The development of efficacious and safe drugs for the treatment of neurological diseases
related to glutamate toxicity has been a focus in neuropharmacological research. Specifically,
discovering antagonists to modulate the activity and kinetics of AMPA receptors,
which are the fastest ligand-gated ion channels involved in excitatory neurotransmission in
response to glutamate. Thus, the current study investigated novel curcumin derivatives on
the biophysical properties of AMPA receptors, specifically on the homomeric GluA2 and the
heteromeric GluA2/A3 subunits and assessed for inhibitory actions. The biophysical parameter
(i.e., desensitization, deactivation, and peak currents) were measured by using wholecell
patch clamp electrophysiology with and without the administration of the derivatives
onto HEK293 cells. CR-NN, CR-NNPh, CR-MeNH, and CR-NO of the tested derivatives
showed inhibition on all AMPA receptors up to 6 folds. Moreover, the inhibitory derivatives
also increased desensitization and deactivation, which further intensifies the compounds’
neuroprotective effects. However, CR-PhCl, CR-PhF, and CR-PhBr did not show any significant
changes on the peak current, deactivation or desensitization rates. By comparison to
other discovered and widely used antagonist, the prepared curcumin derivatives are not
selective to a specific AMPA subunit, instead implement its effect in the same way between
all types of AMPA receptors. Additionally, the obtained results provide derivatives that not
only noncompetitively inhibit AMPARs but also decrease its biophysical kinetics, specifically
desensitization and deactivation rates. Hence, to potentially serve as a new AMPAR inhibitor
with therapeutic potential, the current study provides compounds that are non-selective
and non-competitive antagonist, which also effect the desensitization and deactivation rates
of the receptor.

العنوان

PLOS ONE

الناشر

Public Library of Science

بلد الناشر

الولايات المتحدة الأمريكية

Indexing

Thomson Reuters

معامل التأثير

2,7

نوع المنشور

مطبوع فقط

المجلد

14

السنة

2019

الصفحات

e0221132.