Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood–brain barrier

Abstract

The blood–brain barrier (BBB), which imposes significant water permeability restriction, effectively isolates the brain from the systemic circulation. Seemingly paradoxical, the abundance of aquaporin-4 (AQP-4) on the inside of the BBB strongly indicates the presence of unique water dynamics essential for brain function. On the basis of the highly specific localization of AQP-4, namely, astrocyte end feet at the glia limitans externa and pericapillary Virchow–Robin space, we hypothesized that the AQP-4 system serves as an interstitial fluid circulator, moving interstitial fluid from the glia limitans externa to pericapillary Virchow–Robin space to ensure proper glymphatic flow draining into the cerebrospinal fluid. The hypothesis was tested directly using the AQP-4 facilitator TGN-073 developed in our laboratory, and [17O]H2O JJ vicinal coupling proton exchange MRI, a method capable of tracing water molecules delivered into the blood circulation. The results unambiguously showed that facilitation of AQP-4 by TGN-073 increased turnover of interstitial fluid through the system, resulting in a significant reduction in [17O]H2O contents of cortex with normal flux into the cerebrospinal fluid. The study further suggested that in addition to providing the necessary water for proper glymphatic flow, the AQP-4 system produces a water gradient within the interstitial space promoting circulation of interstitial fluid within the BBB.

Aquaporin-4 facilitator TGN-073 demonstrates novel analgesic activity

“…Test compound: TGN-073 was obtained in bulk form from Key Organics, Ltd (Camelford, Cornwall, UK). The material obtained was found to be chemically identical to an in-house synthesized sample, 5 and was consistent with having a chemical purity >95% according to 1 H-NMR and UPLC-HR-MS analysis. The sodium salt for in vivo administration was prepared as described in Reference 5, and the resulting material was used as thusly obtained.…”

“…Our laboratory recently identified TGN-073 (3-benzyloxy-2phenylsulfonamido-pyridine) as a pharmacologic AQP-4 facilitator that can be used to test the effects of increased AQP-4 function in vivo. 5 However, reduced pain stimuli response was observed in AQP-4 null rodents, [6][7] and an analgesic effect was reported for the AQP-4 inhibitor TGN-020 in a rodent neuropathic pain model. 8 Consequently, we were concerned that AQP-4 facilitators, such as TGN-073, could promote a neurogenic pain syndrome, and felt it essential to test such compounds in an appropriate rodent pain model.…”

Inhibition of Aquaporin 4 Decreases Amyloid Aβ40 Drainage Around Cerebral Vessels

“…Moreover, there was a clear-cut colocalization of the vascular BM’s laminin with endogenous murine albumin in the walls of the vessels of these animals, this being a first direct proof that AQP4 inhibition decreases fluid passage around BBB at the level of the outer vascular basement membranes [ 27 ]. More recent data utilizing the AQP4 facilitator TGN-073 showed an increased fluid turnover at the level of the BBB, promoting circulation and clearance of the interstitial fluid along the BBB [ 55 ]. Also, the observation that intraparenchymal injection of ovalalbumin and dextran also leads to their drainage alongside the vascular basement membranes [ 56 ] consolidates this route as a general fluid drainage pathway, not specific but essential for the clearance of soluble Aβ pool.…”

Neurofluid Dynamics and the Glymphatic System: A Neuroimaging Perspective

“…Regarding the evaluation of the brain parenchyma, one study that assessed the permeation of intravenously injected gadolinium into normal brain tissue by permeability imaging reported an elevated blood-brain barrier transfer coefficient in patients with Alzheimer's disease ( 30 ). Several reports have also used permeability imaging to evaluate the correlation between glymphatic function and blood-brain barrier function ( 31 32 ). One study using dynamic GBCA-enhanced MRI to quantify blood-brain barrier permeability demonstrated that enlarged perivascular spaces were associated with compromised blood-brain barrier integrity supporting the hypothesis that blood-brain barrier dysfunction may be involved in the pathogenesis of enlarged perivascular spaces ( 31 ).…”

“…Another report used 17 O, a stable isotope of oxygen, as an MRI tracer to evaluate blood-brain barrier function. The study observed the effect of an AQP4 facilitator, TGN-073, and showed increased ISF turnover through the system, suggesting that the AQP4 system produces a water gradient within the interstitial space that promoted ISF circulation within the blood-brain barrier in addition to providing the necessary water for proper glymphatic flow ( 32 ).…”