ACS Chemical Neuroscience最新文献

Microbial infections have long been implicated in the gut-brain link to Alzheimer’s disease (AD). These infections may influence AD development either directly, through brain invasion, or indirectly via bacterial metabolites crossing the blood-brain-barrier (BBB) or interacting with the enteric nervous system (ENS). Such findings have inspired clinicians to repurpose antimicrobial drugs for AD, yielding promising results. However, the sole bacterial link to AD may be insufficiently understood. Bacterial amyloid presence in biofilms is well-documented, with certain bacterial proteins exacerbating amyloid formation while others inhibit it. For instance, Curli-specific gene protein C (CsgC) in E. coli suppresses curli amyloid formation. This review investigates the possibility of human CsgC-like proteins, identifying beta-2 microglobulin (β2M) and E3 ubiquitin ligases (E3s) as potential analogs that may influence amyloid degradation. We propose that nanoparticles (NPs) could serve as platforms to anchor these proteins, forming Amyloid Dissociating Bifunctional NanoChaperones (ADBiNaCs) with enhanced antiamyloidogenic activity. This innovative approach holds promise for novel AD treatment strategies, meriting further investigation into the role of bacterial and human amyloid-modulating proteins in AD pathology.

Engineered nanoparticles (ENPs) have widely revolutionized many fields, including medicine, technology, environmental science, and industry. However, with the wide use of ENPs in everyday life, concerns are increasingly being raised about their potential neurotoxic effects on the central nervous system (CNS), particularly in relation to neurodegeneration and neuroinflammation. The present systematic review focuses on reporting the current knowledge about the neurotoxic potential of ENPs, with particular attention to their mechanism of action in neuroinflammation and neurodegeneration. This PRISMA based systematic review encompassed studies from Pubmed, Embase, and Web of Science. Eligibility criteria included focusing on engineered NPs and their impacts on neuroinflammation, neurodegeneration, and neurotoxicity. Evidence shows that ENPs easily can cross the blood-brain barrier (BBB) inducing neuronal damage and neurotoxicity due to oxidative stress, inflammation, mitochondrial dysfunction, and cell death. Inflammation plays a crucial role in activating glial cells, such as microglia and astrocytes, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS). This increases the vulnerability of the brain to systemic inflammation. In conclusion, as ENP exposure continues to increase, understanding their long-term effects on the brain is fundamental to developing effective strategies to mitigate their impact on neuronal human health.

PANoptosis is a newly identified form of cell death that encompasses pyroptosis, apoptosis, and necroptosis. Numerous studies have highlighted the significance of PANoptosis in brain ischemia-reperfusion (I/R) injury. Calycosin, a natural product with diverse biological activities, has demonstrated a significant reduction in neuronal death caused by ischemic brain injury by modulating multiple cell death pathways. In order to investigate the potential mechanisms underlying the neuroprotective role of calycosin in alleviating PANoptosis-induced damage in ischemic stroke therapy, we used mouse hippocampal neuronal cell line HT22 to stimulate ischemia in vitro through Oxygen and Glucose Deprivation/Reperfusion (OGD/R) and established molecular docking to assess the binding affinity of Calycosin with key targets and molecular dynamics simulations (MDS) to study the stability of the ligand-protein complex. The results demonstrate that Calycosin could improve the cell growth of HT22, leading to enhanced cell viability, reduced lactate dehydrogenase leakage, and decreased cell apoptosis after OGD/R. It also regulated the expression of PANoptosis-related genes such as NLRP3, GSDMD, MLKL, and RIPK1 and increased the Bcl-2/Bax ratio, effectively reducing cellular damage and providing protection. Molecular docking and MDS simulations demonstrated strong binding activity and stability between Calycosin and PANoptosis-related targets. Furthermore, Calycosin successfully passed the drug similarity (DS) evaluation and exhibited favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and biological activity. In conclusion, Calycosin could alleviate ischemic stroke by inhibiting PANoptosis, reducing neuronal inflammation and apoptosis, and improving damage caused by the OGD/R. Thus, it could serve as a potential therapy for ischemic stroke.

Amyloid β peptide (Aβ) aggregation in the brain represents an initial detrimental episode in the etiology of Alzheimer's disease (AD). Recently, it has been discovered that inhibiting Aβ neurotoxicity by modulating highly toxic Aβ oligomers (AβOs) is more rewarding than reducing the overall amyloid fibril production. In line with this, here, we discussed the efficiency of multifunctional quinazolinone and vanillin acrylamide hybrids (QVA_1-5) as modulators of aggregation behavior. The thioflavin T (ThT) assay inferred dose-dependent intensification of Aβ_1-42 aggregation by QVA_1-5, which may be due to the coassembly of hybrids with AβOs. Field emission-scanning electron microscopy (FE-SEM) disclosed enormously distinctive differences among the aggregate morphologies of Aβ_1-42 and Aβ_1-42+ QVA_1-5, which intensely reinforced the modulatory action of QVA_1-5 on the molecular assembly of the Aβ_1-42 peptide. Supportingly, the Alamar Blue assay proved QVA_1-5 as an effective neuroprotector in the SH-SY5Y cell line against Aβ_1-42-induced toxicity. Consistent with these findings, western blot data showed an increased number of Aβ_1-42 fibrils in SH-SY5Y cells treated with QVA_1-5. In our molecular docking approach, all ligands had identical binding positions at sites 4-6 of the Aβ fibril structure (PDB ID: 2M4J). In the interaction pattern, ligands spanned across five Aβ monomers that were stacked together and stabilized the fibril formation by hydrophobic interactions with the Aβ monomer residues as well as neighboring ligands. In the molecular dynamics simulations, the lower RMSD and similar rGyr values for the ligands further supported the stability of the ligands inside the binding pocket of the 2M4J Aβ fibril. Overall, the present study provided a mechanistic explanation at the atomic level for the impact of small molecules (QVA_1-5) on Aβ fibril stabilization for the first time. Hence, we strongly believe that these findings will be a resource for the development of imminent drug candidates against AD that can manipulate Aβ aggregate formation.

A novel neurotrophic factor, human mesencephalic astrocyte-derived neurotrophic factor (hMANF), is being considered a therapeutic agent for a variety of diseases. However, little, if anything, has been reported about its stability. A preformulation study was conducted to assess the stability of hMANF as a function of pH and temperature. In addition, the effects of buffers and other excipients were evaluated as well. While the chemical and physical stability of hMANF decreases near pH 4, overall, the protein appears to be quite stable, especially near pH 6. Both histidine and phosphate appear to be suitable buffers in this pH range. Some loss of stability was noted above pH 6.5 as well. The stability profile of hMANF was comparable at 1 and 10 mg/mL. The decreased stability at acidic pH is correlated with the loss of the native α-helical conformation, as shown by FTIR spectroscopy. These studies indicate that hMANF is quite stable near pH 6, and formulations capable of exhibiting adequate long-term stability in aqueous solutions should be possible.

Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.

Nuclear factor erythroid 2 related factor 2 (Nrf2) is closely associated with neurodegenerative diseases, and the Nrf2-mediated activation of antioxidant response elements (AREs) brings about validated strategies for treating neurodegenerative diseases. Here, we discovered that troglitazone, a clinical medication for diabetes mellitus, could serve as a Nrf2 activator to rescue neuronal damages both in vitro and in vivo. The mechanism of troglitazone action involves binding with kelch-like ECH-associated protein 1 (Keap1) and the activation of Nrf2. This process leads to the migration of Nrf2 to the cell nucleus and transactivates the AREs. Troglitazone exhibits significant alleviation of oxidative stress in PC12 cells induced by hydrogen peroxide or 6-hydroxydopamine (6-OHDA). In vivo studies indicate that troglitazone could rescue the motor activity and neurodevelopmental deficiency in zebrafish induced by 6-OHDA. Additionally, mass spectrometry imaging demonstrates that troglitazone could cross the zebrafish blood-brain barrier, supporting the application of troglitazone in treating neurodegenerative diseases. Overall, this work reveals that the novel Nrf2 activator troglitazone has potential therapeutic value for neurodegeneration and provides a foundation for its repurposing.

The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Many traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. Of those that are not regulated, a lack of opioid receptor subtype selectivity can cause confounding in interpreting results. In the present study, we sought to design and characterize a library of 24 antagonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood-brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of 1A and 3A at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [¹¹C]1A was prepared via metallophotoredox of the aryl-bromide functional group to [¹¹C]methyl iodide. The nascent radioligand demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [¹¹C]1A binding, though the interactions were not as pronounced as naloxone's ability to displace [¹¹C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.

There currently are no medications proven to be effective for the treatment of stimulant-use disorder (SUD). Sigma-receptor (σR) antagonists block many effects of stimulant drugs but not the reinforcing effects assessed with self-administration in rats. However, a recent study suggests that σR antagonism combined with a dopamine (DA) transporter (DAT) blockade selectively attenuates stimulant self-administration. A compound with potential for dual DAT/σR inhibition, CM699, was synthesized and had the necessary ex vivo affinities of 311 and 14.1 nM at DAT and σ₁Rs, respectively. CM699 inhibited DA uptake ex vivo. Antagonist effects at σ₁Rs by CM699 were confirmed with a recently reported pharmacological assay: CM699 increased, whereas the σ₁R agonist, (+)-pentazocine, decreased σ₁R multimers detected in nondenaturing protein gels, and CM699 blocked the effects of (+)-pentazocine. CM699 after intravenous administration (5.0 mg/kg) in rats had an elimination half-life of 4.4 h. In rats, CM699 after intraperitoneal administration blunted the stimulatory effects of cocaine on DA levels in the nucleus accumbens and insurmountably blocked cocaine self-administration, indicating efficacy as a cocaine antagonist in vivo. When given alone, CM699 was not self-administered nor had significant effects on nucleus accumbens DA, suggesting minimal, if any, abuse potential. Further, in a biochemical assay designed to probe the conformation of DAT, (+)-pentazocine potentiated cocaine-induced cysteine accessibility of DAT transmembrane domain 6a, suggesting a shift in the conformational equilibrium of DAT toward outward-facing, whereas CM699 blocked this effect. The results provide preclinical proof of concept for dual DAT/σR inhibition as a novel DAT-conformational approach for the development of medications to treat SUD.

Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy (¹H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel ¹H-MRS. ¹H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between ¹H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (p < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (p < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (p > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (p = 0.001, r = 0.71), FVC (p = 0.03, r = 0.58), and ΔFS (p = 0.01, r = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (p = 0.02, r = 0.41). In the INC, tCho concentrations (p = 0.04, r = -0.54) and mIns/tNAA ratio (p = 0.02, r = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (p = 0.01, r = 0.33) and (p = 0.001, r = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.