AbstractAcute ischemic stroke continues to devastate millions of individuals worldwide. Current treatments work to restore blood flow but not rescue affected tissue. Our goal was to develop a combination of neuroprotective agents administered intra‐arterially following recanalization to target ischemic tissue. Using C57Bl/6J male mice, we performed tandem transient ipsilateral middle cerebral/common carotid artery occlusion, followed by immediate intra‐arterial pharmacotherapy administration through a standardized protocol. Two pharmacotherapy agents, verapamil and lubeluzole, were selected based on their potential to modulate different aspects of the ischemic cascade; verapamil, a calcium channel blocker, works in an acute fashion blocking L‐type calcium channels, whereas lubeluzole, an N‐methyl‐D‐aspartate modulator, works in a delayed fashion blocking intracellular glutamate trafficking. We hypothesized that combination therapy would provide complimentary and potentially synergistic benefit treating brain tissue undergoing various stages of injury. Physiological measurements for heart rate and pulse distention (blood pressure) demonstrated no detrimental effects between groups, suggesting that the combination drug administration is safe. Tissue analysis demonstrated a significant difference between combination and control (saline) groups in infarct volume, neuronal health, and astrogliosis. Although a significant difference in functional outcome was not observed, we did note that the combination treatment group had a greater percent change from baseline in forced motor movement as compared with controls. This study demonstrates the safety and feasibility of intra‐arterial combination therapy following successful recanalization and warrants further study.

01 Feb 2021·Pharmacological ReportsQ4 · MEDICINE

Lubeluzole: from anti-ischemic drug to preclinical antidiarrheal studies

Q4 · MEDICINE

Article

Author: De Salvia, Maria Antonietta ; Franchini, Carlo ; Rosato, Antonio ; Viale, Maurizio ; Corazza, Ivan ; Milani, Gualtiero ; Cavalluzzi, Maria Maddalena ; Micucci, Matteo ; Gualdani, Roberta ; Caputo, Leonardo ; Piarulli, Monica ; Quintieri, Laura ; Budriesi, Roberta ; Lentini, Giovanni

BACKGROUNDLubeluzole, a neuroprotective anti-ischemic drug, was tested for its ability to act as both antibiotic chemosensitizing and antipropulsive agent for the treatment of infectious diarrhea.METHODSIn the present report, the effect of lubeluzole against antidiarrheal target was tested. The antimicrobial activity towards Gram-positive and Gram-negative bacteria was investigated together with its ability to affect ileum and colon contractility.RESULTSConcerning the antimicrobial activity, lubeluzole showed synergistic effects when used in combination with minocycline against four common Gram-positive and Gram-negative bacteria (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922), although relatively high doses of lubeluzole were required. In ex vivo experiments on sections of gut smooth muscles, lubeluzole reduced the intestinal contractility in a dose-dependent manner, with greater effects observed on colon than on ileum, and being more potent than reference compounds otilonium bromide and loperamide.CONCLUSIONAll above results identify lubeluzole as a possible starting compound for the development of a novel class of antibacterial adjuvants endowed with spasmolytic activity.

01 Jan 2018·Cellular Physiology and Biochemistry

Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole

Article

Author: Cavalluzzi, Maria Maddalena ; Gualdani, Roberta ; Stary-Weinzinger, Anna ; Convertino, Marino ; Tadini-Buoninsegni, Francesco ; Gailly, Philippe ; Lentini, Giovanni

Background/Aims: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking. Methods: We tested the affinity of lubeluzole, its enantiomer, and the racemate for hERG channel using the patch-clamp technique. We synthesized and tested two simplified model compounds corresponding to two moieties included in the lubeluzole structure. The obtained experimental results were rationalized by docking simulation on the recently reported cryo-electron microscopy (cryo-EM) structure of hERG. Group efficiency analysis was performed in order to individuate the fragment most contributing to binding. Results: We found that lubeluzole and its R enantiomer are highly potent inhibitors of human ether-ago-go-related gene (hERG) channel with an IC50 value of 12.9 ± 0.7 nM and 11.3 ± 0.8 nM, respectively. In the presence of lubeluzole, steady-state activation and inactivation of hERG channel were shifted to more negative potentials and inactivation kinetics was accelerated. Mutations of aromatic residues (Y652A and F656A) in the channel inner cavity significantly reduced the inhibitory effect of lubeluzole. Molecular docking simulations performed on the near atomic resolution cryo-electron microscopy structures of hERG supported the role of Y652 and F656 as the main contributors to high affinity binding. Group efficiency analysis indicated that both 1,3-benzothiazol-2-amine and 3-aryloxy-2-propanolamine moieties contribute to drug binding with the former giving higher contribution. Conclusions: This study suggests the possibility to modulate lubeluzole hERG blockade by introducing suitable substituents onto one or both constituting portions of the parent compound in order to either reduce potency (i. e. torsadogenic potential) or potentiate affinity (useful for class III antiarrhythmic and anticancer agent development).

100 Deals associated with Lubeluzole

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KEGG	Wiki	ATC	Drug Bank
D04789	Lubeluzole	-	-

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Ischemic Stroke	NDA/BLA	DE	University of Duisburg-Essen	01 Nov 2000
Stroke	NDA/BLA	US	Janssen Pharmaceuticals, Inc.	10 Dec 1998

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