Gamma-aminobutyric acid receptor agonists, aquaporin-4, and neuromyelitis optica: a potential link

Jarius, Sven; Aktaş, Orhan; Wildemann, Brigitte

doi:10.1016/j.mehy.2015.08.003

Cited by 6 publications

(10 citation statements)

References 38 publications

(47 reference statements)

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“…GABA enhanced glymphatic clearance in wild-type but not AQP4 -/- mice, indicating that GABA-mediated clearance was AQP4-dependent. Earlier studies suggested that the GABA receptor co-localizes with AQP4 16, 25 . Further research is warranted to ascertain whether direct interactions between GABA and AQP4 promote glymphatic clearance.…”

Section: Discussionmentioning

confidence: 99%

“…A 2×2mm 2 cranial window was prepared over the right parietal cortex (2 mm caudal from bregma, 1.7 mm lateral from the midline) with a micro-drill and a metal plate glued at the edge of the cranial window 16, 17 . The mouse was fixed on the stage of two-photon microscope (Leica, DM6000, Wetzlar, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Aquaporin-4 (AQP4) and arterial pulsation are two main driving forces in the glymphatic pathway 4, 15 . The GABA-A receptor co-localizes with AQP4 in brain tissue 16, 17 . In addition, glutamate has been shown to influence vascular smooth muscle cell function, which is associated with pulsation 18 .…”

Section: Introductionmentioning

confidence: 99%

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Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

Feng

Zhang

et al. 2020

Preprint

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The glymphatic system contributes to a large proportion of brain waste clearance, including removal of amyloid β (Aβ). We have demonstrated that glutamate and γ-aminobutyric acid (GABA) influence glymphatic clearance through distinct mechanisms whereby GABA exerts modulatory effects in an aquaporin-4 (AQP4)-dependent manner while the actions of glutamate are pulsation-dependent. The efficacy of GABA and glutamate in alleviating Aβ in APP-PS1 and Angiotensin-II (Ang-II) induced hypertension mouse models was further evaluated. Notably, increasing GABA or inhibiting glutamate levels led to reduced binding of Aβ to pre-labeled plaques to similar extents in APP-PS1 mice while GABA appeared more efficient in Aβ clearance in hypertensive animals than the glutamate inhibitor. Our findings support the modulation of neurotransmitters that influence the glymphatic pathway via distinct mechanisms as a potentially effective therapeutic strategy for clearance of Aβ deposits from the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

Feng

Zhang

et al. 2020

Preprint

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“…The objective was to delicately thin the skull to the point of translucency, enabling visualization of the cortical blood vessels. A custom‐made perforated aluminum plate was securely affixed to the periphery of the cranial window using modified acrylic adhesive (Jarius et al, 2015; Li et al, 2014). This arrangement proved advantageous for subsequent imaging procedures.…”

Section: Methodsmentioning

confidence: 99%

GABA promotes interstitial fluid clearance in an AQP4‐dependent manner by activating the GABA_AR

Zhang

Feng

et al. 2023

Journal of Neurochemistry

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The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin‐4 (AQP4) expressed on the perivascular astrocytic end‐feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ‐aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAAR) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation‐continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4‐dependent manner by activating the GABAAR. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition‐related diseases.

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“…The latter group has shown modest but controversial evidence in randomized controlled trials of MS-related spasticity [ 51 ] and their general use in NMOSD is not evidence based. The use of benzodiazepines (GABA-A modulators) for NMOSD-related spasticity is also controversial because of the implication of GABA-A enhancement in the overexpression of AQP4 water channels on the surface of astrocytes potentially increasing the risk of relapse [ 52 ].…”

Section: Spasticity and Other Muscle Tone Abnormalitiesmentioning

confidence: 99%

Symptomatic and restorative therapies in neuromyelitis optica spectrum disorders

et al. 2021

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Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune inflammatory conditions that primarily target the optic nerves, spinal cord, brainstem, and occasionally the cerebrum. NMOSD is characterized by recurrent attacks of visual, motor, and/or sensory dysfunction that often result in severe neurological deficits. In recent years, there has been a significant progress in relapse treatment and prevention but the residual disability per attack remains high. Although symptomatic and restorative research has been limited in NMOSD, some therapeutic approaches can be inferred from published case series and evidence from multiple sclerosis literature. In this review, we will discuss established and emerging therapeutic options for symptomatic treatment and restoration of function in NMOSD. We highlight NMOSD-specific considerations and identify potential areas for future research. The review covers pharmacologic, non-pharmacologic, and neuromodulatory approaches to neuropathic pain, tonic spasms, muscle tone abnormalities, sphincter dysfunction, motor and visual impairment, fatigue, sleep disorders, and neuropsychological symptoms. In addition, we briefly discuss remyelinating agents and mesenchymal stem cell transplantation in NMOSD.

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Gamma-aminobutyric acid receptor agonists, aquaporin-4, and neuromyelitis optica: a potential link

Cited by 6 publications

References 38 publications

Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

GABA promotes interstitial fluid clearance in an AQP4‐dependent manner by activating the GABA_AR

Symptomatic and restorative therapies in neuromyelitis optica spectrum disorders

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Gamma-aminobutyric acid receptor agonists, aquaporin-4, and neuromyelitis optica: a potential link

Cited by 6 publications

References 38 publications

Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

GABA promotes interstitial fluid clearance in an AQP4‐dependent manner by activating the GABAAR

Symptomatic and restorative therapies in neuromyelitis optica spectrum disorders

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GABA promotes interstitial fluid clearance in an AQP4‐dependent manner by activating the GABA_AR