ACS Chemical Neuroscience最新文献

Angiotensin receptor blockers (ARBs) have been relatively less explored in the field of neuroprotection and dementia; however, ample preclinical and clinical evidence suggests their potential cognitive benefits. Despite these findings, there remains limited evidence on precise mechanistic pathways involved, highlighting the critical need to bridge the gap. In our previous work, we presented the beneficial effect of azilsartan in a dementia model and observed promising neuroprotective outcomes. Building on these findings, this study sought to compare the activity of azilsartan with other commonly used ARBs, including telmisartan, olmesartan, valsartan, eprosartan, irbesartan, and candesartan, using an integrative network pharmacology approach. Our network analysis identified 12 key target proteins implicated in dementia pathology, which were further subjected to docking studies with the seven ARBs, revealing strong binding affinities of azilsartan, olmesartan, and telmisartan with critical signaling proteins, including AKT1, PIK3CA, and PIK3CB. Molecular dynamics simulations further confirmed the stability and favorable interactions of azilsartan with these targets. To experimentally validate these predictions, in vivo studies were conducted in a scopolamine-induced memory-impaired model, which demonstrated significant restoration of the levels of AKT1 and PIK3CA. These findings clearly demonstrate the PI3K/AKT modulating effects of azilsartan, reinforcing its repurposing potential in dementia and related disorders, thereby expanding novel therapeutic opportunities within this drug class.

The presence of wild-type (WT) Cu, Zn superoxide dismutase-1 (SOD1) can increase the toxicity of mutant SOD1 proteins linked to amyotrophic lateral sclerosis (ALS). The mechanism of synergy is unclear but might involve interactions between WT and mutant SOD1 in native or non-native states. One unanswered question is will the diverse rates of mutant SOD1 homofibrillization converge in the presence of WT SOD1? To answer this question, we assessed the coaggregation of mutant and WT SOD1 in vitro, including (i) how WT SOD1 affected the formation rate and stability of mutant fibrils and (ii) the proximity of WT and mutant SOD1 in heterofibrils. For most mutations studied, the presence of WT SOD1 slowed nucleation and propagation of mutant fibrils while increasing fibril thermostability. The D90A SOD1 protein was one exception: WT SOD1 had a nearly negligible effect on its rate of nucleation. The cross-seeding of soluble mutant SOD1 with WT fibrils (and of soluble WT SOD1 with mutant fibrils) suggests that both proteins can occupy the same fibril. Mass spectrometry of heterofibrils treated with an NHS-ester cross-linker (∼8 Å) suggested that WT and E100G mutant SOD1 are colocalized in heterofibrils, possibly stacked in an alternating configuration.

DNA polymerase-β (DNA pol-β) plays a critical role in β-amyloid-induced neurodegeneration by mediating aberrant DNA replication in postmitotic neurons. In previous work, we demonstrated that 5-methoxyflavone inhibits DNA pol-β, though computational analyses suggested potential binding to the primase p58 subunit. Through molecular modeling, here, we designed (S)-2-cyclohexyl-5-methoxy-2H-chromene (S-chromene), a novel flavone-derived inhibitor exhibiting strong electrostatic complementarity with DNA pol-β but weak interaction with primase p58, suggesting enhanced selectivity. (R)-2-cyclohexyl-5-methoxy-2H-chromene (R-chromene) exhibited indistinguishable binding properties from S-chromene. The compound was obtained as a racemic mixture (chromene). Since the separated enantiomers were unstable, all biological assays used the racemate. DNA polymerase activity assay confirmed that chromene inhibited selectively DNA pol-β without affecting the primase/DNA pol-α complex activity. Also, the compound amplified methylmethanesulfonate toxicity in wild-type but not DNA pol-β-null fibroblasts, validating target-engagement. In cultured neurons, chromene effectively prevented β-amyloid-induced DNA replication and apoptosis. Ours is the first demonstration of a chromene acting as a selective DNA pol-β inhibitor endowed with a unique mechanism of neuroprotection.

Chemical neuroscience wields tools to uncover the molecular mysteries of the brain. Sensors can be fabricated with properties tailored to the scales needed to decode neurochemical information. Current instrumentation is capable of measurement rates that exceed neurochemical release rates. Modern machine learning models are approaching parameterization near the number of brain synapses. Fast voltammetry has remained a neuroanalytical workhorse technique for nearly half a century and has undergone significant transformations in many aspects due to advances in hardware and computation. Here, we review current and future uses of machine learning coupled with fast voltammetry to quantify neurochemical dynamics in the brains of behaving animal and human subjects. We focus on the advances that machine learning offers to pervasive problems in fast voltammetry. We identify current challenges and limitations for in vivo studies and delineate several routes for future development.

Ciguatera poisoning (CP) is a foodborne illness caused by the consumption of seafood containing ciguatoxins (CTXs). There is a wide variety of symptoms associated with ciguatera poisoning; however, the origin and physiological cause of many of them remains still unclear. Although the primary effect of ciguatoxins and brevetoxins (BTX) is their effect in voltage-gated sodium channels, in this work, the effect of both toxins on human transient receptor potential vanilloid 1 (TRPV1) channels was investigated under different physiological conditions that may contribute to CP. The results obtained showed that different physiological conditions that may occur in the organism potentiated the effect of ciguatoxins on TRPV1. Among these conditions, low pH, the presence of oxidative stress products, or endogenous ligands increased the TRPV1 currents induced by CTX3C and hyperpolarized their activation voltage. In addition, neurotoxic shellfish poisoning symptomatology (NSP), caused by brevetoxins, was previously linked to TRPV1 channels; therefore, in this study brevetoxins and ciguatoxins were combined to evaluate their effects on TRPV1 channels. The results obtained demonstrated that brevetoxin 3 alone did not alter TRPV1 channel currents or their activation; however, in the presence of the endogenous ligand anandamide BTX3 effects were potentiated. Furthermore, an allosteric effect of ciguatoxins and brevetoxins was observed, since the simultaneous presence of 0.5 nM CTX3C with different concentrations of BTX activated TRPV1 channels, increasing their maximum current intensity and hyperpolarizing the activation voltage.

Tau undergoes fibrillogenesis in a group of neurodegenerative diseases, termed tauopathies. Each tauopathy is characterized by tau fibrils with disease-specific conformations, highlighting the complexity of tau self-assembly. This has led to debate surrounding the precise mechanisms that govern the self-assembly of tau in disease, especially the involvement of disulfide bonding (DSB) between cysteine residues. In this study, we use a truncated form of tau, dGAE, capable of forming filaments identical to those in disease. We reveal the impact of DSB on dGAE assembly and propagation by resolving the global mechanisms that dominate its assembly. We found evidence of surface-mediated secondary nucleation and fragmentation being active in dGAE assembly. The inhibition of DSB during dGAE assembly leads to an enhanced aggregation rate through a reduced lag phase but with no effect on the global assembly mechanisms. We suggest this is due to the formation of a dominant, seed-competent species in the absence of DSB that facilitates elongation and secondary nucleation, resulting in enhanced assembly. In vitro seeding assays reveal the recruitment of endogenous tau in a cell model only when using dGAE species formed under conditions that inhibit DSB. Our results further support the use of the in vitro dGAE tau aggregation model for investigating the mechanism of tau assembly, show the effect of varying conditions on tau assembly, and how these conditions affect the resultant species. Further studies may utilize dGAE and its aggregates to investigate tau seeding, propagation, and to highlight or test potential targets for therapies that reduce the spread of pathological tau throughout the brain.

Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases; yet, the source of cholesterol ester accumulation and whether it is directly linked to demyelination remain undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, implying the potential involvement of both proteins in the formation of cholesterol esters. Colocalization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination, highlighting the active roles of glial cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination, underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.

Alzheimer’s disease (AD) is characterized by deleterious amyloid plaques deposited in the brain, formed through the interaction of Amyloid β-peptides (Aβ_1–42) with the cell membrane. Despite promising preclinical results, Aβ_1–42 aggregation inhibitors have not delivered the anticipated benefits in clinical trials for AD. This discrepancy may stem from the fact that the cause of sporadic AD is unknown. Mounting evidence suggests that herpes simplex virus type-1 (HSV-1) may significantly contribute to the onset of AD by facilitating the aggregation of Aβ_1–42 into oligomers, leading to neurotoxicity and neuronal cell loss in the brain. However, the mechanism of neurotoxicity remains elusive. Understanding the relationship between the HSV-1 envelope glycoprotein D (gD) and Aβ_1–42 oligomers and their impact on neuronal membranes, is the most demanding task for unveiling the underlying mechanism. Thus, we performed extensive all-atom molecular dynamics (MD) simulations to thoroughly investigate the molecular mechanism underlying the interaction between the gD protein and Aβ_1–42 oligomers in both aqueous environments and in the presence of lipid bilayers, which mimic the composition of neuronal membranes in vivo. Our simulation study provides valuable insights into the initial stages of this process, in which the Aβ_1–42 tetramer (Aβ_1–42t) associates with gD via hydrogen bonds formed at their interface. Consequently, we observed that Aβ_1–42t–gD, rather than Aβ_1–42t alone, demonstrates significant adsorption to the membrane, driven by robust electrostatic interactions between the charged residues of Aβ_1–42t–gD and the phosphate groups of lipids such as POPC, POPS, POPE, and PSM. This interaction significantly reduces the electrostatic and van der Waals interactions among the lipids, in contrast to Aβ_1–42t binding alone. As a result, disruptions of the lipid membrane integrity are more pronounced upon the Aβ_1–42t–gD binding than the Aβ_1–42t alone. This study provides atomic-level evidence that gD amplifies Aβ_1–42t–membrane interactions, potentially altering membrane phase behavior and contributing to the initial molecular events underlying neuronal dysfunction, thereby suggesting a link between HSV-1 infection and the pathogenesis of AD.

α-Ethyltryptamine (AET), a synthetic tryptamine formerly used as an antidepressant, has resurfaced as a compound of interest due to its structural and functional overlap with serotonergic psychedelics and entactogens. Here, we characterized the pharmacological properties of racemic AET and its optical isomers, R(−)-AET and S(+)-AET, focusing on their interactions with the serotonin (or 5-hydroxytryptamine) 5-HT_2A receptor (5-HT_2AR) and serotonin transporter (SERT). In vitro, all three compounds displaced [³H]ketanserin from 5-HT_2AR with micromolar affinity; however, only S(+)-AET elicited weak partial agonist activity in calcium mobilization assays, an effect abolished by the 5-HT_2AR antagonist volinanserin. In vivo, all forms of AET induced a dose-dependent effect on the head-twitch response (HTR) in mice, which was completely blocked by volinanserin, confirming the 5-HT_2AR involvement. Notably, pretreatment with fluoxetine abolished AET-induced HTR without affecting responses to the classical psychedelic DOI, implicating SERT-mediated serotonin release in AET’s mechanism of action. These findings indicate that AET’s behavioral effects rely on a dual mechanism involving both direct 5-HT_2AR activation and indirect serotonergic potentiation via SERT. This dual pharmacology distinguishes AET from classical psychedelics and places it within a unique niche alongside MDMA-like serotonergic agents, highlighting the therapeutic and neuropsychiatric potential of AET isomers for modulating mood and cognition.

Anxiety and other neurotic disorders are significant medical and social issues, affecting 10–20% of people in developed countries, with an annual increase of over 10%. These conditions are becoming a greater concern due to treatment costs, missed work, decreased productivity, and their impact on relationships and socialization. As a result, developing effective treatments for neurotic disorders is a key goal in medicine and pharmacology. For the first time, we synthesized derivatives containing both tryptamine and triazine fragments and demonstrated their neurotropic activity, in particular their anxiolytic effect. When examining their binding using the docking method (Autodock Vina multiligand) to the GABAa receptor (PDB ID: 6X3X) and GABA-AT (PDB ID: 1SF2), compounds 4–11a–i showed minimal binding energies. In animal studies, compounds 9b and 11g demonstrated notable antianxiety effects, influencing behaviors such as approach to the arena center, grooming, and bolus count. Compound 11g 6-(4-chlorobenzyl)-3-[2-(6-methoxy-1H-indol-3-yl)-ethylamino]-4H-[1,2,4]triazin-5-one had the lowest IC₅₀ value at 19.8 ± 0.62, indicating high potency, and appeared to function similarly to diazepam without impairing normal exploration or movement. Notably, 9b outperformed other tested drugs. Its derivative 11g displayed the lowest energy binding with GABA_A receptor and GABA-AT, which likely accounts for its high activity.