Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion

Dominguez, Reymundo; Zitting, Madison; Liu, Qinghai; Patel, Arati; Babadjouni, Robin; Hodis, Drew M; Chow, Robert H.; Mack, William J.

doi:10.1016/j.jstrokecerebrovasdis.2018.01.030

Cited by 23 publications

(24 citation statements)

References 74 publications

(79 reference statements)

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“…Given that impairments in NOP test outcomes are observed after 1 mo of CCH in the mouse model of VCID we used (Patel et al, 2017;Dominguez et al, 2018;Miyanohara et al, 2018;Ben-Ari et al, 2019), it is not surprising that, in our study, 3 mo of CCH resulted in significant decreases in discrimination indices and novelty preferences based on exploration time. Important are our findings that both RHC-treated mice and the adult F1 offspring of RHC-treated males and females were resilient to such CCH-induced deficits, with both cohorts exhibiting no loss of recognition memory.…”

Section: Discussionmentioning

confidence: 75%

“…Novel object preference (NOP) testing is a well-established neurobehavioral tool to assess recognition memory (Antunes & Biala 2012; Vogel-Ciernia et al, 2014; Lueptow et al, 2017; Morena-Castilla et al, 2018). In the VCID model we used, impairments in recognition memory have been confirmed by NOP following 1 month (Patel et al, 2017; Dominguez et al, 2018) of CCH. We commenced NOP testing 3 mo after CCH or sham surgery in both F0 and F1 mice.…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

Kcd

et al. 2021

Preprint

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Background: Vascular cognitive impairment and dementia (VCID), which occurs immediately or in delayed fashion in 25-30% of stroke survivors, or secondary to chronic cerebral hypoperfusion, is the second leading cause of dementia following Alzheimers disease. To date, efficacious therapies are unavailable. We have shown previously in mice that repetitive hypoxic preconditioning (RHC) induces a long-lasting resilience to acute stroke (Stowe et al., 2011). More recently, we documented that untreated, first-generation adult progeny of mice exposed to RHC prior to mating are protected from retinal ischemic injury (Harman et al., 2020), consistent with accumulating evidence supporting the concept that long-lasting phenotypes induced epigenetically by intermittent stressors may be heritable. We undertook the present study to test the hypothesis that RHC will induce resilience to VCID, and that such RHC-induced resilience can also be inherited. Methods: Chronic cerebral hypoperfusion (CCH) was induced in C57BL/6J mice secondary to bilateral carotid artery stenosis with microcoils in both the parental (F0) generation, and in their untreated first-generation (F1) offspring. Cohorts of F0 mice were directly exposed to either 8 wks of RHC (1 h of systemic hypoxia 11% oxygen, 3x/week) or normoxia prior to CCH. Cohorts of F1 mice were derived from F0 mice treated with RHC prior to mating, and untreated, normoxic controls that were age-matched at the time of stenosis induction. Demyelination in the corpus callosum of F0 mice was assessed following 3 months of CCH by immunohistochemistry. Mice from both generations were assessed for short-term recognition memory in vivo by novel object preference (NOP) testing following 3 months of CCH, and a month thereafter, ex vivo measurements of CA1 hippocampal long-term potentiation (LTP) were recorded from the same animals as a metric of long-lasting changes in synaptic plasticity. Results: Three months of CCH caused demyelination and concomitant impairments in recognition memory in control mice from both generations. However, these CCH-induced memory impairments were prevented in F0 animals directly treated with RHC, as well as in their untreated adult F1 progeny. Similarly, hippocampal LTP was preserved in the 4-month CCH cohorts of mice directly treated with RHC, and in their untreated offspring with CCH. Conclusions: Our findings demonstrate that RHC or other repetitively-presented, epigenetic-based therapeutics may hold promise for inducing a long-lasting resilience to VCID in treated individuals, and in their first-generation adult progeny.

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Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

Kcd

et al. 2021

Preprint

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“…The fact that our cohort consisted of exclusively male mice is a potential limitation of this study. Previous studies have suggested that estrogen may have a protective effect against white matter injury [ 61 , 73 ]. This effect, particularly in the setting of inflammatory damage, may be explained by microglial expression of estrogen receptors.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticulate matter exposure results in neuroinflammatory changes in the corpus callosum

et al. 2018

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Epidemiological studies have established an association between air pollution particulate matter exposure (PM2.5) and neurocognitive decline. Experimental data suggest that microglia play an essential role in air pollution PM-induced neuroinflammation and oxidative stress. This study examined the effect of nano-sized particulate matter (nPM) on complement C5 deposition and microglial activation in the corpus callosum of mice (C57BL/6J males). nPM was collected in an urban Los Angeles region impacted by traffic emissions. Mice were exposed to 10 weeks of re-aerosolized nPM or filtered air for a cumulative 150 hours. nPM-exposed mice exhibited reactive microglia and 2-fold increased local deposition of complement C5/ C5α proteins and complement component C5a receptor 1 (CD88) in the corpus callosum. However, serum C5 levels did not differ between nPM and filtered air cohorts. These findings demonstrate white matter C5 deposition and microglial activation secondary to nPM exposure. The C5 upregulation appears to be localized to the brain.

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“…Similarly, it reproduces metabolic damage in parameters such as: cerebral acidosis, decreased cerebral blood flow, and decreased glucose uptake [52] and has the ability to show the neuroprotective effect of different therapeutic approaches like hypothermia [67,68]. Bilateral ligation of the carotid artery is also used to accentuate white matter damage [69,70] .…”

Section: Experimental Modelsmentioning

confidence: 99%

Neuroactive Steroids in Hypoxic–Ischemic Brain Injury: Overview and Future Directions

Toro-Urrego¹,

Ávila-Rodriguez²,

Herrera³

et al. 2020

Neuroprotection - New Approaches and Prospects

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Hypoxic–ischemic brain injury is a number one cause of long-term neurologic disability and death worldwide. This public health burden is mainly characterized by a decrease in oxygen concentration and blood flow to the tissues, which lead to an inefficient supply of nutrients to the brain. This condition induces cell death by energy depletion and increases free radical generation and inflammation. Hypoxic–ischemic brain injury may occur in ischemic-stroke and over perinatal asphyxia, being both leading causes of morbidity in adults and children, respectively. Currently, there are no effective pharmaceutical strategies to prevent the triggering of secondary injury cascades, including oxidative stress and metabolic dysfunction. Neuroactive steroids like selective estrogen receptor modulators, SERMs, and selective tissue estrogenic activity regulators, STEARs, exert several neuroprotective effects. These encompass mitochondrial survival, a decrease in reactive oxygen species, and maintenance of cell viability, among others. In this context, these neurosteroids constitute promising molecules, which could modify brain response to injury. Here we show an updated overview of the underlying mechanisms of hypoxic–ischemic brain injury. We also highlight the neuroprotective effects of neurosteroids and their future directions.

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Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion

Abstract: This study demonstrates a potentially protective role for oral estradiol therapy in the setting of white matter injury and declarative memory deficits secondary to murine chronic cerebral hypoperfusion.

Cited by 23 publications

References 74 publications

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

Nanoparticulate matter exposure results in neuroinflammatory changes in the corpus callosum

Neuroactive Steroids in Hypoxic–Ischemic Brain Injury: Overview and Future Directions

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