Temporal and Regional Evolution of Aquaporin-4 Expression and Magnetic Resonance Imaging in a Rat Pup Model of Neonatal Stroke

Abstract

Edema formation can be observed using magnetic resonance imaging (MRI) in patients with stroke. Recent studies have shown that aquaporin-4 (AQP4), a water channel, is induced early after stroke and potentially participates in the development of brain edema. We studied whether induction of AQP4 correlated with edema formation in a rat pup filament stroke model using high field (11.7-Tesla) MRI followed by immunohistochemical investigation of AQP4 protein expression. At 24 h, we observed increased T2 values and decreased apparent diffusion coefficients (ADC) within injured cortical and striatal regions that reflected the edema formation. Coincident with these MR changes were significant increases in AQP4 expression on astrocytic end-feet in the border regions of injured tissues. Striatal imaging findings were still present at 72 h with a slow normalization of AQP4 expression in the border regions. At 28 d, AQP4 expression normalized in the border while in this region ADC values increased. We show that induction of AQP4 is increased during the period of active edema formation in the border region without regional correlation with edema. Finally, induction of AQP4 on astrocyte end-feet could participate in tissue preservation after ischemia in the immature rat brain. A rterial ischemic stroke, often within the distribution of the MCA, occurs in approximately 1 per 4,000 neonates and as in adults there are significant sequelae over the lifespan that make this disease an important public health concern (1). Increasingly, magnetic resonance imaging (MRI) is used to evaluate neonatal ischemic brain injury and several recent studies have demonstrated the added value of DWI in assessing injury severity and in determining long-term outcome (2-4). MRI also has been used to visualize brain edema that contributes to the morbidity and mortality of many of these conditions (5). In general, diffusion restriction with reduced ADC values correlates with cytotoxic edema, whereas increased T2WI values reflects the development of vasogenic edema (6,7).In the past decade, attention has focused on AQP in the development of brain edema. AQP are water-specific channels that provide a direct water route through the plasma membrane and are important in the regulation of water movement. Expression of AQP4 and AQP9, detected in mammalian brain, is altered in several conditions, including ischemia (7-9). Although astrocytic expression of AQP4 and AQP9 increases after ischemia, only AQP4 expression temporally correlates with the evolution of brain edema in adult mice and suggests that regulation of AQP4 expression could be a potential therapeutic target (9).The role of AQP4 in the evolution of cytotoxic and vasogenic edema after stroke remains uncertain. In the adult mouse, increased astrocytic AQP4 expression was observed at 1 h and 48 h after stroke (9). In contrast to adult stroke model studies, investigations in a neonatal rat pup model of HII found that AQP4 expression (decreased at 1 h and 24 h after HII), was associated with d...

Protective Role of Early Aquaporin 4 Induction against Postischemic Edema Formation

“…In young rats, AQP4 expression was increased 24 h after stroke at the edge of the lesion where there was no significant modification of water content measured by magnetic resonance imaging (Badaut et al, 2007a), suggesting that increased AQP4 expression could limit or prevent the formation and extension of edema. The role of AQP4 in cerebral edema is dual and depends of the model used (Badaut et al, 2007b;Verkman et al, 2006).…”

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

“…AQP4 expression has also been observed at 48 h in transient occlusions. In a mild stroke model (30 min of MCA occlusion), up-regulated AQP4 expression was detected for up to 7 d, whereas in a severe stroke model, elevated AQP4 expression persisted for up to 28 d [32,33] . The pattern of AQP4 expression in cerebrovascular diseases has revealed that this molecule plays a critical role in regulating water movement during brain edema [17] .…”

Traumatic Brain Injury in Young Rats Leads to Progressive Behavioral Deficits Coincident with Altered Tissue Properties in Adulthood

“…NF200, MBP, and CNPase coronal sections that were immunostained with infrared secondary antibodies were scanned using the same parameters for sham and CCI with a Licor-Odyssey scanner at 21 lm/pixel resolution (Licor BioScience, Lincoln, NE). The infrared method proposed to quantify the immunohistochemistry has recently been described by different authors (Bloch et al, 2011;Wong, 2004), and by our group (Badaut et al, 2007(Badaut et al, ,2011. For surface area measurements of the CC with NF200 (see Fig.…”