Spreading Depression: From Serendipity to Targeted Therapy in Migraine                Prophylaxis

Despite the relatively well-characterized headache mechanisms in migraine, upstream events triggering individual attacks are poorly understood. This lack of mechanistic insight has hampered a rational approach to prophylactic drug discovery. Unlike targeted abortive and analgesic interventions, mainstream migraine prophylaxis has been largely based on serendipitous observations (e.g. propranolol) and presumed class effects (e.g. anticonvulsants). Recent studies suggest that spreading depression is the final common pathophysiological target for several established or investigational migraine prophylactic drugs. Building on these observations, spreading depression can now be explored for its predictive utility as a preclinical drug screening paradigm in migraine prophylaxis.

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Oxcarbazepine does not suppress cortical spreading depression

Cephalalgia ◽

10.1177/0333102410388433 ◽

2010 ◽

Vol 31 (5) ◽

pp. 537-542 ◽

Cited By ~ 12

Author(s):

Ulrike Hoffmann ◽

Ergin Dileköz ◽

Chiho Kudo ◽

Cenk Ayata

Keyword(s):

Single Dose ◽

Cortical Spreading Depression ◽

Chronic Treatment ◽

Spreading Depression ◽

Screening Tool ◽

Positive Control ◽

Migraine Prophylaxis ◽

Migraine Aura ◽

Predictive Utility ◽

Prophylactic Drugs

Background: Cortical spreading depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress cortical spreading depression, implicating spreading depression as a common therapeutic target in migraine prophylaxis. Materials and methods: In order to assess the negative predictive value of spreading depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical spreading depression susceptibility was measured in rats using topical KCl or electrical stimulation. Results: Oxcarbazepine did not suppress spreading depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed spreading depression susceptibility after chronic dosing, while a single dose was ineffective. Conclusions: These data provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models.

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Pearls and pitfalls in experimental models of spreading depression

Cephalalgia ◽

10.1177/0333102412470216 ◽

2013 ◽

Vol 33 (8) ◽

pp. 604-613 ◽

Cited By ~ 42

Author(s):

Cenk Ayata

Keyword(s):

Brain Injury ◽

Data Quality ◽

Drug Screening ◽

Therapeutic Target ◽

Spreading Depression ◽

Experimental Models ◽

Migraine Prophylaxis ◽

Migraine Aura ◽

Pharmacological Modulation ◽

Potential Trigger

Background Spreading depression (SD) is the electrophysiological substrate of migraine aura and a potential trigger for headache. Since its discovery by Leão in 1944, SD has transformed from being viewed as an epiphenomenon into a therapeutic target relevant in the pathophysiology of migraine and brain injury. Aim Despite decades of research, the underpinnings of SD are still poorly understood, hampering our efforts to selectively block its initiation and spread. Experimental models have nevertheless been useful to measure the likelihood of SD occurrence (i.e. SD susceptibility) and characterize genetic, physiological and pharmacological modulation of SD in search of potential therapies, such as in migraine prophylaxis and stroke. Here, I review experimental SD susceptibility endpoints and surrogates, and minimum essential model requirements to improve their utility in drug screening. Conclusion A critical reappraisal of strengths and caveats of experimental models of SD susceptibility is needed to set standards and improve data quality, interpretation and reconciliation.

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High-Throughput Drug Screening of ECM Deposition Inhibitors for Antifibrotic Drug Discovery

10.1055/s-0039-1678397 ◽

2019 ◽

Author(s):

Michael Gerckens ◽

Hani Alsafadi ◽

Darcy Wagner ◽

Katharina Heinzelmann ◽

Kenji Schorpp ◽

...

Keyword(s):

Drug Discovery ◽

High Throughput ◽

Drug Screening ◽

High Throughput Drug Screening

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Faculty Opinions recommendation of Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1161355.621864 ◽

2009 ◽

Author(s):

David Dodick ◽

Todd Schwedt

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Migraine Prophylaxis ◽

Proof Of Concept ◽

Double Blind ◽

Double Blind Placebo ◽

Concept Study

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Mechanistic Insight of Sensing Hydrogen Phosphate in Aqueous Medium by Using Lanthanide(III)-Based Luminescent Probes

Nanomaterials ◽

10.3390/nano11010053 ◽

2020 ◽

Vol 11 (1) ◽

pp. 53

Author(s):

Jashobanta Sahoo ◽

Santlal Jaiswar ◽

Pabitra B. Chatterjee ◽

Palani S. Subramanian ◽

Himanshu Sekhar Jena

Keyword(s):

Drug Discovery ◽

Aqueous Medium ◽

Hydrogen Phosphate ◽

Heterocyclic Ligand ◽

Luminescent Probes ◽

Mechanistic Insight ◽

Sensitivity And Selectivity ◽

Spectrophotometric Titrations ◽

Ethanesulfonic Acid ◽

High Degree

The development of synthetic lanthanide luminescent probes for selective sensing or binding anions in aqueous medium requires an understanding of how these anions interact with synthetic lanthanide probes. Synthetic lanthanide probes designed to differentiate anions in aqueous medium could underpin exciting new sensing tools for biomedical research and drug discovery. In this direction, we present three mononuclear lanthanide-based complexes, EuLCl3 (1), SmLCl3 (2), and TbLCl3 (3), incorporating a hexadentate aminomethylpiperidine-based nitrogen-rich heterocyclic ligand L for sensing anion and establishing mechanistic insight on their binding activities in aqueous medium. All these complexes are meticulously studied for their preferential selectivities towards different anions such as HPO42−, SO42−, CH3COO−, I−, Br−, Cl−, F−, NO3−, CO32−/HCO3−, and HSO4− at pH 7.4 in aqueous HEPES (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid) buffer. Among the anions scanned, HPO42− showed an excellent luminescence change with all three complexes. Job’s plot and ESI-MS support the 1:2 association between the receptors and HPO42−. Systematic spectrophotometric titrations of 1–3 against HPO42− demonstrates that the emission intensities of 1 and 2 were enhanced slightly upon the addition of HPO42− in the range 0.01–1 equiv and 0.01–2 equiv., respectively. Among the three complexes, complex 3 showed a steady quenching of luminescence throughout the titration of hydrogen phosphate. The lower and higher detection limits of HPO42− by complexes 1 and 2 were determined as 0.1–4 mM and 0.4–3.2 mM, respectively, while complex 3 covered 0.2–100 μM. This concludes that all complexes demonstrated a high degree of sensitivity and selectivity towards HPO42−.

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Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

International Journal of Molecular Sciences ◽

10.3390/ijms22052659 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2659

Author(s):

Gianluca Costamagna ◽

Giacomo Pietro Comi ◽

Stefania Corti

Keyword(s):

Drug Discovery ◽

Drug Screening ◽

Neural Development ◽

Neurological Disorders ◽

Large Scale ◽

Three Dimensional ◽

Induced Pluripotent Stem Cell ◽

Cellular Level ◽

Complex Data ◽

Complex Data Sets

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

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Structure–Activity Relationships by NMR: A New Procedure for Drug Discovery by a Combinatorial–Rational Approach

Angewandte Chemie International Edition in English ◽

10.1002/anie.199708291 ◽

1997 ◽

Vol 36 (8) ◽

pp. 829-831 ◽

Cited By ~ 15

Author(s):

Horst Kessler

Keyword(s):

Drug Discovery ◽

Rational Approach ◽

Structure Activity Relationships ◽

Structure Activity

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The Discovery Channel: microfluidics and microengineered systems in drug screening

Integrative Biology ◽

10.1039/c5ib90004b ◽

2015 ◽

Vol 7 (3) ◽

pp. 285-288 ◽

Cited By ~ 5

Author(s):

Christopher Moraes

Keyword(s):

Drug Discovery ◽

Engineering Design ◽

High Throughput ◽

Drug Screening ◽

High Throughput Screening ◽

Recent Literature ◽

Analytical Strategies ◽

Discovery Pipeline

We highlight exciting findings and promising approaches in the recent literature in which researchers integrate advanced micro-engineering, design, and analytical strategies to improve the relevance and utility of high-throughput screening in the drug discovery pipeline.

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