2025-09-22 テキサスA&M大学
<関連情報>
- https://stories.tamu.edu/news/2025/09/22/why-women-bear-the-burden-of-dementia-unraveling-the-sex-gap/
- https://www.biorxiv.org/content/10.1101/2025.02.01.636074v1
- https://www.sciencedirect.com/science/article/pii/S0889159124005300
- https://www.sciencedirect.com/science/article/pii/S0197458023000945
- https://www.jneurosci.org/content/30/20/6852/tab-article-info
雌ラットにおける虚血性脳卒中慢性期における白質路の喪失と持続性ミクログリア活性化、およびmiR-20a-3p治療の効果 Loss of white matter tracts and persistent microglial activation in the chronic phase of ischemic stroke in female rats and the effect of miR-20a-3p treatment
Dayalan Sampath, Macy E. Zardeneta, Zara Akbari, Jacob Singer, Balaji Gopalakrishnan, David Austin Hurst, Monserrat Villarreal, Erin A. McDaniel, Brenda Patricia Noarbe, Andre Obenaus, Farida Sohrabji
BioRxiv Posted: February 06, 2025
DOI:https://doi.org/10.1101/2025.02.01.636074
ABSTRACT
Our previous studies showed that intravenous injections of the small non-coding RNA mir-20a-3p is neuroprotective for stroke in the acute phase and attenuates long-term cognitive impairment in middle-aged female rats. In this study, we evaluated postmortem brain pathology at 100+d after stroke in a set of behaviorally characterized animals. This included Sham (no stroke) controls or stroke animals that received either mir20a-3p at 4h, 24h and 70d iv post stroke (MCAo+mir20a-3p) or a scrambled oligo (MCAo+Scr). Brain volumetric features were analyzed with T2 weighted and Diffusion Tensor magnetic resonance imaging (MRI) followed by histological analysis. Principal component analysis of Fractional Anisotropy (FA)-diffusion tensor MRI measures showed that MCAo+Scr and MCAo+mir20a-3p groups differed significantly in the volume of white matter but not gray matter. Weil myelin-stained sections confirmed decreased volume of the corpus callosum, internal capsule and the anterior commissure in the ischemic hemisphere of MCAo+Scr animals compared to the non-ischemic hemisphere, while sham and MCAo+Mir-20a-3p showed no hemispheric asymmetries. The MCAo+Scr group also exhibited asymmetry in hemisphere and lateral ventricle volumes, with ventricular enlargement in the ischemic hemisphere as compared to the non-ischemic hemisphere. The numbers of microglia were significantly elevated in white matter tracts in the MCAo+Scr group, with a trend towards increased myelin phagocytic microglia in these tracts. Regression analysis indicated that performance on an episodic memory test (novel object recognition test; NORT) was associated with decreased white matter volume and increased microglial numbers. These data support the hypothesis that stroke-induced cognitive impairment is accompanied by white matter attrition and persistent microglial activation and is consistent with reports that cognitive deterioration resulting from vascular diseases, such as stroke, is associated with secondary neurodegeneration in regions distal from the initial infarction.
中齢雌スプルーグ・ドーリーラットにおける脳卒中誘発性認知障害の軽減:末梢(中枢ではない)IGF-1治療の効果と腸管を治療標的とするアプローチ Peripheral, but not central, IGF-1 treatment attenuates stroke-induced cognitive impairment in middle-aged female Sprague Dawley rats: The gut as a therapeutic target
Yumna El-Hakim, Kathiresh Kumar Mani, Kaylin A. Pickle, Zara Akbari, Nadia Samiya, Chloe Pham, Gianna Salas, Rachel Pilla, Farida Sohrabji
Brain, Behavior, and Immunity Available online: 12 August 2024
DOI:https://doi.org/10.1016/j.bbi.2024.08.008
Highlights
- This study compared the effect of intraperitoneal (IP) and intracerebroventricular (ICV) IGF1 on acute and chronic stroke.
- ICV-IGF-1 initiated 4h after MCAo reduces infarct volume, improves sensory motor impairment, while IP-IGF-1 does not.
- In contrast, IP-IGF1 reduces inflammatory cytokines and stroke induced cognitive impairment, while ICV-IGF-1 does not.
- IP-IGF1 restores the gut epithelium and maintains normal gut microbial flora, while ICV-IGF1 does not.
- Overall, these data support the hypothesis that repairing the gut can improve chronic stroke outcomes.
Abstract
Stroke results in immediate sensory or motor disability and increases the risk for long term cognitive-affective impairments. Thus, therapies are urgently needed to improve quality of life for stroke survivors, especially women who are at a greater risk for severe stroke after menopause. Most current research on stroke therapies target the central nervous system; however, stroke also impacts peripheral organ systems. Our studies using acyclic (estrogen-deficient) middle aged female Sprague Dawley rats show that this group not only displays worse outcomes after stroke as compared to adult females, but also has lower levels of the neuroprotective peptide Insulin-like Growth Factor (IGF1) in circulation. Intracerebroventricular (ICV) administration of IGF1 to this group decreases infarct volume and improves sensory motor performance in the acute phase. In this study, we show that, despite this neuroprotection, ICV-IGF1 did not reduce peripheral inflammation or improve post stroke cognitive impairment in the chronic phase. In view of the evidence that stroke induces rapid gut dysfunction, we tested whether systemic delivery of IGF1 (intraperitoneal, IP) would promote gut health and consequently improve long-term behavioral outcomes. Surprisingly, while IP-IGF1, delivered 4 h and 24 h after ischemic stroke, did not reduce infarct volume or acute sensory motor impairment, it significantly attenuated circulating levels of pro-inflammatory cytokines, and attenuated stroke-induced cognitive impairment. In addition, IP-IGF1 treatment reduced gut dysmorphology and gut dysbiosis. Our data support the conclusion that therapeutics targeting peripheral targets are critical for long-term stroke recovery, and that gut repair is a novel therapeutic target to improve brain health in aging females.
中齢ラットにおける局所虚血後の認知障害における性差と、静脈内miR-20a-3p治療の効果 Sex differences in cognitive impairment after focal ischemia in middle-aged rats and the effect of iv miR-20a-3p treatment
Dayalan Sampath, Taylor E. Branyan, Kylee G. Markowsky, Rithvik Gunda, Nadia Samiya, Andre Obenaus, Farida Sohrabji
Neurobiology of Aging Available online: 5 May 2023
DOI:https://doi.org/10.1016/j.neurobiolaging.2023.05.001
Abstract
Stroke is a major cause of death and disability worldwide and is also a leading cause of vascular dementia and Alzheimer’s disease, with older women experiencing accelerated decline. Our previous studies show that intravenous (iv) injections of miR-20a-3p, a small noncoding RNA (miRNA) delivered after stroke improves acute stroke outcomes in middle-aged male and female rats. The present study tested whether mir-20a-3p treatment would also ameliorate stroke-induced cognitive decline in the chronic phase. Acyclic middle-aged females and age-matched male Sprague Dawley rats were subjected to middle cerebral artery occlusion using endothelin-1 or sham surgery, and treated iv with miR-20a-3p mimics or scrambled oligos at 4 hours, 24 hours, and 70 days post-stroke. Stroke resulted in a significant sensory motor deficit, while miR-20a-3p treatment reduced these deficits in both sexes. Cognitive impairment was assessed periodically for 3 months after stroke using contextual fear conditioning and the novel object recognition task. Overall, the tests of associative and episodic memory were affected by focal ischemia only in female rats, and miR-20a-3p ameliorated the rate of decline.
高齢雌ラットにおける虚血性脳卒中に対するエストロゲンの神経毒性効果は、加齢依存性のインスリン様成長因子-1喪失と関連している The Neurotoxic Effects of Estrogen on Ischemic Stroke in Older Female Rats Is Associated with Age-Dependent Loss of Insulin-Like Growth Factor-1
Amutha Selvamani and Farida Sohrabji
Journal of Neuroscience Published:19 May 2010
DOI:https://doi.org/10.1523/JNEUROSCI.0761-10.2010
Abstract
Hormone therapy to postmenopausal females increases the risk and severity of ischemic stroke. Our previous work using an animal model of menopause (reproductive senescence) shows that middle cerebral artery occlusion (MCAo) causes a larger cortical–striatal infarct in this older acyclic group compared with younger females. Moreover, although estrogen treatment is neuroprotective in younger females, estrogen paradoxically increases infarct volume in acyclic females. We hypothesized that the neurotoxic effects of estrogen in older females occurs because of decreased availability of IGF-1, a neuroprotectant that decreases with advancing age and is downregulated by estrogen treatment. Our data show that plasma IGF-1 levels are significantly reduced in reproductive senescent females and further reduced by estrogen at all ages. The neuroprotective effect of estrogen on MCAo-induced cortical infarct volume in mature adult female is reversed by intracerebroventricular injections of IGF-1 receptor antagonist JB-1. Similarly, estrogens neurotoxic effects on cortical infarct volume in senescent females is attenuated by concurrent IGF-1 treatment, and reversed when IGF-1 is infused 4 h after the onset of ischemia (delayed IGF-1 treatment). Delayed IGF-1/estrogen treatment also suppressed ischemia-induced ERK1 phosphorylation, reduced protein oxidation, and stimulated an early increase in prostaglandin E2 at the infarct site. IGF-1 treatment was only protective in senescent females that received estrogen, indicating that the neuroprotective actions of this peptide require interaction with the steroid hormone receptor. These data support the hypothesis that stroke severity in older females is associated with decreased IGF-1 and further indicate that short-term postischemic IGF-1 therapy may be beneficial for stroke.
