A Comprehensive Review of Essential Oils and Their Pharmacological Activities in Neurological Disorders: Exploring Neuroprotective Potential.

Numerous studies have demonstrated essential oils' diverse chemical compositions and pharmacological properties encompassing antinociceptive, anxiolytic-like, and anticonvulsant activities, among other notable effects. The utilization of essential oils, whether inhaled, orally ingested, or applied topically, has commonly been employed as adjunctive therapy for individuals experiencing anxiety, insomnia, convulsions, pain, and cognitive impairment. The utilization of synthetic medications in the treatment of various disorders and symptoms is associated with a wide array of negative consequences. Consequently, numerous research groups across the globe have been prompted to explore the efficacy of natural alternatives such as essential oils. This review provides a comprehensive overview of the existing literature on the pharmacological properties of essential oils and their derived compounds and the underlying mechanisms responsible for these observed effects. The primary emphasis is on essential oils and their constituents, specifically targeting the nervous system and exhibiting significant potential in treating neurodegenerative disorders. The current state of research in this field is characterized by its preliminary nature, highlighting the necessity for a more comprehensive overlook of the therapeutic advantages of essential oils and their components. Integrating essential oils into conventional therapies can enhance the effectiveness of comprehensive treatment regimens for neurodegenerative diseases, offering a more holistic approach to addressing the multifaceted nature of these conditions.

Assessing the Effects of Thiazole-Carboxamide Derivatives on the Biophysical Properties of AMPA Receptor Complexes as a Potential Neuroprotective Agent.

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer's, and Autism. One of the critical agents mediating excitatory neurotransmission is α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, which are concerned with synaptic plasticity, memory, and learning. An imbalance in neurotransmission finally results in excitotoxicity and neurological pathologies that should be corrected through specific compounds. Hence, the current study will prove to be an evaluation of new thiazole-carboxamide derivatives concerning AMPAR-modulating activity and extended medicinal potential. In the current project, five previously synthesized thiazole-carboxamide derivatives, i.e., TC-1 to TC-5, were used to interact with the AMPARs expressed in HEK293T cells, which overexpress different subunits of the AMPAR. Patch-clamp analysis was carried out while the effect of the drugs on AMPAR-mediated currents was followed with a particular emphasis on the kinetics of inhibition, desensitization, and deactivation. All tested TC compounds, at all subunits, showed potent inhibition of AMPAR-mediated currents, with TC-2 being the most powerful for all subunits. These compounds shifted the receptor kinetics efficiently, mainly enhancing the deactivation rates, and hence acted as a surrogate for their neuroprotective potentials. Additionally, recently published structure-activity relationship studies identified particular substituent groups as necessary for improving the pharmacologic profiles of these compounds. In this regard, thiazole-carboxamide derivatives, particularly those classified as TC-2, have become essential negative allosteric modulators of AMPAR function and potential therapeutics in neurological disturbances underlain by the dysregulation of excitatory neurotransmission. Given their therapeutic effectiveness and safety profiles, these in vivo studies need to be further validated, although computational modeling can be further developed for drug design and selectivity. This will open possibilities for new drug-like AMPAR negative allosteric modulators with applications at the clinical level toward neurology.

Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel.

Three major subtypes of ionotropic receptors regulate glutamatergic synaptic transmission, one of which is α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). They are tetrameric, cation-permeable ionotropic glutamate receptors found across the brain. Abnormalities in AMPA receptor trafficking and synaptic assembly are linked to cognitive decline and neurological diseases such as Alzheimer's, Parkinson's, and Huntington's. The present study will investigate the effects of four novel 2,3-benzodiazepine derivatives on AMPA receptor subunits by comparing their effects on synaptic responses, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits using whole-cell patch-clamp electrophysiology. All four 2,3-BDZ compounds showed inhibitory activity against all the homomeric and heteromeric subunits tested. While the desensitization and deactivation rates in 2,3-BDZ-1 and 2,3-BDZ-2 decreased and increased, respectively, in the other two compounds (i.e., 2,3-BDZ-3 and 2,3-BDZ-4), there was no change in the desensitization or deactivation rates. These results contribute to a better understanding of AMPARs by identifying potential 2,3-BDZ drugs that demonstrate inhibitory effects on the AMPAR subunits.

Targeting the kinetics mechanism of AMPA receptor inhibition by 2-oxo-3H-benzoxazole derivatives.

Ionotropic glutamate receptors are ligand-gated ion channels found in most excitatory synapses in the brain that allow for rapid information transfer. Due to their quick excitatory processes, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate (AMPA) receptors have been linked to various neurodegenerative disorders, including epilepsy and Parkinson's disease. It has been critical to develop new neuroprotective compounds that inhibit AMPA-sensitive glutamate-controlled channels allosterically, and many classes of AMPA receptor-inhibiting compounds have been synthesized and evaluated. The current study focuses on thirteen 2-oxo-3H-benzoxazole derivatives (COBs) as potential AMPA receptor modulators. The whole-cell patch-clamp technique was used to assess the effects of COBs on AMPA receptor subunits (i.e., GluA1, GluA2, GluA1/2, and GluA2/3) amplitudes in the human embryonic kidney (HEK293) cells and the rates of desensitization and deactivation before and after COBs delivery. According to our findings, the COBs bind AMPA receptors allosterically and alter AMPAR characteristics in various ways. COB-1, COB-2, and COB-13 were the most effective in decreasing AMPAR currents by around 10-12 folds compared to the other COBs. Furthermore, the COBs significantly impacted AMPA receptor deactivation and desensitization rates. Of the examined homomeric and heteromeric AMPAR subunits, GluA2 was the most impacted. COB compounds appear to be a viable candidate for future study and development in regulating neurological diseases involving AMPA receptors.

Deciphering the Biophysical Properties of Ion Channel Gating Pores by Coumarin-Benzodiazepine Hybrid Derivatives: Selective AMPA Receptor Antagonists.

In the 1980s, the identification of specific pharmacological antagonists played a crucial role in enhancing our comprehension of the physiological mechanisms associated with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). The primary objective of this investigation was to identify specific AMPA receptor antagonists, namely 2,3-benzodiazepines, that function as negative allosteric modulators (NAMs) at distinct locations apart from the glutamate recognition site. These compounds have exhibited a diverse array of anticonvulsant properties. In order to conduct a more comprehensive investigation, the study utilized whole-cell patch-clamp electrophysiology to analyze the inhibitory effect and selectivity of benzodiazepine derivatives that incorporate coumarin rings in relation to AMPA receptors. The study's main objective was to acquire knowledge about the relationship between the structure and activity of the compound and comprehend the potential effects of altering the side chains on negative allosteric modulation. The investigation provided crucial insights into the interaction between eight CD compounds and AMPA receptor subunits. Although all compounds demonstrated effective blockade, CD8 demonstrated the greatest potency and selectivity towards AMPA receptor subunits. The deactivation and desensitization rates were significantly influenced by CD8, CD6, and CD5, distinguishing them from the remaining five chemicals. The differences in binding and inhibition of AMPA receptor subunits can be attributed to structural discrepancies among the compounds. The carboxyl group of CD8, situated at the para position of the phenyl ring, substantially influenced the augmentation of AMPA receptor affinity. The findings of this study highlight the potential of pharmaceutical compounds that specifically target AMPA receptors to facilitate negative allosteric modulation.

AMPA receptor neurotransmission and therapeutic applications: A comprehensive review of their multifaceted modulation.

The neuropharmacological community has shown a strong interest in AMPA receptors as critical components of excitatory synaptic transmission during the last fifteen years. AMPA receptors, members of the ionotropic glutamate receptor family, allow rapid excitatory neurotransmission in the brain. AMPA receptors, which are permeable to sodium and potassium ions, manage the bulk of the brain's rapid synaptic communications. This study thoroughly examines the recent developments in AMPA receptor regulation, focusing on a shift from single chemical illustrations to a more extensive investigation of underlying processes. The complex interplay of these modulators in modifying the function and structure of AMPA receptors is the main focus, providing insight into their influence on the speed of excitatory neurotransmission. This research emphasizes the potential of AMPA receptor modulation as a therapy for various neurological disorders such as epilepsy and Alzheimer's disease. Analyzing these regulators' sophisticated molecular details enhances our comprehension of neuropharmacology, representing a significant advancement in using AMPA receptors for treating intricate neurological conditions.

Multi-biological activity assessment and phytochemical characterization of an aqueous extract of the Cymbopogon citratus grown in Palestine.

BACKGROUND: Plants have historically been a rich source of medicinal compounds, with many modern pharmaceuticals derived from botanical origins. In contemporary healthcare, there is a resurgence in utilizing botanical substances as recognized medicinal agents. This study delved into understanding the phytochemical makeup and the multifaceted biological activities of an aqueous extract from Cymbopogon citratus (C. citratus). The investigated activities were its effect on AMPA receptors, antioxidant capacity, anti-lipase, anti-α-amylase actions, cytotoxicity, and antimicrobial properties. METHODS: The extract of C. citratus received a comprehensive investigation, which included the study of its phytochemical composition, assessment of its antioxidant and anti-lipase properties, evaluation of its capacity to inhibit α-amylase, analysis of its impact on cell viability, and assessment of its antimicrobial activity. The approaches are used to clarify the complex physiological and biochemical characteristics. RESULTS: The results were compelling; receptor kinetics had a marked impact, notably on the GluA2 subunit. Regarding its medicinal potential, the extract demonstrated potent antioxidant and anti-diabetic activities with IC50 values of 15.13 and 101.14 µg/mL, respectively. Additionally, it displayed significant inhibitory effects on the lipase enzyme and showed cytotoxicity against the Hep3B cancer cell line, with IC50 values of 144.35 and 148.37 µg/mL. In contrast, its effects on the normal LX-2 cell line were minimal, indicating selectivity. CONCLUSION: The aqueous extract of C. citratus shows promising therapeutic properties. The findings advocate for further research into its compounds for potential isolation, purification, and in-depth pharmacological studies, especially in areas like nervous system disorders, diabetes, obesity, and combating oxidative stress.

Evaluating the Neuroprotective Potential of Novel Benzodioxole Derivatives in Parkinson's Disease via AMPA Receptor Modulation.

Parkinson's disease (PD) is a significant health issue because it gradually damages the nervous system. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play a significant role in the development of PD. The current investigation employed hybrid benzodioxole-propanamide (BDZ-P) compounds to get information on AMPA receptors, analyze their biochemical and biophysical properties, and assess their neuroprotective effects. Examining the biophysical characteristics of all the subunits of the AMPA receptor offers insights into the impact of BDZ-P on the desensitization and deactivation rate. It demonstrates a partial improvement in the locomotor capacities in a mouse model of Parkinson's disease. In addition, the in vivo experiment assessed the locomotor activity by utilizing the open-field test. Our findings demonstrated that BDZ-P7 stands out with its remarkable potency, inhibiting the GluA2 subunit nearly 8-fold with an IC50 of 3.03 µM, GluA1/2 by 7.5-fold with an IC50 of 3.14 µM, GluA2/3 by nearly 7-fold with an IC50 of 3.19 µM, and GluA1 by 6.5-fold with an IC50 of 3.2 µM, significantly impacting the desensitization and deactivation rate of the AMPA receptor. BDZ-P7 showed an in vivo impact of partially reinstating locomotor abilities in a mouse model of PD. The results above suggest that the BDZ-P7 compounds show great promise as top contenders for the development of novel neuroprotective therapies.

The effect of Lavandula Coronopifolia essential oil on the biophysical properties of desensitization and deactivation gating currents in ionotropic receptors.

The rising incidence of cancer and the lack of effective therapeutic interventions for many neurological illnesses like Alzheimer's and epilepsy has prompted us to investigate the composition and effects of the Lavandula coronopifolia oil from Palestine on cancer cells and AMPA receptor subunits in the brain due to the vast range of beneficial properties of Lavandula coronopifolia essential oil (EO). GC/MS was used to analyze L. coronopifolia's EO chemistry. EO's cytotoxicity and biophysical effects on AMPA receptors were investigated using MTS and electrophysiological techniques. The GC-MS results revealed that L. coronopifolia EO has a high content of eucalyptol (77.23%), ß-pinene (6.93%), and α-pinene (4.95%). The EO showed more significant antiproliferative selectivity activities against HepG2 cancer cell lines than HEK293T cell lines with IC50 values of 58.51 and 133.22 µg/mL, respectively. The EO of L. coronopifolia affected AMPA receptor kinetics (desensitization and deactivation) and preferred homomeric GluA1 and heteromeric GluA1/A2 receptors. These findings indicate the potential therapeutic use of L. coronopifolia EO in the selective treatment of HepG2 cancer cell lines and neurodegenerative diseases.

Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

Glutamatergic chemical synapses mediate excitatory neurotransmission by the ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors in the central nervous system (CNS). AMPA receptor-mediated synaptic transmission abnormalities may play a role in neurologic and neurodegenerative diseases, and compounds that can modulate AMPA receptor (AMPAR) signaling have been studied for decades as possible therapies for Alzheimer's disease, Parkinson's disease, depression, and epilepsy. Here, we aimed to determine the modulating effect of allosteric regulators on AMPA receptors by comparing their actions on AMPA-evoked currents, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits. In this study, patch-clamp electrophysiology was performed to examine how the AMPA subunit responded to benzodioxole (BDZ) derivatives. Our results showed that the BDZ derivatives affected AMPARs as negative modulators, particularly BDZs (8, 9, and 15), where they increased the desensitization rate and delayed the deactivation process. The BDZ compounds were utilized in this study as AMPA modulators to investigate fundamental and clinical AMPA receptor processes. We test BDZs as negative allosteric AMPAR modulators to reestablish glutamatergic synaptic transmission. These efforts have resulted in important molecules with neuroprotective properties on AMPA receptors.

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors' Gating Modules.

The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8-11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.