Organotypic Hippocampal Slices as Models for Stroke and Traumatic Brain Injury

Li, Qian; Han, Xiaoning; Wang, Jian

doi:10.1007/s12035-015-9362-4

Cited by 52 publications

(33 citation statements)

References 152 publications

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“…The advantage of OHSCs is that the complexity of the brain structure is well maintained. Therefore this system can be used as an ex-vivo model for neuronal development and degradation [ 50 ]. Apart from neurons, non-neuronal cell types like astrocytes, microglia and oligodendrocytes are present and their origin and development can be studied [ 7 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-aggregant tau mutant promotes neurogenesis

Joseph

Anglada-Huguet

Paesler

et al. 2017

Mol Neurodegeneration

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BackgroundThe microtubule-associated protein Tau plays a role in neurodegeneration as well as neurogenesis. Previous work has shown that the expression of the pro-aggregant mutant Tau repeat domain causes strong aggregation and pronounced neuronal loss in the hippocampus whereas the anti-aggregant form has no deleterious effects. These two proteins differ mainly in their propensity to form ß structure and hence to aggregate.MethodsTo elucidate the basis of these contrasting effects, we analyzed organotypic hippocampal slice cultures (OHSCs) from transgenic mice expressing the repeat domain (RD) of Tau with the anti-aggregant mutation (TauRDΔKPP) and compared them with slices containing pro-aggregant TauRDΔK. Transgene expression in the hippocampus was monitored via a sensitive bioluminescence reporter gene assay (luciferase).ResultsThe expression of the anti-aggregant TauRDΔKPP leads to a larger volume of the hippocampus at a young age due to enhanced neurogenesis, resulting in an increase in neuronal number. There were no signs of activation of microglia and astrocytes, indicating the absence of an inflammatory reaction. Investigation of signaling pathways showed that Wnt-5a was strongly decreased whereas Wnt3 was increased. A pronounced increase in hippocampal stem cell proliferation (seen by BrdU) was observed as early as P8, in the CA regions where neurogenesis is normally not observed. The increase in neurons persisted up to 16 months of age.ConclusionThe data suggest that the expression of anti-aggregant TauRDΔKPP enhances hippocampal neurogenesis mediated by the canonical Wnt signaling pathway, without an inflammatory reaction. This study points to a role of tau in brain development and neurogenesis, in contrast to its detrimental role in neurodegeneration at later age.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0230-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Anti-aggregant tau mutant promotes neurogenesis

Joseph

Anglada-Huguet

Paesler

et al. 2017

Mol Neurodegeneration

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“…OHSCs. OHSCs were cultured as previously described (67)(68)(69). Briefly, mouse pups (P7-P9) from C57BL/6 or CX3CR1 GFP/+ mice on C57BL/6 background were rapidly decapitated and the hippocampus placed in ice-cold Hanks' balanced salt solution (HBSS, with Ca 2+ and Mg 2+ ; Life Technologies) supplemented with 25 mM HEPES (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of neuronal ferroptosis protects hemorrhagic brain

Li¹,

Han²,

Lan³

et al. 2017

JCI Insight

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462

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Intracerebral hemorrhage (ICH) causes high mortality and morbidity, but our knowledge of post-ICH neuronal death and related mechanisms is limited. In this study, we first demonstrated that ferroptosis, a newly identified form of cell death, occurs in the collagenase-induced ICH model in mice. We found that administration of ferrostatin-1, a specific inhibitor of ferroptosis, prevented neuronal death and reduced iron deposition induced by hemoglobin in organotypic hippocampal slice cultures (OHSCs). Mice treated with ferrostatin-1 after ICH exhibited marked brain protection and improved neurologic function. Additionally, we found that ferrostatin-1 reduced lipid reactive oxygen species production and attenuated the increased expression level of and its gene product cyclooxygenase-2 ex vivo and in vivo. Moreover, ferrostatin-1 in combination with other inhibitors that target different forms of cell death prevented hemoglobin-induced cell death in OHSCs and human induced pluripotent stem cell-derived neurons better than any inhibitor alone. These results indicate that ferroptosis contributes to neuronal death after ICH, that administration of ferrostatin-1 protects hemorrhagic brain, and that cyclooxygenase-2 could be a biomarker of ferroptosis. The insights gained from this study will advance our knowledge of the post-ICH cell death cascade and be essential for future preclinical studies.

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“…In addition, organotypic slice cultures preserve the interaction between neurons and glial cells, necessary for supporting the energetic status of neurons in ischemic conditions [8]. Hippocampal slice cultures in particular can be subjected to transient oxygen-glucose deprivation (OGD) and subsequent reoxygenation to simulate ischemic neuronal injury and reperfusion [9]. In addition, hippocampal slice cultures exposed to OGD respond to therapeutic hypothermia [10], thus allowing the testing of neuroprotective agents in combination with hypothermia.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

et al. 2018

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Background: Hypoxic-ischemic encephalopathy is a major cause of neonatal morbidity. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Thus, adjunctive therapies, such as melatonin, are needed to provide additional neuroprotection. Objectives: The aim of this study was to determine a range of melatonin concentrations that could result in neuroprotective synergy with hypothermia. Methods: Hypoxia-ischemia was simulated by transient oxygen-glucose deprivation (OGD) in organotypic hippocampal slice cultures derived from neonatal rats. Cell damage was quantified by propidium iodide (PI) labeling. Results: Melatonin reduced OGD- induced cell death in a concentration-dependent manner (1–100 μM) with an EC₅₀ of about 25 μM. Hypothermia attenuated cell death in a time-dependent manner, with a nearly full protection upon 24-h exposure (78%) and partial protection (40%) upon 6-h exposure. When submaximal effective concentrations of melatonin (25 or 50 μM, resulting in 54 and 64% protection) were combined with 6 h of hypothermia, nearly full protection (73 and 78%, respectively; p < 0.05 and p < 0.01) was observed. Conclusion: Melatonin acts in synergy with hypothermia in attenuating OGD-induced damage in organotypic hippocampal cultures. This reductionist approach allows the determination of a range of concentrations of melatonin capable of enhancing hypothermic neuroprotection. This information, coupled with pharmacokinetic data, will help to define the therapeutic dosage of melatonin in vivo and, ultimately, in patients.

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Organotypic Hippocampal Slices as Models for Stroke and Traumatic Brain Injury

Cited by 52 publications

References 152 publications

Anti-aggregant tau mutant promotes neurogenesis

Anti-aggregant tau mutant promotes neurogenesis

Inhibition of neuronal ferroptosis protects hemorrhagic brain

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

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