Age-related changes in brain support cells: Implications for stroke severity

Abstract

Stroke is one of the leading causes of adult disability and the fourth leading cause of mortality in the US. Stroke disproportionately occurs among the elderly, where the disease is more likely to be fatal or lead to long-term supportive care. Animal models, where the ischemic insult can be controlled more precisely, also confirm that aged animals sustain more severe strokes as compared to young animals. Furthermore, the neuroprotection usually seen in younger females when compared to young males is not observed in older females. The preclinical literature thus provides a valuable resource for understanding why the aging brain is more susceptible to severe infarction. In this review, we discuss the hypothesis that stroke severity in the aging brain may be associated with reduced functional capacity of critical support cells. Specifically, we focus on astrocytes, that are critical for detoxification of the brain microenvironment and endothelial cells, which play a crucial role in maintaining the blood brain barrier. In view of the sex difference in stroke severity, this review also discusses studies of middle-aged acyclic females as well as the effects of the estrogen on astrocytes and endothelial cells

Ischemia-induced Angiogenesis is Attenuated in Aged Rats

“…First, aged animals after stroke sustain more severe brain injuries compared to young animals [26][27][28], and it's highly probable that different brain damage will induce different angiogenesis. Second, intravascular flow rate is an important mediator for angiogenesis, and previous studies showed that aging is greatly related to blood flow velocity and flow volume [29].…”

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

“…The majority of studies suggest that these effects do not persist in older female rodents (Leon et al, 2012; Sohrabji et al, 2013b; Strom et al, 2011). In addition to the loss of the anti-inflammatory properties of 17βE2 in young, Ovx mice, recent studies strongly suggest that the anti-inflammatory effects of 17βE2 are lost during a period of prolonged hypoestrogenicity in middle-aged (Suzuki et al, 2007a), or reproductively senescent (Selvamani and Sohrabji, 2010a; Sohrabji et al, 2013a), mice. 17βE2 also suppresses a systemic post-stroke immunosuppression phenotype in animal models that closely mimics a peripheral immunosuppressive phenotype seen in human patients (Ritzel et al, 2013; Zhang et al, 2010).…”

“…Several excellent reviews address cell type-specific anti-inflammatory mechanisms of 17βE2 in microglia (Habib and Beyer, 2015; Vegeto et al, 2008), astrocytes (Acaz-Fonseca et al, 2014), endothelial cells (Sohrabji et al, 2013a), and oligodendrocytes (Arevalo et al, 2010) during neurological injury. In young and middle-aged preclinical animal models of stroke, 17βE2 inhibits the activation of the pro-inflammatory transcription factor, nuclear factor-κβ, which induces transcription of numerous cytokines such as tumor necrosis factor-α (TNFα), chemokine ligand 2 (CCL2), interleukin-6 (Vegeto et al, 2008).…”

“…17βE2 treatment significantly impacts neurotrophin systems in young and aged Ovx rats, increasing neurotrophin and its receptor mRNA levels in basal forebrain, frontal cortex, and hippocampus (McMillan et al, 1996; Pan et al, 1999; Singh et al, 1995; Sohrabji et al, 1995) as well as elevating NGF and BDNF protein levels in cognitive brain regions (Bimonte-Nelson et al, 2004a,b). Moreover, there is mounting evidence from the Sohrabji group that estrogen imparts neuroprotective action via interations with insulin-like growth factor (IGF) receptor (Sohrabji and Williams, 2013). Indeed, in young animals, blockade of IGF receptors obviates the protective actions of 17βE2 against endothelin-1 (ET-1) induced stroke damage (Selvamani and Sohrabji, 2010b).…”

Hypoxia-Induced Gene Expression of Aquaporin-4, Cyclooxygenase-2 and Hypoxia-Inducible Factor 1α in Rat Cortical Astroglia Is Inhibited by 17β-Estradiol and Progesterone

“…This allows astrocytes to play a critical and leading role in the detoxification of the CNS microenvironment and, due to their involvement in the fine-tuning of brain inflammatory responses, in the local inflammatory regulation under acute devastating conditions [7,11,12] . Astroglia cells convey a multitude of cellular actions which all can be attributed a protective role such as growth factor supply, reduction of excitotoxicity, minimizing oxidative stress, influencing the interplay of immunological cells and innate immune responses, and regulating water balance as well as astrocyte swelling [11,[13][14][15][16][17] .…”