Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis

Abstract

The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitisinduced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 ؎ 1 versus 25 ؎ 5 cm H 2 O) and brain water accumulation (2 ؎ 1 versus 9 ؎ 1 l) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a ϳ5-fold higher water permeability (P f ) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P f and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.Streptococcus pneumoniae (pneumococcus) is the most common and aggressive meningeal pathogen (1-3). The overall incidence of pneumococcal meningitis is rising (4, 5) and the emergence of penicillin-resistant S. pneumoniae makes treatment harder (6, 7). Even with effective antibiotic treatment, mortality from pneumococcal meningitis is 10 -30%, with 30 -50% of patients acquiring permanent neurological deficits (1-3). A major complication associated with unfavorable outcome in bacterial meningitis is brain edema, which causes a rise in intracranial pressure potentially leading to brain ischemia, herniation, and death (8, 9). The molecular mechanisms responsible for the formation and absorption of excess fluid in brain edema associated with meningitis are poorly understood.The two main types of brain edema are cytotoxic and vasogenic (10). Cytotoxic edema, as occurs in ischemic stroke, refers to cell swelling that primarily affects astroglial cells. Vasogenic edema, as occurs in brain tumors, involves accumulation of excess fluid in the extracellular space of the brain parenchyma because of a leaky blood-brain barrier (BBB). 1 Although both types of brain edema are thought to co-exist in meningitis (8, 9), their relative contributions to brain swelling are not known.Recently, the bidirectional water channel aquaporin-4 (AQP4) has been found to play an important role in brain-water homeostasis (11-16). AQP4 protein is expressed strongly in astroglia at the BBB and CSF-brain interfaces (17, 18), suggesting involvement in water movement between fluid compartments (blood and CSF) and brain parenchyma. AQP4 deletion markedly reduced brain swelling in mouse models of cytotoxic brain edema, includin...

Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin

“…Overexpression of AQP4 may cause an increased propensity for cerebral edema. Experiments using AQP4 knockout mice revealed that AQP4 deletion offered protection from cytotoxic brain edema (Papadopoulos et al 2005) and vasogenic (noncellular) brain edema (Papadopoulos et al 2004). Our laboratory has observed a significant decrease in AQP4 in the cerebellum of patients with autism (Fatemi et al unpublished observations).…”

An emerging consensus on aquaporin translocation as a regulatory mechanism

“…Manipulation of AQP abundance may therefore provide novel methods for treating specific diseases. For example, AQP4 knockout mice show an increased protection and reduced accumulation of water in the brain in models of ischemic stroke, cerebral injury and meningitis (Manley et al, 2000, Papadopoulos andVerkman, 2005). The opposite is the case for hydrocephalus and vasogenic oedema, where AQP4 null mice show greater water accumulation in the brain and a worse clinical outcome (Papadopoulos et al, 2004).…”

Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides

“…Phenotype analysis of AQP4 knockout mice has revealed the involvement of AQP4 in water movement into and out of the brain, in neuroexcitation phenomena such as seizure activity and cortical spreading depression, and in glial cell migration 1 . AQP4 knockout mice showed improved survival compared to control wildtype mice in models of cytotoxic brain edema, including water intoxication, ischemic stroke and bacterial meningitis 2,3 . Recently, greatly improved neurological outcome was found in AQP4 knockout mice following spinal cord injury, which was associated with reduced spinal cord swelling and nerve cell protection 4 .…”