Transient Global Forebrain Ischemia Induces a Prolonged Expression of the Caspase-3 mRNA in Rat Hippocampal CA1 Pyramidal Neurons

The authors recently cloned a cDNA for an ICE/CED3-related cysteine protease from rat brain, which is closely related to human CPP32 (now designated caspase-3). In situ hybridization histochemistry revealed a profound developmental regulation of the caspase-3 transcript in rat brain, with relatively high levels of caspase-3 mRNA observed in neurons of the fetal and neonatal brain and low levels of mRNA in neurons of the adult brain. The authors report that transient forebrain ischemia, which results in a delayed apoptotic death of CA1 pyramidal neurons, results in prolonged expression of caspase-3 mRNA in these same pyramidal neurons. Up-regulation of caspase-3 mRNA in CA1 pyramidal neurons is prominent 24 hours after transient global ischemia, and expression is maintained at higher levels for at least 72 hours after ischemia. However, by 96 hours after ischemia, a marked decrease in caspase-3 mRNA expression is observed in CA1 pyramidal neurons, showing severe degenerative changes (e.g., nuclear condensation). By contrast, there is no change in the expression of a closely related member of caspase family, caspase-2, in CA1 pyramidal neurons after global ischemia. Instead, caspase-2 mRNA is induced in lamina layers of cerebral cortex 24 hours after the ischemia. A selective and prolonged induction of the caspase-3 gene in committed CA1 pyramidal neurons suggests that transcriptional activation of this caspase-3 gene may be involved in the apoptotic cell death cascade of CA1 neurons after transient global ischemia.

Download Full-text

Cloning and Characterization of Rat Caspase-9: Implications for a Role in Mediating Caspase-3 Activation and Hippocampal Cell Death after Transient Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200205000-00005 ◽

2002 ◽

Vol 22 (5) ◽

pp. 534-546 ◽

Cited By ~ 67

Author(s):

Guodong Cao ◽

Yumin Luo ◽

Tetsuya Nagayama ◽

Wei Pei ◽

R. Anne Stetler ◽

...

Keyword(s):

Neuronal Death ◽

Hippocampal Neurons ◽

Caspase 3 ◽

Neuronal Survival ◽

Global Ischemia ◽

Adult Brain ◽

Caspase 8 ◽

Intrinsic Pathway ◽

Caspase 9 ◽

Transient Global Ischemia

Delayed hippocampal neurodegeneration after transient global ischemia is mediated, at least in part, through the activation of terminal caspases, particularly caspase-3, and the subsequent proteolytic degradation of critical cellular proteins. Caspase-3 may be activated by the membrane receptor-initiated caspase-8–dependent extrinsic pathway and the mitochondria-initiated caspase-9–dependent intrinsic pathway; however, the precise role of these deduced apoptosis-signaling pathways in activating caspase-3 in ischemic neurons remains elusive. The authors cloned the caspase-9 gene from the rat brain and investigated its potential role in mediating ischemic neuronal death in a rat model of transient global ischemia. Caspase-9 gene expression and protease activity were extremely low in the adult brain, whereas they were developmentally upregulated in newborn rats, especially at postnatal 12 weeks, a finding consistent with the theory of an essential role for caspase-9 in neuronal apoptosis during brain development. After 15-minute transient global ischemia, caspase-9 was overexpressed and proteolytically activated in the hippocampal CA1 neurons at 8 to 72 hours of reperfusion. The temporal profile of caspase-9 activation coincided with that of cytochrome c release and caspase-3 activation, but preceded CA1 neuronal death. Immunoprecipitation experiments revealed that there was enhanced formation of Apaf-1/caspase-9 complex in the hippocampus 8 and 24 hours after ischemia. Furthermore, intracerebral ventricular infusion of the relatively specific caspase-9 inhibitor N-benzyloxycarbonyl-Leu-Glu-His-Asp-fluoro-methylketone before ischemia attenuated caspase-3–like activity and significantly enhanced neuronal survival in the CA1 sector. In contrast, inhibition of caspase-8 activity had no significant effect on caspase-3 activation or neuronal survival. These results suggest that the caspase-9–dependent intrinsic pathway may be the primary mechanism responsible for the activation of caspase-3 in ischemic hippocampal neurons.

Download Full-text

Induction and selective accumulation of mutant ubiquitin in CA1 pyramidal neurons after transient global ischemia

Neuroscience ◽

10.1016/j.neuroscience.2007.03.048 ◽

2007 ◽

Vol 147 (1) ◽

pp. 71-79 ◽

Cited By ~ 11

Author(s):

K. Yamashiro ◽

R. Liu ◽

M. Maeda ◽

N. Hattori ◽

T. Urabe

Keyword(s):

Pyramidal Neurons ◽

Global Ischemia ◽

Ca1 Pyramidal Neurons ◽

Transient Global Ischemia ◽

Selective Accumulation

Download Full-text

Diversity and fluctuation of spine morphology in CA1 pyramidal neurons after transient global ischemia

Journal of Neuroscience Research ◽

10.1002/jnr.21816 ◽

2009 ◽

Vol 87 (1) ◽

pp. 61-68 ◽

Cited By ~ 28

Author(s):

Yi-Wen Ruan ◽

Zhigang Lei ◽

Yuan Fan ◽

Bende Zou ◽

Zao C. Xu

Keyword(s):

Pyramidal Neurons ◽

Global Ischemia ◽

Spine Morphology ◽

Ca1 Pyramidal Neurons ◽

Transient Global Ischemia

Download Full-text

Dendritic plasticity of CA1 pyramidal neurons after transient global ischemia

Neuroscience ◽

10.1016/j.neuroscience.2006.01.039 ◽

2006 ◽

Vol 140 (1) ◽

pp. 191-201 ◽

Cited By ~ 32

Author(s):

Y.-W. Ruan ◽

B. Zou ◽

Y. Fan ◽

Y. Li ◽

N. Lin ◽

...

Keyword(s):

Pyramidal Neurons ◽

Global Ischemia ◽

Ca1 Pyramidal Neurons ◽

Dendritic Plasticity ◽

Transient Global Ischemia

Download Full-text

Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal

Current Molecular Medicine ◽

10.2174/1566524019666190704100444 ◽

2019 ◽

Vol 19 (8) ◽

pp. 597-604

Author(s):

Li Pang ◽

Shouqin Ji ◽

Jihong Xing

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Caspase 3 ◽

Global Ischemia ◽

Neurological Deficits ◽

Global Cerebral Ischemia ◽

Caspase 9 ◽

Tnf Α ◽

The Central Nervous System ◽

Transient Global Ischemia

Background: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. Methods: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. Results: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1β, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. Conclusion: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

Download Full-text

Increased Calbindin D28k Expression via Long-Term Alternate-Day Fasting Does Not Protect against Ischemia-Reperfusion Injury: A Focus on Delayed Neuronal Death, Gliosis and Immunoglobulin G Leakage

International Journal of Molecular Sciences ◽

10.3390/ijms22020644 ◽

2021 ◽

Vol 22 (2) ◽

pp. 644

Author(s):

Hyejin Sim ◽

Tae-Kyeong Lee ◽

Yeon Ho Yoo ◽

Ji Hyeon Ahn ◽

Dae Won Kim ◽

...

Keyword(s):

Immunoglobulin G ◽

Pyramidal Neurons ◽

Short Term Memory ◽

Forebrain Ischemia ◽

Short Term ◽

Term Memory ◽

Transient Forebrain Ischemia ◽

Ca1 Pyramidal Neurons ◽

Ca1 Region ◽

Calbindin D28k

Calbindin-D28k (CB), a calcium-binding protein, mediates diverse neuronal functions. In this study, adult gerbils were fed a normal diet (ND) or exposed to intermittent fasting (IF) for three months, and were randomly assigned to sham or ischemia operated groups. Ischemic injury was induced by transient forebrain ischemia for 5 min. Short-term memory was examined via passive avoidance test. CB expression was investigated in the Cornu Ammonis 1 (CA1) region of the hippocampus via western blot analysis and immunohistochemistry. Finally, histological analysis was used to assess neuroprotection and gliosis (microgliosis and astrogliosis) in the CA1 region. Short-term memory did not vary significantly between ischemic gerbils with IF and those exposed to ND. CB expression was increased significantly in the CA1 pyramidal neurons of ischemic gerbils with IF compared with that of gerbils fed ND. However, the CB expression was significantly decreased in ischemic gerbils with IF, similarly to that of ischemic gerbils exposed to ND. The CA1 pyramidal neurons were not protected from ischemic injury in both groups, and gliosis (astrogliosis and microgliosis) was gradually increased with time after ischemia. In addition, immunoglobulin G was leaked into the CA1 parenchyma from blood vessels and gradually increased with time after ischemic insult in both groups. Taken together, our study suggests that IF for three months increases CB expression in hippocampal CA1 pyramidal neurons; however, the CA1 pyramidal neurons are not protected from transient forebrain ischemia. This failure in neuroprotection may be attributed to disruption of the blood–brain barrier, which triggers gliosis after ischemic insults.

Download Full-text

Prolonged enhancement and depression of synaptic transmission in CA1 pyramidal neurons induced by transient forebrain ischemia in vivo

Neuroscience ◽

10.1016/s0306-4522(98)00150-x ◽

1998 ◽

Vol 87 (2) ◽

pp. 371-383 ◽

Cited By ~ 37

Author(s):

T.-M Gao ◽

W.A Pulsinelli ◽

Z.C Xu

Keyword(s):

Synaptic Transmission ◽

Pyramidal Neurons ◽

Forebrain Ischemia ◽

Transient Forebrain Ischemia ◽

Ca1 Pyramidal Neurons

Download Full-text

Down-regulation of cyclin-dependent kinase 5 attenuates p53-dependent apoptosis of hippocampal CA1 pyramidal neurons following transient cerebral ischemia

Scientific Reports ◽

10.1038/s41598-019-49623-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Bich Na Shin ◽

Dae Won Kim ◽

In Hye Kim ◽

Joon Ha Park ◽

Ji Hyeon Ahn ◽

...

Keyword(s):

Cerebral Ischemia ◽

Caspase 3 ◽

Pyramidal Neurons ◽

Transient Cerebral Ischemia ◽

Cyclin Dependent Kinase ◽

Neuroprotective Effects ◽

Expression Levels ◽

Ca1 Pyramidal Neurons ◽

Hippocampal Ca1 ◽

Cyclin Dependent Kinase 5

Abstract Abnormal activation of cyclin-dependent kinase 5 (Cdk5) is associated with pathophysiological conditions. Ischemic preconditioning (IPC) can provide neuroprotective effects against subsequent lethal ischemic insult. The objective of this study was to determine how Cdk5 and related molecules could affect neuroprotection in the hippocampus of gerbils after with IPC [a 2-min transient cerebral ischemia (TCI)] followed by 5-min subsequent TCI. Hippocampal CA1 pyramidal neurons were dead at 5 days post-TCI. However, treatment with roscovitine (a potent inhibitor of Cdk5) and IPC protected CA1 pyramidal neurons from TCI. Expression levels of Cdk5, p25, phospho (p)-Rb and p-p53 were increased in nuclei of CA1 pyramidal neurons at 1 and 2 days after TCI. However, these expressions were attenuated by roscovitine treatment and IPC. In particular, Cdk5, p-Rb and p-p53 immunoreactivities in their nuclei were decreased. Furthermore, TUNEL-positive CA1 pyramidal neurons were found at 5 days after TCI with increased expression levels of Bax, PUMA, and activated caspase-3. These TUNEL-positive cells and increased molecules were decreased by roscovitine treatment and IPC. Thus, roscovitine treatment and IPC could protect CA1 pyramidal neurons from TCI through down-regulating Cdk5, p25, and p-p53 in their nuclei. These findings indicate that down-regulating Cdk5 might be a key strategy to attenuate p53-dependent apoptosis of CA1 pyramidal neurons following TCI.

Download Full-text