Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3

So you have identified a possible solution to a stroke problem. WHAT EXACTLY ARE YOU DOING TO GET THIS TO HUMAN CLINICAL TRIALS? Not doing anything is the height of incompetence and you, your mentors and senior researchers should all be fired.  My vacations did not calm me down(Italy, London). 

This from August 2015 should already have initiated human trials:

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3 August 2015

The latest here:

Modified Citrus Pectin Prevents Blood-Brain Barrier Disruption in Mouse Subarachnoid Hemorrhage by Inhibiting Galectin-3

Hirofumi Nishikawa

,

Lei Liu

,

Fumi Nakano

,

Fumihiro Kawakita

,

Hideki Kanamaru

,

Yoshinari Nakatsuka

,

Takeshi Okada

, and

Hidenori Suzuki

Originally published25 Sep 2018https://doi.org/10.1161/STROKEAHA.118.021757Stroke. 2018;49:2743–2751

Abstract

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Background and Purpose—

Plasma levels of galectin-3—a matricellular protein—are increased after aneurysmal subarachnoid hemorrhage (SAH), but the functional significance remains undetermined. This study was conducted to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier disruption.

Methods—

C57BL/6 male adult mice (n=251) underwent sham or filament perforation SAH modeling, followed by a random intracerebroventricular injection of vehicle or drug at 30 minutes post-modeling. First, vehicle-treated and 0.8, 4, 16, or 32 µg MCP-treated mice were assessed by neuroscore and brain water content at 24 and 48 hours post-modeling. Second, Evans blue extravasation, Western blotting, coimmunoprecipitation and immunostaining were performed in vehicle-treated or 4 µg MCP-treated mice at 24 hours post-modeling. Third, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore and Evans blue extravasation were evaluated at 24 hours post-modeling. Fourth, vehicle or R-galectin-3 was administered to MCP-treated SAH mice at 24 hours, and neuroscore and IgG immunostaining were evaluated at 48 hours post-SAH.

Results—

Among tested dosages, 4 µg MCP showed the best neuroprotective effects as to preventing neurological impairments and brain edema at 24 to 48 hours post-SAH. Four micrograms MCP attenuated post-SAH blood-brain barrier disruption and galectin-3 upregulation in brain capillary endothelial cells, associated with inactivation of ERK (extracellular signal-related kinase) 1/2, STAT (signal transducer and activator of transcription)-3, and MMP (matrix metalloproteinase)-9, and the consequent preservation of a tight junction protein ZO-1 (zonula occludens-1). Coimmunoprecipitation assay demonstrated physical interactions between galectin-3 and TLR (Toll-like receptor) 4. R-galectin-3 blocked the neuroprotective effects of MCP.

Conclusions—

MCP prevents post-SAH blood-brain barrier disruption possibly by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. This study suggests galectin-3 to be a novel therapeutic target against post-SAH early brain injury.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.021757.

Correspondence to Hidenori Suzuki, MD, PhD, Department of Neurosurgery, Mie University Graduate School of Medicine, 2–174 Edobashi, Tsu, Mie 514–8507, Japan. Email suzuki02@clin.medic.mie-u.ac.jp