ACS Chemical Neuroscience最新文献

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.

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.

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.

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.

Neuromelanin (NM) is an iron-rich, insoluble brown or black pigment that exhibits protective properties. However, its accumulation over time may render it a source of free radicals. In Parkinson’s disease, dopaminergic neurons with the highest NM levels and increased iron content are preferentially vulnerable to degeneration. Considering NM’s iron binding capacity and the critical role of iron in ferroptosis, we aimed to investigate the interplay between neuromelanin and ferroptosis in dopaminergic cells. We prepared two NM pigments: iron-free NM (ifNM) and iron-containing NM (Fe³⁺NM) and, exposed to cells. After verifying NM accumulation, cell viability was assessed in the absence or presence of antioxidants (NAC (1 mM), Trolox (100 μM)) and specific inhibitors of cell death types. Ferroptosis-related parameters, including lipid peroxidation byproducts (4-HNE), lipid ROS, glutathione, intracellular iron, GPX4, and ACSL4, and cellular iron metabolism-related proteins (TfR1, ferroportin, ferritin, IREB2) were evaluated following ifNM and Fe³⁺NM treatments, with or without Ferrostatin-1, Liproxstatin-1 and deferoxamine. Both NMs induced cell death via distinct mechanisms. Ferroptotic cell death by ifNM and Fe³⁺NM was reversed by ferrostatin-1 and NAC (p < 0.05). Significant alterations in lipid peroxidation, GPX4 levels, and iron metabolism were observed independent of NM’s iron composition (p < 0.05). Ferritin levels increased following ifNM treatment, reflecting an adaptive response to iron overload, while Fe³⁺NM treatment led to ferritin depletion, possibly via ferritinophagy. Our findings reveal a distinct role of iron-rich and iron-free neuromelanin in modulating ferroptotic pathways, highlighting the potential of targeting neuromelanin-iron interactions as a therapeutic strategy to mitigate neuronal ferroptosis in Parkinson’s disease.

Alzheimer’s disease is characterized by the accumulation of amyloid plaques in the brain. Recent studies suggest that amyloid-β (Aβ) peptides interact with cell membranes, potentially catalyzing plaque formation. However, the effect of varying cell membrane compositions on this catalytic process requires further investigation. Using molecular dynamics simulations, we demonstrate that a model gray matter membrane significantly influences the secondary structure of β-amyloid peptides. Notably, residues Asp1 and Glu22 play crucial roles in the membrane interaction. Glutamic acid at position 22, located in the middle of the peptide chain, appears to promote the formation of β-hairpin conformations, which are critical for aggregation. Additionally, our simulations reveal that the model white matter membrane allows a spontaneous insertion of segments of the peptide into the membrane, suggesting that membrane interaction not only alters the peptide structure but may also compromise membrane integrity. Our results show that the different membrane compositions in the brain may play different roles when interacting with β-amyloid peptides.

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.

Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.

Recently, we disclosed VU0467319, an M₁ positive allosteric modulator (PAM) clinical candidate that had successfully completed a phase I single ascending dose clinical trial. Pharmacokinetic assessment revealed that, in humans upon increasing dose, a circulating, inactive metabolite constituted a major portion of the total drug-related area under the curve (AUC). One approach the team employed to reduce inactive metabolite formation in the back-up program was the kinetic isotope effect, replacing the metabolically labile C–H bonds with shorter, more stable C–D bonds. The C–D dipole afforded VU6045422, a more potent M₁ PAM (human EC₅₀ = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC₅₀ = 492 nM, 71% ACh Max), and retained the desired profile of minimal M₁ agonism. Overall, the profile of VU6045422 supported advancement, as did greater in vitro metabolic stability in both microsomes and hepatocytes than did VU0467319. In both rat and dog in vivo, low doses proved to mirror the in vitro profile; however, at higher doses in 14-day exploratory toxicology studies, the amount of the same undesired metabolite derived from VU6045422 was equivalent to that produced from VU0467319. This unexpected IVIVC result, coupled with less than dose-proportional increases in exposure and no improvement in solubility, led to discontinuation of VU0467319/VU6045422 development.

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.