Changes in Experimental Stroke Outcome across the Life Span

Liu, Fudong; Yuan, Rongwen; Benashski, Sharon E.; McCullough, Louise D.

doi:10.1038/jcbfm.2009.5

Cited by 197 publications

(224 citation statements)

References 48 publications

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“…Variation in plasma Cryab levels may be one of the several differences between younger and older patients to explain the worse outcome in older patients (33,34). Earlier studies have described Cryab as a guardian molecule in brain inflammation in multiple sclerosis, and this descriptive name clearly translates to its role in stroke (10,35).…”

Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

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

128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

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

128

View full text Add to dashboard Cite

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“…Most experimental stroke studies have been performed on young animals, and therefore may not fully replicate the effects of ischemia on neural tissue in aged subjects. Aged male mice have less histological damage after MCAO despite increased functional deficits and mortality, the underlying mechanism of which remains elusive (Liu et al 2009b). Recent studies have demonstrated that aging is accompanied by an increase in AMP/ ATP ratio in multiple tissues (Hardie and Hawley 2001;Petersen et al 2003;Wang et al 2003), yet AMPK levels are surprisingly lower in aged muscle (Qiang et al 2007;Reznick et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Age-related changes in AMP-activated protein kinase after stroke

Liu

Benashski

Persky

et al. 2011

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Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Strokeinduced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.

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“…Rectal temperatures were maintained at ∼37°C during surgery and ischemia with an automated temperature control feedback system. Due to weight adjusted variation in vessel diameter, 0.21 mm and 0.23 mm siliconecoated sutures were used in mice weighing <30 g and >30 g, respectively, to achieve equivalent occlusion, as described previously (52). Sham-operated animals underwent the same surgical procedure, but the suture was not advanced into the middle cerebral artery.…”

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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Changes in Experimental Stroke Outcome across the Life Span

Cited by 197 publications

References 48 publications

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Age-related changes in AMP-activated protein kinase after stroke

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

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