Why is Hippocampal CA1 Especially Vulnerable to Ischemia?

Amara, Amro Abd Al Fattah

doi:10.15226/2376-4589/2/2/00114

Cited by 8 publications

(8 citation statements)

References 32 publications

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“…After CA1 lesions, both recent and remote memory are impaired (55). Furthermore, this area is vulnerable to ischaemia injury (56). Thus, we chose the hippocampal CA1 area to measure the number of survival neurons and the expression of certain protein.…”

Section: Figure 4 |mentioning

confidence: 99%

Combination of Isoflurane and Propofol as General Anesthesia During Orthopedic Surgery of Perioperative Cerebral Hypoperfusion Rats to Avoid Cognitive Impairment

Tang

Wang

et al. 2020

Front. Med.

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Background: Perioperative cerebral hypoperfusion (CH) is common, although the underlying mechanism of cognitive impairment that results due to perioperative cerebral hypoperfusion remains to be determined. Isoflurane anesthesia induces neuronal injury via endoplasmic reticulum (ER) stress, whereas a sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common aesthetic combination administered to patients, on ER stress and cognition remain unknown. Methods: We sought to determine the effects of isoflurane plus propofol on ER stress and cognitive function in rats insulted by cerebral hypoperfusion. Ligation of the bilateral common carotid arteries (CCA) was adopted to develop the cerebral hypoperfusion rat model. A second surgery, open reduction and internal fixation (ORIF), requiring general anesthesia, was performed 30 days later so that the effects of anesthetics on the cognitive function of CH rats could be assessed. Rats received isoflurane alone (1.9%), propofol alone (40 mg•kg −1 •h −1) or a combination of isoflurane and propofol (1% and 20 mg•kg −1 •h −1 or 1.4% and 10 mg•kg −1 •h −1). Behavioral studies (contextual fear conditioning [FC] test), histological analyses (Nissl staining) and biochemical analyses (western blotting of the harvested rat brain tissues) were employed. Results: Hippocampus-dependent memory of rats in group IP 1 (1% isoflurane plus 20 mg•kg −1 •h −1 propofol) was not impaired, and expression level of γ-aminobutyric acid A type receptor α1 subunit, a key cognition-related protein, remained normal. ER stress alleviator, binding immunoglobulin protein, increased extremely while ER stress transcription factor, C/EBP homologous protein, showed no statistical Bu et al. Anesthesia During Perioperative Cerebral Hypoperfusion difference compared with the control group. Numbers of surviving neurons confirmed the substantial neuronal damage caused by propofol or isoflurane alone. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and that the combination of isoflurane and propofol did not aggravate cognitive impairment and ER stress in aging rats with CH that were further subjected to ORIF surgery.

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Section: Figure 4 |mentioning

confidence: 99%

Combination of Isoflurane and Propofol as General Anesthesia During Orthopedic Surgery of Perioperative Cerebral Hypoperfusion Rats to Avoid Cognitive Impairment

Tang

Wang

et al. 2020

Front. Med.

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“…Calpain cleaves Hsp70.1 involved in the monkey hippocampal CA1 tissue in vitro following incubation with synthetic 4-HNE or hydrogen peroxide ( Sahara and Yamashima, 2010 ). In addition, the in vitro oxidation of Hsp70.1 involved within other brain tissues of monkeys also facilitated its proteolysis by μ-calpain ( Yamashima et al, 2014 ; Liang et al, 2016 ). Subsequently, under diverse pathological conditions of monkeys and humans, the same cascade of the μ-calpain-mediated cleavage of the carbonylated Hsp70.1 was demonstrated to occur in vivo in the pancreas and liver that were exposed to consecutive injections of 4-HNE ( Boontem and Yamashima, 2021 ; Seike et al, 2022 ).…”

Section: Post-translational Modification Of Hsp701 Under Cell Stress ...mentioning

confidence: 99%

“…We conducted in vitro cleavage assay using the monkey brain tissues and recombinant human Hsp70.1. This showed that Hsp70.1, being involved in the brain tissue, is prone to cleavage by activated μ-calpain, especially after oxidative modification by synthetic 4-HNE or hydrogen peroxide ( Sahara and Yamashima, 2010 ; Liang et al, 2016 ). For example, similar results were obtained in the hippocampal CA1 and thalamus tissues of the monkey brain and recombinant human Hsp70.1, which indicated calpain-mediated cleavage of the carbonylated Hsp70.1 from 70 kDa to ∼30 kDa ( Figure 7 ).…”

Section: Calpain-mediated Cleavage Of Carbonylated Hsp701mentioning

confidence: 99%

Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions

Yamashima,

Mochly-Rosen,

Wakatsuki

et al. 2024

Front. Mol. Biosci.

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Autophagy mediates the degradation of intracellular macromolecules and organelles within lysosomes. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Heat shock protein 70.1 (Hsp70.1) exhibits dual functions as a chaperone protein and a lysosomal membrane stabilizer. Since chaperone-mediated autophagy participates in the recycling of ∼30% cytosolic proteins, its disorder causes cell susceptibility to stress conditions. Cargo proteins destined for degradation such as amyloid precursor protein and tau protein are trafficked by Hsp70.1 from the cytosol into lysosomes. Hsp70.1 is composed of an N-terminal nucleotide-binding domain (NBD) and a C-terminal domain that binds to cargo proteins, termed the substrate-binding domain (SBD). The NBD and SBD are connected by the interdomain linker LL1, which modulates the allosteric structure of Hsp70.1 in response to ADP/ATP binding. After the passage of the Hsp70.1–cargo complex through the lysosomal limiting membrane, high-affinity binding of the positive-charged SBD with negative-charged bis(monoacylglycero)phosphate (BMP) at the internal vesicular membranes activates acid sphingomyelinase to generate ceramide for stabilizing lysosomal membranes. As the integrity of the lysosomal limiting membrane is critical to ensure cargo protein degradation within the acidic lumen, the disintegration of the lysosomal limiting membrane is lethal to cells. After the intake of high-fat diets, however, β-oxidation of fatty acids in the mitochondria generates reactive oxygen species, which enhance the oxidation of membrane linoleic acids to produce 4-hydroxy-2-nonenal (4-HNE). In addition, 4-HNE is produced during the heating of linoleic acid-rich vegetable oils and incorporated into the body via deep-fried foods. This endogenous and exogenous 4-HNE synergically causes an increase in its serum and organ levels to induce carbonylation of Hsp70.1 at Arg469, which facilitates its conformational change and access of activated μ-calpain to LL1. Therefore, the cleavage of Hsp70.1 occurs prior to its influx into the lysosomal lumen, which leads to lysosomal membrane permeabilization/rupture. The resultant leakage of cathepsins is responsible for lysosomal cell death, which would be one of the causative factors of lifestyle-related diseases.

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“…The hippocampus is known for its high density of neurons and high susceptibility to injuries and inflammation [35][36][37]. Therefore, we analyzed microglia size at the hippocampus 7 days post-SAH showed the circadian dependency of their morphological features.…”

Section: Sah At Zt2 Increases Vasospasm and Inflammation Following Sahmentioning

confidence: 99%

Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke

Henrich,

Kiessling,

Steimer

et al. 2023

J Inflamm

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Background The heme oxygenase-1 (HO-1) enzyme pathway is of crucial importance in the removal of toxic blood components and regulation of neuroinflammation following hemorrhagic stroke. Although a circadian pattern dependency in the incidence and severity of hemorrhagic stroke exists, it is unknown whether the activity of the HO-1 system in the context of hemorrhagic injury also exhibits circadian dependency. We hypothesized that the circadian regulation of microglial HO-1 would determine the extent of neuroinflammation and neuronal injury in a murine model of subarachnoid hemorrhage (SAH). Methods In vitro expression patterns of HO-1 and circadian rhythm genes were analyzed in the microglial BV-2 cell line and primary microglia (PMG) using Western blot and qPCR. PMG isolated from Hmox1fl/fl and LyzM-Cre-Hmox1fl/fl mice were used to evaluate the role of microglial HO-1. We further investigated the in vivo relevance in a murine subarachnoid hemorrhage (SAH) model using Hmox1fl/fl and LyzM-Cre-Hmox1fl/fl mice with myeloid cell HO-1 deficiency, inducing SAH at different zeitgeber (ZT) times and analyzing the expression of HO-1 and the circadian control gene Period-2 (Per-2), respectively. Furthermore, we measured the inflammatory cytokine Monocyte Chemoattractant Protein-1 (MCP-1) in the cerebrospinal fluid of SAH patients in correlation with clinical outcome. Results HO-1 baseline expression and response to CO with blood exposure depended on ZT. In vitro expression of circadian control genes was de-synchronized in LyzM-Cre-Hmox1fl/fl PMG and did not respond to exogenous CO exposure. We found that circadian rhythm plays a crucial role in brain damage after SAH. At ZT2, we observed less phagocytic function, more vasospasm and increased microglial activation. CO reduced mortality at ZT12 in HO-1 deficient mice and reduced the difference between ZT2 and ZT12 in the inflammatory response. Induction of MCP-1 in the CSF from SAH patients was time-dependent and correlated with the expression of circadian control genes, SAH severity, functional impairment and delirium. Conclusions Our data point towards a crucial role for the HO-1 enzyme system and circadian control in neuronal injury after a hemorrhagic stroke.

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Why is Hippocampal CA1 Especially Vulnerable to Ischemia?

Cited by 8 publications

References 32 publications

Combination of Isoflurane and Propofol as General Anesthesia During Orthopedic Surgery of Perioperative Cerebral Hypoperfusion Rats to Avoid Cognitive Impairment

Combination of Isoflurane and Propofol as General Anesthesia During Orthopedic Surgery of Perioperative Cerebral Hypoperfusion Rats to Avoid Cognitive Impairment

Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions

Circadian dependency of microglial heme oxygenase-1 expression and inflammation determine neuronal injury in hemorrhagic stroke

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