Gamma-aminobutyric acid receptor agonists, aquaporin-4, and neuromyelitis optica: a potential link.
Neuromyelitis optica (NMO; also termed Devic's disease) is a severely disabling autoimmune disorder of the central nervous system (CNS), which predominantly affects the optic nerves and spinal cord. In up to 80% of cases, NMO is associated with antibodies to aquaporin-4 (AQP4-IgG), the most abundant water channel in the CNS. AQP4-IgG have been demonstrated to be directly pathogenic. Gamma-aminobutyric acid A receptor (GABAAR) agonists are frequently used in patients with NMO, e.g., for symptomatic treatment of spasticity or epilepsy or for non-NMO-related indications such as treatment of insomnia. However, GABAAR signaling has recently been shown to strongly promote AQP4 expression. This is of potential clinical importance since any increase in AQP4 membrane expression during acute NMO attacks may enhance the complement-mediated humoral immune reaction against AQP4-expressing cells characteristic for NMO and, thus, result in more severe CNS damage. We therefore hypothesize that GABAAR agonist-induced AQP4 upregulation may be a potential risk factor in NMO. This would also include a potential role for (GABAAR-enhanced) damage to the subependymal zone neural stem cells, the major source of both glial cells and neuroblasts in the adult brain, in NMO. We also make proposals on how to test that hypothesis and underline the general need for evaluating possible detrimental effects of commonly used drugs affecting AQP4 expression in NMO.
Department of Neurology, University of Heidelberg, Germany. Electronic address: sven.jarius@med.uni-heidelberg.de.
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S
Jarius
Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany.
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O
Aktas
Department of Neurology, University of Heidelberg, Germany.
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B
Wildemann
D051401:Aquaporin 4 / Q000378:metabolism*; D018755:GABA Agonists / Q000494:pharmacology*; D006801:Humans; D009471:Neuromyelitis Optica / Q000378:metabolism*
D051401:Aquaporin 4; D018755:GABA Agonists