Social interaction plays a critical role in neurogenesis and recovery after stroke

Venna, Venugopal Reddy; Xu, Yan; Doran, Sarah J.; Patrizz, Anthony; McCullough, Louise D.

doi:10.1038/tp.2013.128

Cited by 102 publications

(106 citation statements)

References 52 publications

(89 reference statements)

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“…Similar reports have demonstrated cross‐talk between secreted factors (e.g., apoptosis, inflammation, oxidative stress) (; Brill et al, 2009; Chapman et al, 2015; Lu, Jones, Snyder, & Tuszynski, 2003; Zhang et al, 2015) and neurogenesis following brain insults, including stroke (Kernie and Parent, 2010; Yamashita et al, 2006). We (Hara et al, 2007; Morimoto et al, 2011; Tajiri et al, 2013), and others, have shown the important contribution of neurogenic factors in stroke brain remodeling (Jablonska et al, 2016; Rosell et al, 2013; Seo et al, 2014; Venna, Xu, Doran, Patrizz, & McCullough, 2014). Altogether, these results allude to host neurogenesis and its secreted neurogenic factors as key therapeutic targets of NSI‐189 in affording behavioral and neurostructural benefits in stroke.…”

Section: Discussionmentioning

confidence: 88%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI‐189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti‐depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, 2016, ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI‐189 in adult Sprague–Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke‐induced motor and neurological deficits, which was maintained up to 24 weeks post‐stroke. Histopathological assessment of stroke brains from NSI‐189‐treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI‐189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI‐189 treatment characterized by significant attenuation of OGD/R‐mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI‐189 as a therapeutic agent well beyond the initial 6‐hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

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Section: Discussionmentioning

confidence: 88%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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“…Female mice were ovariectomized (Ovx) as in 6 ten days before pre-screening for baseline laterality deficits and locomotor activity. Mice were then pair housed (male with Ovx female) for 14 days before subjecting them to a 90 min right middle cerebral artery occlusion (MCAO) followed by reperfusion as described previously 6,7 . Mice were randomly assigned using SPSS software to either individual housing immediately after stroke or continued pair housing (PH) with their original partner.…”

Section: Methodsmentioning

confidence: 99%

“…Following 72 hours of reperfusion, the NDS were recorded by a blinded investigator as in 6,7 . Infarcts were quantified from 2,3,5-triphenyltetrazolium chloride (TTC) stained coronal sections as detailed previously 6,7 .…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Mitochondrial P53 Abolishes the Detrimental Effects of Social Isolation on Ischemic Brain Injury

Venna

Verma

O'Keefe

et al. 2014

Stroke

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Background and Purpose Social Isolation (SI) increases stroke incidence and delays post-stroke recovery. Women may be at greater risk from the negative consequences of SI, but few studies have examined both sexes in experimental models, and none have evaluated the effects of isolation initiated after stroke. The effects of post-stroke SI in males and females were examined and the role of mitochondrial P53 was evaluated. Methods C57Bl6 mice were pair-housed (male and ovariectomized female) for 2 weeks, subjected to stroke and then assigned to a housing condition (isolated or pair-housed (PH)). The effects of housing on infarct volume and recovery were examined. Changes in Bcl-2 and mitochondrial p53 were assessed by western blot. A mitochondrial p53 inhibitor (PFT-μ) was given to mice of both sexes. Results Compared to PH mice, post-stroke SI significantly increased infarct size in both sexes; SI mice also had worse neurological deficits. The detrimental effects of SI paralleled increases in mitochondrial p53 levels. Pharmacological inhibition of mitochondrial p53 using PFT-μ abolished the detrimental effects of SI and reduced cell death. Conclusions Post-stroke SI results in increased ischemic injury in both sexes. The effect of housing on infarct was more pronounced in females. Targeting the mitochondrial P53 pathway could minimize the detrimental effects of isolation after stroke.

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“…Newborn cells in the infarct cortex were identified by colabeling with BrdU and DAPI. To perform quantification of BrdU + cells, four coronal brain slices per animal were stained from ∼1.1 mm bregma, 0.8 mm bregma, 0.5 mm bregma and −0.1 mm bregma as described previously (59). AngioTool software (National Cancer Institute) was used to quantify total vessel length, the number of vascular endpoints and junctions, and the percentage of area vascularized from microscopic images collected from brain sections adjacent to BrdU-quantified sections (60).…”

Section: Methodsmentioning

confidence: 99%

Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk

Ritzel

Patel

Spychala

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Females show a varying degree of ischemic sensitivity throughout their lifespan, which is not fully explained by hormonal or genetic factors. Epidemiological data suggest that sex-specific life experiences such as pregnancy increase stroke risk. This work evaluated the role of parity on stroke outcome. Age-matched virgin (i.e., nulliparous) and multiparous mice were subjected to 60 min of reversible middle cerebral artery occlusion and evaluated for infarct volume, behavioral recovery, and inflammation. Using an established mating paradigm, fetal microchimeric cells present in maternal mice were also tracked after parturition and stroke. Parity was associated with sedentary behavior, weight gain, and higher triglyceride and cholesterol levels. The multiparous brain exhibited features of immune suppression, with dampened baseline microglial activity. After acute stroke, multiparous mice had smaller infarcts, less glial activation, and less behavioral impairment in the critical recovery window of 72 h. Behavioral recovery was significantly better in multiparous females compared with nulliparous mice 1 mo after stroke. This recovery was accompanied by an increase in poststroke angiogenesis that was correlated with improved performance on sensorimotor and cognitive tests. Multiparous mice had higher levels of VEGF, both at baseline and after stroke. GFP + fetal cells were detected in the blood and migrated to areas of tissue injury where they adopted endothelial morphology 30 d after injury. Reproductive experience has profound and complex effects on neurovascular health and disease. Inclusion of female mice with reproductive experience in preclinical studies may better reflect the life-long patterning of ischemic stroke risk in women.sex differences | multiparity | microglia | ischemic stroke | microchimerism N early 800,000 people in the United States experience a new or recurrent stroke each year, and 55,000 more women than men are affected by stroke (1). Stroke is a sexually dimorphic disease impacted by genetics, hormones, and the environment (2). According to CDC data, 85% of women in the United States have given birth by age 40, whereas the number of lifetime pregnancies per woman varies by race and socioeconomic status. Therefore, child-bearing women represent a significant proportion of the female population, including those at risk for stroke. Moreover, this suggests that a large proportion of the elderly female populationwho is at highest risk for stroke-may be differentially at risk. Epidemiological data suggest that increasing parity is associated with higher risk of cardiovascular disease (CVD) and stroke and late-life vascular comorbidities, including carotid atherosclerosis (3, 4). However, recent reports suggest that parity has a significant protective effect against CVD mortality (5). The effect of parity on outcome following ischemic stroke is yet unresolved.Pregnancy induces profound acute and long-term physiological changes in the body that influence future vascular health through hormonally med...

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Social interaction plays a critical role in neurogenesis and recovery after stroke

Cited by 102 publications

References 52 publications

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Inhibition of Mitochondrial P53 Abolishes the Detrimental Effects of Social Isolation on Ischemic Brain Injury

Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk

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