are not fatal to other brain structures may nonetheless result in significant damage to the hippocampus. However, not all hippocampal areas exhibit the same degree of susceptibility to the ischemic injury, with the CA3 area showing greater resistance to ischemic damage compared with area CA1 (12). Accordingly, a brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons 48-72 hours after reperfusion, with neuronal preservation in other hippocampal layers.…”

Section: Introductionmentioning

confidence: 99%

Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus

Echeverry¹,

Wu²,

Haile³

et al. 2010

J. Clin. Invest.

116

View full text Add to dashboard Cite

The best-known function of the serine protease tissue-type plasminogen activator (tPA) is as a thrombolytic enzyme. However, it is also found in structures of the brain that are highly vulnerable to hypoxia-induced cell death, where its association with neuronal survival is poorly understood. Here, we have demonstrated that hippocampal areas of the mouse brain lacking tPA activity are more vulnerable to neuronal death following an ischemic insult. We found that sublethal hypoxia, which elicits tolerance to subsequent lethal hypoxic/ischemic injury in a natural process known as ischemic preconditioning (IPC), induced a rapid release of neuronal tPA. Treatment of hippocampal neurons with tPA induced tolerance against a lethal hypoxic insult applied either immediately following insult (early IPC) or 24 hours later (delayed IPC). tPA-induced early IPC was independent of the proteolytic activity of tPA and required the engagement of a member of the LDL receptor family. In contrast, tPA-induced delayed IPC required the proteolytic activity of tPA and was mediated by plasmin, the NMDA receptor, and PKB phosphorylation. We also found that IPC in vivo increased tPA activity in the cornu ammonis area 1 (CA1) layer and Akt phosphorylation in the hippocampus, as well as ischemic tolerance in wild-type but not tPA-or plasminogen-deficient mice. These data show that tPA can act as an endogenous neuroprotectant in the murine hippocampus.

show abstract

Differential Vulnerability of the CA1 and CA3 Subfields of the Hippocampus to Superoxide and Hydroxyl Radicals In Vitro

Cited by 135 publications

References 17 publications

Gastrodia elata Blume and an Active Component, p-Hydroxybenzyl Alcohol Reduce Focal Ischemic Brain Injury through Antioxidant Related Gene Expressions

Gastrodia elata Blume and an Active Component, p-Hydroxybenzyl Alcohol Reduce Focal Ischemic Brain Injury through Antioxidant Related Gene Expressions

Akt-mediated Valosin-containing Protein 97 Phosphorylation Regulates Its Association with Ubiquitinated Proteins

Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus

Contact Info

Product

Resources

About