Abstract
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 whole-cell 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.
Highlights
The amino acid (S)-Glutamate (Glu) is the major excitatory neurotransmitter in the vertebrate central nervous system (CNS)
Excessive activity and fast desensitization and deactivation rates of amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been linked to neurotoxicity and hypoxic/ischemic insults, which is associated with the pathogenesis of several neurodegenerative and neuropsychiatric diseases, such as Alzheimer Diseases (AD), Parkinson Disease (PD) Epilepsy, Amyotrophic Lateral Sclerosis (ALS) and strokes [5]
We propose three different mechanisms for the observed effects of CR-MeNH, CR-NO, CR-NN, and CR-NNPh on AMPAR kinetics; first, the derivatives might affect AMPAR trafficking, reducing AMPAR density on the postsynaptic cleft
Summary
The amino acid (S)-Glutamate (Glu) is the major excitatory neurotransmitter in the vertebrate central nervous system (CNS). The three receptors that the iGluRs consist of have been pharmacologically classified according to the ligands that selectively activate them. They are regarded as α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR) and kainate receptor, according to their agonists AMPA, NMDA, and kainate respectively. AMPARs mediate most of the fast-excitatory neurotransmission as they are activated in a microsecond domain time scale. It undergoes profound desensitization on the millisecond timescale in favor of a more stable structure [4]. It was demonstrated that neuronal death can be triggered from excessive ionic influx via AMPARs, which is linked to numerous neurodegenerative diseases [6,7,8], for example, the excessive influx of calcium has been correlated with the neurodegeneration of motor neurons in ALS
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