Age-related severity of focal ischemia in female rats is associated with impaired astrocyte function

Abstract

In middle-aged female rats, focal ischemia leads to a larger cortical infarction as compared with younger females. To determine if stroke-induced cytotoxicity in middle-aged females was associated with impaired astrocyte function, astrocytes were harvested and cultured from the ischemic cortex of young and middle-aged female rats. Middle-aged astrocytes cleared significantly less glutamate from media as compared with young female astrocytes. Furthermore, astrocyte-conditioned media from middle-aged female astrocytes induced greater migration of peripheral blood monocyte cells (PBMCs) and expressed higher levels of the chemoattractant macrophage inflammatory protein-1 (MIP-1). Middle-aged astrocytes also induced greater migration of neural progenitor cells (NPCs), however, their ability to promote neuronal differentiation of neural progenitor cells was similar to young astrocytes. In males, where cortical infarct volume is similar in young and middle-aged animals, no age-related impairment was observed in astrocyte function. These studies show that the aging astrocyte may directly contribute to infarct severity by inefficient glutamate clearance and enhanced cytokine production and suggest a cellular target for improved stroke therapy among older females.

The Effects of Estrogen in Ischemic Stroke

“…Although decreased ischemic damage occurs in adult female vs. male rodents in many models of induced global [53] and focal [48] cerebral ischemia (for reviews, see [54, 55]), we have found that female mice are more susceptible to stroke damage than males [24] after the age of 15 months. This has also been seen by others [56, 57] and the loss of circulating E2 with gonadal senescence has been one accepted etiology of this sex difference [58]. However, as hormone levels are similar in males and females prior to puberty yet females show reduced ischemic damage, there must be an unknown interaction with age and hormone loss or an intrinsic sex difference mediated by chromosome compliment and/or organizational effects of steroids (see recent reviews [25, 59]).…”

Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging

“…In addition, IGF-1 protected astrocytes, but not neurons against H 2 O 2 -induced death (Genis et al, 2014). IGF-1 plasma levels are decreased in middle-aged females, and astrocytes from middle-aged females secrete significantly less IGF-1 as compared to adult astrocytes (Lewis et al, 2012; Selvamani and Sohrabji, 2010a) (Fig. 1).…”

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

“…An alternative MCAO model employs injection of the vasoconstrictive peptide, ET-1; this method occludes blood flow to 30–50% of normal and results in a delayed hypoperfusion (Biernaskie et al, 2001). This model has been widely used to demonstrate the loss of estrogen's neuroprotective effects in aged, reproductively senescent rats (Lewis et al, 2012; Selvamani and Sohrabji, 2010a,b). Similarly, Leon and colleagues (Leon et al, 2012) also showed a deleterious effect of estrogen in aged rats using a tMCAO model coupled with the tPA during reperfusion.…”