Elsevier

Neuroscience

Volume 168, Issue 4, 28 July 2010, Pages 1036-1046
Neuroscience

Neuropathophysiological Roles of AQPs
Review
Aquaporin-4 in brain and spinal cord oedema

https://doi.org/10.1016/j.neuroscience.2009.08.019Get rights and content

Abstract

Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood–brain border), the glia limitans (subarachnoid cerebrospinal fluid—brain border) and ependyma (ventricular cerebrospinal fluid—brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases.

Section snippets

Brain oedema formation

Two major types of brain oedema were defined by Igor Klatzo, cytotoxic and vasogenic (Klatzo, 1994). Cytotoxic oedema occurs when brain cells are damaged and the Na+–K+ ATP-ase fails, but the blood-brain barrier (BBB) is still intact. Cytotoxic oedema also occurs in hyponatraemia when an osmotic gradient is created between plasma and brain. The cells swell from influx of fluid from the vascular compartment (Fig. 1A). Cytotoxic oedema contracts the interstitial compartment and expands the

Brain oedema elimination

The brain has no lymphatic system and therefore brain oedema fluid is eliminated through the glia limitans into the subarachnoid CSF, through the ependyma into the ventricular CSF, and through the BBB into the blood (Fig. 2) (Tait et al., 2008). The relative contribution of each route to oedema resolution may depend on the surface area of each barrier and the intracranial pressure (ICP). Different sized dyes infused into the brain interstitial space are eliminated at comparable rates into the

Fluid compartments inside the skull

The human intracranial volume is ∼1.4 L (Tait et al., 2008) and comprises the brain parenchyma (∼1.2 L), intravascular (∼100 ml) and CSF (∼100 ml) compartments. Within the brain parenchyma, water is distributed intracellularly (∼1.1 L) and interstitially (∼100 ml). Because the adult skull is non-compliant, the sum of the volumes of all fluid compartments remains constant even with major fluid shifts between compartments (Monro-Kellie doctrine). The intracranial pressure-volume curve is

Detrimental effects of brain oedema

As cerebral perfusion pressure (CPP), defined as the difference between mean arterial and intracranial pressures, varies between 60–150 mmHg, cerebral blood flow (CBF) remains constant at ∼50 mL/100 g/min. This is termed autoregulation. Brain oedema causes a rise in ICP, which reduces CPP, causing brain ischaemia (Lang and Chesnut, 1995, Czosnyka et al., 2006, Czosnyka et al., 2007). Elevated arterial CO2 (PACO2, normally 3.5–4.5 kPa) causes an increase in CBF and is detrimental in brain oedema

Spinal cord oedema

Little is known about the mechanisms producing spinal cord oedema or whether spinal cord oedema is clinically important. Indirect evidence suggests that spinal cord oedema adversely affects outcome after spinal cord injury (SCI). Water accumulation in spinal cord parenchyma occurs acutely after SCI in humans (Flanders et al., 1999, Boldin et al., 2006, Miyanji et al., 2007), and several animal species (Wagner and Stewart, 1981, Fujii et al., 1993, Sharma et al., 2005), with substantial evidence

Treatment of brain oedema

Clinical treatments for brain oedema are limited (Marmarou, 2007). Corticosteroids (dexamethasone) are widely used to reduce brain oedema associated with brain tumours since their introduction in the 1950s (McClelland and Long, 2008). Dexamethasone often improves the neurological symptoms in brain tumour patients, by reducing the mass effect on adjacent brain tissue, and improves the safety of surgery by reducing intraoperative and postoperative brain swelling. The CRASH trial concluded that

Treatment of spinal cord oedema

In contrast to brain oedema, spinal cord oedema is not usually clinically treated. Following two clinical trials in the 1990s (Bracken et al., 1990, Bracken et al., 1997), methylprednisolone became widely used in traumatic SCI. These trials have been criticized and the use of methylprednisolone has recently declined (Miller, 2008). Corticosteroids are used to treat tumour-associated spinal cord oedema. In contrast to brain oedema, hypertonic mannitol and saline are not used in spinal cord

Aquaporins in general

The aquaporins are a family of water channel proteins highly expressed in plasma cell membranes that typically raise the osmotic permeability of the plasma cell membrane by 5–20 fold. The first AQP, termed AQP1, was discovered by Peter Agre in 1988 (Denker et al., 1988). At least 10 aquaporins have subsequently been identified in mammals and several in other animal and plant species (Verkman, 2009). Mammalian AQPs are divided into two groups, those that only transport water and those that also

Aquaporin expression in the CNS

The most abundant water channel in the CNS is AQP4 (Fig. 4A), which is found in three locations: the perimicrovessel astrocyte foot processes (Fig. 4C), glia limitans (Fig. 4D) and ependyma (Tait et al., 2008). AQP4 is highly expressed in a polarized fashion in the plasma cell membranes of astrocyte foot processes around microvascular endothelial cells. The ependymal cells, which line the ventricles, express AQP4 polarized to their basolateral plasma cell membranes. The glia limitans, composed

Molecular properties of AQP4

AQP4 is expressed within plasma cell membranes as tetramers (Verkman and Mitra, 2000, Tait et al., 2008). Each AQP4 monomer is ∼28 kDa and has its own water pore, produced by six membrane–spanning domains. It is unclear whether AQP4 freely diffuses within the plasma cell membrane or whether AQP4 is anchored to intracellular proteins. Ole Ottersen and Amiry Moghaddam suggested that AQP4 binds alpha-syntrophin (Amiry-Moghaddam et al., 2003b), but Alan Verkman used quantum dot single particle

AQP4 and brain oedema

Indirect evidence suggests a key role for AQP4 in brain oedema. AQP4 becomes upregulated in conditions that cause brain oedema such as malignant astrocytomas (Saadoun et al., 2002b, Warth et al., 2004), acute bacterial meningitis (Saadoun et al., 2002b, Papadopoulos and Verkman, 2005) and subarachnoid haemorrhage (Saadoun et al., 2002b, Badaut et al., 2003). In some cases, such as the astrocytomas, the level of AQP4 upregulation correlates with the amount of brain oedema (Saadoun et al., 2002b,

AQP4 and spinal cord oedema

Several studies (Nesic et al., 2006, Xu et al., 2008, Wang et al., 2009) reported correlations between changes in AQP4 immunoreactivity and spinal cord oedema after SCI in rodents, thus providing indirect evidence that AQP4 is important in spinal cord oedema. Our group showed that AQP4 deletion reduces spinal cord oedema assessed at 48 h and markedly improves neurological outcome in a compression SCI model in mice (Fig. 6) (Saadoun et al., 2008). Here we suggest that SCI produces a mixture of

AQP4 in neuromyelitis optica

Neuromyelitis optica (NMO), also known as Devic's disease or opticospinal multiple sclerosis, is a rare demyelinating, inflammatory condition (Wingerchuk et al., 2007, Jarius et al., 2008b). The clinical features of NMO differ from those of multiple sclerosis in that NMO primarily affects the optic nerves and spinal cord and spares the brain, at least in the initial stages. In contrast to multiple sclerosis the spinal cord lesions in NMO often span at least three vertebral levels and are

AQP4 inhibitors and activators

The discovery of AQP4 activators and inhibitors would be a major contribution to AQP4 CNS research (Papadopoulos and Verkman, 2008). AQP4 inhibitors are expected to reduce cytotoxic oedema and AQP4 activators to reduce vasogenic oedema. The recent discovery that AQP4 facilitates the migration of reactive astrocytes towards an injury site and the infiltration of malignant astrocytes in glioblastoma (Saadoun et al., 2002b, Saadoun et al., 2005b, Auguste et al., 2007, Verkman et al., 2008) suggest

Acknowledgments

We thank the Neurosciences Research Foundation (MCP), Harrison Fund (SS) and the Guthy-Jackson Foundation (MCP, SS).

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