Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy

Abstract

In this viewpoint article, I summarize data showing that the astrocytic swelling that occurs early after the acute CNS pathologies ischemia and traumatic brain injury is damaging. We have proposed that one reason may be the release of excitatory amino acids (EAA) via volume-activated anion channels (VRACs) that are activated by such swelling. This release could be a target for therapy, which could involve blocking the astrocytic swelling or the release mechanisms. The transport mechanisms likely causing the early astrocytic swelling are therefore summarized. In terms of targeting the release mechanisms, we have found a potent inhibitor of VRACs, tamoxifen, to be strongly neuroprotective in focal ischemia with a therapeutic window of 3 h after initiation of the ischemia. The question, however, of whether neuroprotection by tamoxifen can be solely attributed to VRAC inhibition in astrocytes has yet to be resolved.

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

“…As a consequence, astrocytes are intimately involved in synaptic transmission, synaptic plasticity, and long term potentiation (Allen and Barres, 2005;Panatier et al, 2006;Robitaille, 1998). Astrocytes are also involved in a variety of brain insults and pathological states (Hansson et al, 2000;Kiening et al, 2002;Kimelberg, 2005;Nakase et al, 2003;Panickar and Norenberg, 2005), therefore these cells are very likely to play an important role in brain damage caused by acute HA and in brain injury caused by chronic HA.…”

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…It has been proposed that low-grade astrocyte swelling, as may be seen in CLF, 46 could have significant functional consequences despite the absence of clinically overt ICH, and impairment of the cross-talk between swollen astrocytes and neurones has also been suggested to alter cerebral function. 47 Evidence suggests that the neuropsychological effects of induced hyperammonaemia, and the subsequent elevation of astrocyte glutamine levels, are determined by the intrinsic ability of the brain to buffer these changes by losing key osmolytes such as myo-inositol 48 ; a process which may in itself be modulated by other factors such as hyponatraemia, a major risk factor for the development of overt HE in patients with CLF. 49,50 In states of hyperammonaemia, ammonia detoxification within astrocytes leads to an intracellular accumulation of glutamine which, it is widely postulated, generates an osmotic stress and causes astrocytes to swell in HE; this is known as the osmotic gliopathy theory, and the reader is directed to a review by Brusilow and colleagues for a more detailed account.…”

Targeting Astrocytes for Stroke Therapy

“…Astrocytes are involved in a number of activities that profoundly influence tissue viability during ischemia, including glutamate homeostasis, water balance, maintenance of the blood-brain barrier, cerebral blood flow regulation, ion homeostasis, and secretion of neuroprotective factors [2][3][4][5][6] (see the article by Kimelberg and Nedergaard in this issue). Although astrocyte function is clearly necessary for maintenance of neuronal health, certain functions of astrocytes can have pathological consequences after stroke.…”

“…46 Astrocytes undergo rapid swelling in ischemic brain injury, which contributes to astrocyte dysfunction during stroke. 5 Several mechanisms could account for astrocyte swelling during ischemia, including decreased osmolarity, Donnan swelling, acidosis, glutamate uptake, and the Na ϩ , K ϩ , 2Cl Ϫ cotransporter. 5 Astrocyte swelling may be detrimental to neuronal survival by inducing glutamate release from astrocytes via VRACs 5 (FIG.…”