ACS Chemical Neuroscience最新文献

Chronic hypoxic exposure triggers the onset and progression of cognitive dysfunction; however, the mechanisms underlying chronic hypoxia-induced neuroinflammation and its contribution to cognitive dysfunction remain poorly understood. Although inflammation and hypoxia are interdependent, numerous recent studies have linked the development of various human diseases to hypoxia-induced inflammation. In this study, we focused on the NLRP3 inflammasome with novel analogues of cytokine release inhibitory drug 3 (CRID3), a class of small molecule inhibitors for the NLRP3 inflammasome, to investigate their potential contribution to alleviating chronic hypoxia-induced neuroinflammation using the zebrafish model. The designed CRID3 analogues 6a–q were prepared from 2-methyl furan-3-carboxylate, following a four-step reaction sequence and fully characterized by NMR and mass spectral analysis. The administration of CRID3 analogues 6a–q led to a notable reduction in neuroinflammation and an increase in glial proliferation markers in both sexes. In addition, we investigated the potential effects of CRID3 analogues 6a–q through various behavioral tasks to assess their role in ameliorating post-hypoxic behavioral deficits and cognitive impairment. Notably, the study revealed that post-chronic hypoxia, male zebrafish exhibited significantly higher levels of inflammatory marker expression than females. Furthermore, we observed that the neurogenic response to treatment with CRID3 derivative 6o varied depending on the sex, with females showing a sex-specific differential increase in neurogenesis compared to males. This work emphasizes the significance of considering sex differences into account in developing therapeutic strategies for neurological disorders, as shown by the sex-specific molecular and behavioral changes in zebrafish cognitive impairment and neuroinflammation.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

Parkinson’s disease, a classical motor disorder affecting the dopaminergic system of the brain, has been as a disease of the brain, but this classical notion has now been viewed differently as the pathology begins in the gut and then gradually moves up to the brain regions. The microorganisms in the gut play a critical role in maintaining the physiology of the gut from maintaining barrier integrity to secretion of microbial products that maintain a healthy gut state. The pathology subsequently alters the normal composition of gut microbes and causes deleterious effects that ultimately trigger strong neuroinflammation and nonmotor symptoms along with characteristic synucleopathy, a pathological hallmark of the disease. Understanding the complex pathomechanisms in distinct and established preclinical models is the primary goal of researchers to decipher how exactly gut pathology has a central effect; the quest has led to many answered and some open-ended questions for researchers. We summarize the popular opinions and some contrasting views, concise footsteps in the treatment strategies targeting the gastrointestinal system.

Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [¹⁸F]fluoro-deoxy-glucose ([¹⁸F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily). Compared with control animals, the relative uptake of [¹⁸F]FDG in CSE mice was decreased in the thalamus and brain stem (p < 0.001, n = 14 per group) and increased in the hippocampus, cortex, cerebellum, and olfactory bulb (p < 0.001). NFL-101 induced a humoral immune response (specific IgGs) in mice and activated human natural-killer lymphocytes in vitro. In CSE mice, but not in control mice, single-dose NFL-101 significantly increased [¹⁸F]FDG uptake in the thalamus (p < 0.01), thus restoring normal brain glucose metabolism after 2-day withdrawal in this nicotinic receptor-rich region. In tobacco research, [¹⁸F]FDG PET imaging provides a quantitative method to evaluate changes in the brain function associated with the withdrawal phase. This method also showed the CNS effects of NFL-101, with translational perspectives for future clinical evaluation in smokers.

In Alzheimer’s disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-β (Aβ) aggregates through the reduction of a Cu²⁺ ion. In the presence of a small amount of redox-active Cu²⁺ ion, ROS is produced by the Aβ-Cu²⁺ complex as Aβ peptide alone is unable to generate excess ROS. Therefore, Cu²⁺ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu²⁺ ions from the Aβ-Cu²⁺ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu²⁺ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood–brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N-salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N-salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure–activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects. Among them, both in vitro and in vivo compound 18 exerted the best antineuroinflammatory effects by suppressing the activation of microglia, which is the culprit of neuroinflammation. The underlying mechanism of its antineuroinflammatory effect may be related to the inhibition of transcription, expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) that subsequently regulated downstream cyclooxygenase-2 (COX-2) expression and activity. With its excellent BBB permeability and pharmacokinetic properties, compound 18 exhibited significant neuroprotective effects in the hippocampal region of lipopolysaccharides (LPS)-induced mice than former N-salicyloyl tryptamine derivative L7. In conclusion, compound 18 has provided a new approach for the development of highly effective antineuroinflammatory therapeutic drugs targeting microglia activation.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D₄R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure–activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D₄R antagonists. However, developing selective D₄R antagonists suitable for clinical translation remains a challenge.

Recently, the abuse of synthetic cathinones is increasing among young people. α-Pyrrolidinobutiothiophenone (α-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of α-PBT using a drug discrimination (DD) task. We also investigated the role of α-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats. Initially, the rats were trained to discriminate between cocaine and saline. After the discrimination training criteria were met, we determined the dose–effect curves of cocaine and conducted generalization tests with α-PBT and α-pyrrolidinopentiothiophenone (α-PVT) using a cumulative dosing protocol. In a separate set of studies, we examined the dopaminergic mechanisms underlying the function of α-PBT as an interoceptive stimulus (17.8 mg/kg) by intraperitoneally injecting either the dopamine (DA) D1 antagonist SCH23390 (0.06 and 0.12 mg/kg) or the D2 antagonist eticlopride (0.05 and 0.1 mg/kg) 15 min before DD testing. Brain reward function was measured using an ICSS procedure to examine the effects of α-PBT on ICSS threshold under the frequency-rate procedure. Our results showed that α-PBT functioned as a discriminative cue similar to cocaine in rats. More importantly, SCH23390 abolished the effects of α-PBT as an interoceptive stimulus in a dose-dependent manner in rats trained to press a lever to receive cocaine. Similarly, eticlopride dose-dependently attenuated the effect of α-PBT used as a discriminative cue. Additionally, cumulative α-PBT administration dose-dependently lowered ICSS thresholds compared with those in saline-treated rats. Furthermore, α-PBT-induced potentiation of BSR was abolished by pretreatment with both SCH23390 and eticlopride. Taken together, our results suggest that α-PBT can function as a cocaine-like discriminative cue via the activation of D1 and D2 receptors. α-PBT also appears to influence BSR by reducing the brain reward threshold via changes in D1 and D2 receptors. The present study suggests that α-PBT could have addictive properties through DA D1 and D2 receptors and thus poses a threat to humans.

Detection of amyloid β (Aβ) oligomers, regarded as the most toxic aggregated forms of Aβ, can contribute to the diagnosis and treatment of Alzheimer's disease (AD). Thus, the development of imaging probes for in vivo visualization of Aβ oligomers is crucial. However, the structural uncertainty regarding Aβ oligomers makes it difficult to design imaging probes with high sensitivity to Aβ oligomers against highly aggregated Aβ fibrils. In this study, we developed Aβ oligomer-selective fluorescent probes based on triphenylmethane dyes through screening of commercially available compounds followed by structure-activity relationship (SAR) studies on cyclic or acyclic 4-dialkylamino groups. We synthesized 11 triarylmethane-based Aβ oligomer probe (TAMAOP) derivatives. In vitro evaluation of fluorescence properties, TAMAOP-9, which had bulky 4-diisobutylamino groups introduced into three benzenes of a twisted triphenylmethane backbone, showed marked fluorescence enhancement in the presence of Aβ oligomers and demonstrated high selectivity for Aβ oligomers against Aβ fibrils. In docking studies using the Aβ trimer model, TAMAOP-9 bound to the hydrophobic surface and interacted with the side chain of Phe₂₀. In vitro section staining revealed that TAMAOP-9 could visualize Aβ oligomers in the brains of AD model mice. An in vivo fluorescence imaging study using TAMAOP-9 showed significantly higher fluorescence signals from the brains of AD model mice than those of age-matched wild-type mice, confirmed by ex vivo section observation. These results suggest that TAMAOP-9 is a promising Aβ oligomer-targeting fluorescent probe applicable to in vivo imaging.

Growth hormone-releasing hormone (Ghrh) neurons in the dorsomedial ventromedial hypothalamic nucleus (VMNdm) express the metabolic transcription factor steroidogenic factor-1 and hypoglycemia-sensitive neurochemicals of diverse chemical structures, transmission modes, and temporal signaling profiles. Ghrh imposes neuromodulatory control of coexpressed transmitters. Multiple metabolic sensory mechanisms are employed in the brain, including screening of the critical nutrient glucose or the energy currency ATP. Here, combinatory laser-catapult-microdissection/single-cell multiplex qPCR tools were used to investigate whether these neurons possess molecular machinery for monitoring cellular metabolic status and if these biomarkers exhibit sex-specific sensitivity to insulin-induced hypoglycemia. Data show that hypoglycemia up- (male) or downregulated (female) Ghrh neuron glucokinase (Gck) mRNA; Ghrh gene silencing decreased baseline and hypoglycemic patterns of Gck gene expression in each sex. Ghrh neuron glucokinase regulatory protein (Gckr) transcript levels were respectively diminished or augmented in hypoglycemic male vs female rats; this mRNA profile was decreased by Ghrh siRNA in both sexes. Gene transcripts encoding catalytic alpha subunits of the energy monitor 5-AMP-activated protein kinase (AMPK), i.e., Prkaa1 and 2, were increased by hypoglycemia in males, yet only the former mRNA was hypoglycemia-sensitive in females. Ghrh siRNA downregulated baseline and hypoglycemia-associated Prkaa subunit mRNAs in males but elicited divergent changes in Prkaa2 transcripts in eu- vs hypoglycemic females. Results provide unique evidence that VMNdm Ghrh neurons express the characterized metabolic sensor biomarkers glucokinase and AMPK and that the corresponding gene profiles exhibit distinctive sex-dimorphic transcriptional responses to hypoglycemia. Data further document Ghrh neuromodulation of baseline and hypoglycemic transcription patterns of these metabolic gene profiles.