Assessment of CA1 injury after global ischemia using supervised 2D analyses of nuclear pyknosis

Rininger, A.; A, Wayland; Prifti, Viollandi; Halterman, Marc W.

doi:10.1016/j.jneumeth.2012.04.010

Cited by 9 publications

(5 citation statements)

References 23 publications

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“…Thus, intraarterial application of LepA through the ipsilateral ICA, in proximity to the target tissue, along the immediate outflow of the receiving vessel, facilitated rapid binding of most of the LepA to local leptin receptors. As IR results in immediate increase in BBB permeability [ 31 ], the drug should have no problem to penetrate locally disrupted BBB and have access to the tissue. Furthermore, although we lack information about LepA capabilities to cross the BBB, an earlier version of leptin antagonist that was injected into the blood stream was shown to penetrate the brain [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

Benbenishty

Schneiderman

2022

PLoS ONE

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Background Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury. Methods C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2. Results The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01). Conclusions Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.

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Section: Discussionmentioning

confidence: 99%

Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

Benbenishty

Schneiderman

2022

PLoS ONE

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“…This finding is consistent with several autopsy studies that detected microclots in small parenchymal vessels and demonstrated a correlation between these microclot densities and the location and severity of histological evidence of ischemia [ 27 ]. It is well know that a brief period of global brain ischemia mainly causes cell death in hippocampal subfields neurons in rodents and humans, whereas other neurons are much less vulnerable [ 44 , 45 ]. Furthermore, microclot formation and neuronal apoptosis were detected in both hemispheres, indicating a more global disease after SAH than the effect of local ischemia caused by microclot formation.…”

Section: Discussionmentioning

confidence: 99%

The Role of Microclot Formation in an Acute Subarachnoid Hemorrhage Model in the Rabbit

Andereggen

Neuschmelting

Gunten³

et al. 2014

BioMed Research International

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Background. Microvascular dysfunction and microthrombi formation are believed to contribute to development of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH). Objective. This study aimed to determine (i) extent of microthrombus formation and neuronal apoptosis in the brain parenchyma using a blood shunt SAH model in rabbits; (ii) correlation of structural changes in microvessels with EBI characteristics. Methods. Acute SAH was induced using a rabbit shunt cisterna magna model. Extent of microthrombosis was detected 24 h post-SAH (n = 8) by fibrinogen immunostaining, compared to controls (n = 4). We assessed apoptosis by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in cortex and hippocampus. Results. Our results showed significantly more TUNEL-positive cells (SAH: 115 ± 13; controls: 58 ± 10; P = 0.016) and fibrinogen-positive microthromboemboli (SAH: 9 ± 2; controls: 2 ± 1; P = 0.03) in the hippocampus after aneurysmal SAH. Conclusions. We found clear evidence of early microclot formation in a rabbit model of acute SAH. The extent of microthrombosis did not correlate with early apoptosis or CPP depletion after SAH; however, the total number of TUNEL positive cells in the cortex and the hippocampus significantly correlated with mean CPP reduction during the phase of maximum depletion after SAH induction. Both microthrombosis and neuronal apoptosis may contribute to EBI and subsequent DCI.

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“…This selective vulnerability was described already in 1988 by Duvernoy by a specific order of damage (CA1 > CA3 > DG), which means that after cerebral hypoxia or ischemia, CA1 is traditionally one of the first regions showing damage, whereas neighboring CA3 neurons are resistant [52,177]. Numerous in vivo and in vitro studies demonstrated selective damage to CA1 pyramidal cells after transient global brain ischemia caused by cardiac arrest [67,170]. Accordingly, certain neuron types appear to have either evolved endogenous neuroprotective mechanisms or a constitution that makes them less vulnerable [22].…”

Section: The Hippocampusmentioning

confidence: 93%

Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells. Collation of possible pathomechanisms for selective damage known to date from various study models. Should more attention be paid to the CA3 region in future studies?

Einenkel¹,

Salameh²

2023

Preprint

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Transient ischemia and reperfusion selectively damage neurons in brain, with hippocampal pyramidal cells being particularly vulnerable. Even within hippocampus, heterogeneous susceptibility is evident, with higher vulnerability of CA1 versus CA3 neurons described for several decades. Therefore, numerous studies have focused exclusively on CA1. Pediatric cardiac surgery is increasingly focusing on studies of hippocampal structures, and a negative impact of cardiopulmonary bypass on the hippocampus cannot be denied. Recent studies show a shift in selective vulnerability from neurons of CA1 to CA3. This review shows that cell damage is increased in CA3, sometimes stronger than in CA1, depending on several factors. Despite a highly variable pattern, several markers illustrate greater damage to CA3 neurons than previously assumed. Nevertheless, the underlying cellular mechanisms have not been fully deciphered to date. The complexity is reflected in possible pathomechanisms discussed here, with numerous factors contributing to either enhanced CA1 or CA3 vulnerability. These results emphasize that future studies should focus on the CA3 field in addition to CA1, especially with regard to improving therapeutic strategies after ischemic/hypoxic brain injury.

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Assessment of CA1 injury after global ischemia using supervised 2D analyses of nuclear pyknosis

Cited by 9 publications

References 23 publications

Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

The Role of Microclot Formation in an Acute Subarachnoid Hemorrhage Model in the Rabbit

Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells. Collation of possible pathomechanisms for selective damage known to date from various study models. Should more attention be paid to the CA3 region in future studies?

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