Indanone is a versatile scaffold that has a number of pharmacological properties. The successful development and ensuing approval of indanone-derived donepezil as a drug of choice for Alzheimer\'s disease attracted significant scientific interest in this moiety. Indanones could act as small molecule chemical probes as they have strong affinity towards several critical enzymes associated with the pathophysiology of various neurological disorders. Inhibition of these enzymes elevates the levels of neuroprotective brain chemicals such as norepinephrine, serotonin and dopamine. Further, indanone derivatives are capable of modulating the activities of both monoamine oxidases (MAO-A and -B) and acetylcholinesterase (AChE), and thus could be useful in various neurodegenerative diseases. This review article presents a panoramic view of the research carried out on the indanone nucleus in the development of potential neuroprotective agents.

Alzheimer\'s disease (AD) is the most prevalent neurodegenerative disease that affects people aged 60 years and above. Yet, the discovery of potent therapeutic agents against this disease has no utmost progress and a number of drug candidates could not make it out of the clinical trials at varied stages. At the same time, the currently available anti-cholinesterase (AChE) and monoamine oxidase-B (MAO-B) for the treatment of AD can only improve the clinical symptoms while the recently approved immunotherapy agent \"remains questionable. Thus, the need for novel therapeutic agents with the potential to treat the aetiology of the disease. Herein, this study sought to examine the potential of a number of bioactive compounds derived from Vitis vinifera as a promising agent against AChE and MAO-B. Using a computational approach via molecular docking 23 bioactive agents were screened against AChE and MAO-B, and the compounds with a binding score below that of the standard ligand were further subjected to drug-likeness and pharmacokinetic screening. Eight and thirteen of the studied agents optimally saturated the active pocket of the AChE and MAO-B respectively, forming principal interactions with a number of amino acids at the active pocket of the targets and among these compounds only rutin failed the drug-likeness test by violating four parameters while all showed moderate pharmacokinetics features. A number of Vitis vinifera-derived bioactive compounds show excellent inhibitory potential against AChE and MAO-B, and moderate pharmacokinetic features when compared to the reference ligand (tacrine). These compounds are therefore proposed as novel AChE and MAO-B inhibitors for the treatment of AD and wet-lab analysis is necessary to affirm their potency.

BACKGROUND: Alzheimer\'s disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
METHODS: This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme\'s pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.
RESULTS: This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.
CONCLUSIONS: Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer\'s disease.

BACKGROUND: As individuals age, they may develop Alzheimer\'s disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer.
OBJECTIVE: This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis.
METHODS: Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed.
RESULTS: Cycloastragenol significantly improved rats\' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1.
CONCLUSIONS: Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.

BACKGROUND: Small molecule phytocompounds can potentially ameliorate degenerative changes in cerebral tissues. Thus, the current study aimed to evaluate the neuroprotective efficacy of phytocompounds of methanolic shoots extract of Calligonum polygonoides L. (MSECP) in hypercholesterolemia-associated neurodegenerations.
METHODS: Phytochemical screening of the extract was made by LCMS/MS and validated by a repository of the chemical library. The hypercholesterolemia was induced through the intraperitoneal administration of poloxamer-407 with a high-fat diet. The in-silico assessments were accomplished by following the molecular docking, ADME and molecular dynamics. MMPBSA and PCA (Principal Component Analysis) analyzed the molecular dynamics simulations. Consequently, in-vivo studies were examined by lipid metabolism, free radical scavenging capabilities and histopathology of brain tissues (cortex and hippocampus).
RESULTS: 22 leading phytocompounds were exhibited in the test extract, as revealed by LCMS/ MS scrutiny. Molecular docking evaluated significant interactions of apigenin triacetate with target proteins (HMGCR (HMG-CoA reductase), (AChE-Acetylcholinesterase) and (BuChE- Butyrylcholinesterase). Molecular dynamics examined the interactions through assessments of the radius of gyration, RSMD, RSMF and SASA at 100 ns, which were further analyzed by MMPBSA (Molecular Mechanics Poisson-Boltzmann) and PCA (Principal Component Analysis). Accordingly, the treatment of test extract caused significant alterations in lipid profile, dyslipidemia indices, antioxidant levels and histopathology of brain tissues.
CONCLUSIONS: It can be concluded that apigenin triacetate is a potent phytoconstituent of MSEPC and can interact with HMGCR, AChE, and BuChE, which resulted in improved hypercholesterolemia along with neuroprotective ameliorations in the cortex and hippocampus.

Chemical insecticides are effective at controlling mosquito populations, but their excessive use can pollute the environment and harm non-target organisms. Mosquitoes can also develop resistance to these chemicals over time, which makes long-term mosquito control efforts challenging. In this study, we assessed the phytochemical, biochemical, and insecticidal properties of the chemical constituents of cajeput oil. Results show that Melaleuca cajuputi essential oil may exhibit mosquito larvicidal properties against Anopheles stephensi larvae (second-fourth instar) at 24 h post-treatment. At 24 h post-exposure, the essential oil resulted in a significant decrease in detoxifying enzymes. All of these findings indicate that cajeput oil infects An. stephensi larvae directly affect the immune system, leading to decreased immune function. Cajeput oil significantly affects the second, third, and fourth instar larvae of An. stephensi, according to the bioassay results. Cajeput oil does not induce toxicity in non-target Eudrilus eugeniae earthworm species, as indicated by a histological study of earthworms. Phytochemical screening and GC-MS analysis of the essential oil revealed the presence of several major phytochemicals that contribute to mosquito larvicidal activity. The importance of cajeput oil as an effective candidate for biological control of the malarial vector An. stephensi is supported by this study.

Acetylcholinesterase (AChE) is a key enzyme in the cholinergic pathway of the nervous systems, with its aberrant expression linked to various diseases. In this study, we have developed a novel Turn-On near-infrared fluorescent probe, TQ-AChE, for the sensitive and selective detection of AChE activity. Characterized by its near-infrared emission at 740 nm, TQ-AChE effectively overcomes the limitations of traditional fluorescent probes, such as short excitation wavelengths and limited tissue penetration, crucial for both in vitro and in vivo applications. The probe\'s low limit of detection (LOD) of 0.02 U/mL for AChE makes it highly sensitive, enabling rapid quantification of AChE activity in serum effectively. Cell imaging studies demonstrate that TQ-AChE can confirm higher AChE activity expression in normal liver cells compared to liver cancer cells. TQ-AChE can also monitor AChE fluctuations in APAP-induced acute effectively, facilitating the evaluation of the efficacy of liver detoxifying agents. Additionally, in vivo studies in mouse models validate the potential of the probe in real-time monitoring of AChE expression in liver injury. The ability of TQ-AChE to visualize AChE expression signifies its potential as a promising tool for early liver disease diagnosis and therapeutic monitoring, opening new possibilities in hepatological research and clinical diagnostics.

Effective therapeutics for Alzheimer\'s disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited the inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer\'s disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

MicroRNA-132 (miR-132) is a highly conserved molecule that plays a crucial regulatory role in central nervous system (CNS) disorders. The expression levels of miR-132 exhibit variability in various neurological disorders and have been closely linked to disease onset and progression. The expression level of miR-132 in the CNS is regulated by a diverse range of stimuli and signaling pathways, including neuronal migration and integration, dendritic outgrowth, and complexity, synaptogenesis, synaptic plasticity, as well as inflammation and apoptosis activation. The aberrant expression of miR-132 in various central neurodegenerative diseases has garnered widespread attention. Clinical studies have revealed altered miR-132 expression levels in both chronic and acute CNS diseases, positioning miR-132 as a potential biomarker or therapeutic target. An in-depth exploration of miR-132 holds the promise of enhancing our understanding of the mechanisms underlying CNS diseases, thereby offering novel insights and strategies for disease diagnosis and treatment. It is anticipated that this review will assist researchers in recognizing the potential value of miR-132 and in generating innovative ideas for clinical trials related to CNS degenerative diseases.