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BioRxiv : the Preprint Server For... Jun 2024Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving...
Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.
PubMed: 38895393
DOI: 10.1101/2024.06.04.597341 -
BioRxiv : the Preprint Server For... Jun 2024Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for nearly 50...
Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for nearly 50 years due to the sample and technique limitations. Past reports used powder X-ray diffraction (PCRD) to shed light on the possible packing of the molecule however a 3D structure remained elusive. Here we used Microcrystal Electron Diffraction (MicroED) to successfully unveil the 3D structure of oxybutynin hydrochloride. We identify several inconsistencies between the reported PXRD analyses and the experimental structure. Using the improved model, molecular docking was applied to investigate the binding mechanism between M muscarinic receptor (MR) and ()-oxybutynin, revealing essential contacts/residues and conformational changes within the protein pocket. A possible universal conformation was proposed for MR antagonists, which is valuable for future drug development and optimization. This study underscores the immense potential of MicroED as a complementary technique for elucidating the unknown pharmaceutical crystal structures, as well as for the protein-drug interactions.
PubMed: 38895300
DOI: 10.1101/2024.06.05.597682 -
Clinical Interventions in Aging 2024Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC).
BACKGROUND
Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC).
OBJECTIVE
This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.
MATERIAL AND METHODS
According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ- patients using a logistic regression analysis.
RESULTS
The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95).
CONCLUSION
The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.
Topics: Humans; Donepezil; Alzheimer Disease; Polymorphism, Single Nucleotide; Female; Male; Aged; Aged, 80 and over; Genotype; Logistic Models; Cholinesterase Inhibitors; Mental Status and Dementia Tests
PubMed: 38894884
DOI: 10.2147/CIA.S462786 -
Molecules (Basel, Switzerland) May 2024Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are...
Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From H and C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-xylopyranoside (), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-glucopyranoside (), 3,3'-di-O-methyl ellagic acid-4-O-β-D-glucopyranoside (), myricetin-3-O-rhamnoside (), shikimic acid (), arjungenin (), terminolic acid (), 24-deoxysericoside (), arjunglucoside I (), and chebuloside II (). The derivatives of ellagic acid (-) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (-). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.
Topics: Molecular Docking Simulation; Cholinesterase Inhibitors; Hypoglycemic Agents; Plant Extracts; alpha-Amylases; Acetylcholinesterase; Terminalia; Humans; Butyrylcholinesterase; alpha-Glucosidases; Glycoside Hydrolase Inhibitors; Molecular Structure
PubMed: 38893333
DOI: 10.3390/molecules29112456 -
Journal of Clinical Medicine May 2024: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central...
Comparative Analysis of High-Frequency and Low-Frequency Transcutaneous Electrical Stimulation of the Right Median Nerve in the Regression of Clinical and Neurophysiological Manifestations of Generalized Anxiety Disorder.
: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central nervous system. Both low-frequency, high-amplitude TENS (LF-TENS) and high-frequency, low-amplitude TENS (HF-TENS) are capable of activating opioid, GABA, serotonin, muscarinic, and cannabinoid receptors. However, there has been no comparative analysis of the effectiveness of HF-TENS and LF-TENS in the treatment of GAD. The purpose of our research was to study the effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of patients with GAD compared with sham TENS. The effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of GAD was studied using Generalized Anxiety Disorder 7-item scale (GAD-7) and the Hamilton Anxiety Rating Scale (HAM-A). 40 patients underwent sham TENS, 40 patients passed HF-TENS (50 Hz-50 μs-sensory response) and 41 patients completed LF -TENS (1 Hz-200 μs-motor response) for 30 days daily. After completion of treatment, half of the patients received weekly maintenance therapy for 6 months. Electroencephalography was performed before and after treatment. Our study showed that a significant reduction in the clinical symptoms of GAD as assessed by GAD-7 and HAM-A was observed after HF-TENS and LF-TENS by an average of 42.4%, and after sham stimulation only by 13.5% for at least 2 months after the end of treatment. However, LF-TENS turned out to be superior in effectiveness to HF-TENS by 51% and only on electroencephalography leads to an increase in PSD for the alpha rhythm in the occipital regions by 24% and a decrease in PSD for the beta I rhythm in the temporal and frontal regions by 28%. The prolonged effect of HF-TENS and LF-TENS was maintained without negative dynamics when TENS treatment was continued weekly throughout the entire six-month observation period. A prolonged anxiolytic effect of direct TENS of the right median nerve has been proven with greater regression of clinical and neurophysiological manifestations of GAD after LF-TENS compared to HF-TENS. Minimal side effects, low cost, safety, and simplicity of TENS procedures are appropriate as a home treatment modality.
PubMed: 38892737
DOI: 10.3390/jcm13113026 -
International Journal of Molecular... Jun 2024Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus....
Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus. Previous studies have suggested that TRPC3 channels may be involved in the hyperexcitability of hippocampal pyramidal neurons and seizures. Genetic ablation of TRPC3 channel expression reduced the intensity of pilocarpine-induced status epilepticus (SE). However, the underlying cellular mechanisms remain unexplored and the contribution of TRPC3 channels to SE-induced neurodegeneration is not determined. In this study, we investigated the contribution of TRPC3 channels to the electrophysiological properties of hippocampal pyramidal neurons and hippocampal synaptic plasticity, and the contribution of TRPC3 channels to seizure-induced neuronal cell death. We found that genetic ablation of TRPC3 expression did not alter basic electrophysiological properties of hippocampal pyramidal neurons and had a complex impact on epileptiform bursting in CA3. However, TRPC3 channels contribute significantly to long-term potentiation in CA1 and SE-induced neurodegeneration. Our results provided further support for therapeutic potential of TRPC3 inhibitors and raised new questions that need to be answered by future studies.
Topics: Animals; TRPC Cation Channels; Mice; Cell Death; Pyramidal Cells; Hippocampus; Seizures; Status Epilepticus; Male; Neurons; Pilocarpine; Long-Term Potentiation; Mice, Knockout; Mice, Inbred C57BL; Neuronal Plasticity
PubMed: 38892448
DOI: 10.3390/ijms25116260 -
International Journal of Molecular... Jun 2024Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson's disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, 'the isodendritic core', which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.
Topics: Alzheimer Disease; Animals; Disease Models, Animal; Humans; tau Proteins; Rodentia; Amyloid beta-Protein Precursor
PubMed: 38892408
DOI: 10.3390/ijms25116222 -
International Journal of Molecular... May 2024A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological...
A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic β-amyloid (Aβ42) species in human neuronal cells in response to treatment. Among the most promising compounds were and , which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.
Topics: Donepezil; Alzheimer Disease; Animals; Humans; Mice; Melatonin; Amyloid beta-Peptides; Neuroprotective Agents; Male; Antioxidants; Cholinesterase Inhibitors; Indans; Disease Models, Animal; Neurons; Piperidines
PubMed: 38892154
DOI: 10.3390/ijms25115969 -
International Journal of Molecular... May 2024Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The...
Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25-57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration.
Topics: Animals; Cholinergic Neurons; Rats; Male; Acetylcholine; Female; Ethanol; Prefrontal Cortex; Atrophy; Behavior, Animal; Receptors, Nerve Growth Factor; Rats, Sprague-Dawley; Disease Models, Animal; Nerve Tissue Proteins; Receptors, Growth Factor
PubMed: 38891978
DOI: 10.3390/ijms25115792 -
International Journal of Molecular... May 2024With projections suggesting an increase in the global use of neonicotinoids, contemporary farmers can get caught on the "pesticide treadmill", thus creating ecosystem...
With projections suggesting an increase in the global use of neonicotinoids, contemporary farmers can get caught on the "pesticide treadmill", thus creating ecosystem side effects. The aim of this study was to investigate the sorption/desorption behavior of acetamiprid, imidacloprid, and thiacloprid that controls their availability to other fate-determining processes and thus could be useful in leveling the risk these insecticides or their structural analogues pose to the environment, animals, and human health. Sorption/desorption isotherms in four soils with different organic matter (OC) content were modelled by nonlinear equilibrium models: Freundlich's, Langmuir's, and Temkin's. Sorption/desorption parameters obtained by Freundlich's model were correlated to soil physico-chemical characteristics. Even though the OC content had the dominant role in the sorption of the three insecticides, the role of its nature as well as the chemical structure of neonicotinoids cannot be discarded. Insecticides sorbed in the glassy OC phase will be poorly available unlike those in the rubbery regions. Imidacloprid will fill the sorption sites equally in the rubbery and glassy phases irrespective of its concentration. The sorption of thiacloprid at low concentrations and acetamiprid at high concentrations is controlled by hydrophilic aromatic structures, "trapping" the insecticides in the pores of the glassy phase of OC.
Topics: Neonicotinoids; Insecticides; Nitro Compounds; Thiazines; Adsorption; Soil; Soil Pollutants; Pyridines; Imidazoles
PubMed: 38891887
DOI: 10.3390/ijms25115700