-
Biomolecules May 2024During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the...
During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the synaptic vesicle must be pre-docked to the plasma membrane. In this primed state, SNAREpins, the protein-coiled coils whose assembly provides the energy to trigger fusion, are partly zippered and clamped like a hairpin and held open and ready to snap close when the clamp is released. Recently, it was suggested that three types of regulatory factors, synaptophysin, synaptotagmins, and complexins act cooperatively to organize two concentric rings, a central and a peripheral ring, containing up to six SNAREpins each. We used a mechanical model of the SNAREpins with two separate states, half-zippered and fully zippered, and determined the energy landscape according to the number of SNAREpins in each ring. We also performed simulations to estimate the fusion time in each case. The presence of the peripheral SNAREpins generally smoothens the energy landscape and accelerates the fusion time. With the predicted physiological numbers of six central and six peripheral SNAREpins, the fusion time is accelerated at least 100 times by the presence of the peripheral SNAREpins, and fusion occurs in less than 10 μs, which is well within the physiological requirements.
Topics: Synaptic Vesicles; SNARE Proteins; Membrane Fusion; Synaptic Transmission; Animals; Humans
PubMed: 38786007
DOI: 10.3390/biom14050600 -
Biomolecules May 2024Posiphen is a small molecule that exhibits neuroprotective properties by targeting multiple neurotoxic proteins involved in axonal transport, synaptic transmission,... (Comparative Study)
Comparative Study
Posiphen is a small molecule that exhibits neuroprotective properties by targeting multiple neurotoxic proteins involved in axonal transport, synaptic transmission, neuroinflammation, and cell death. Its broad-spectrum effects make it a promising candidate for treating neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. Despite extensive investigation with animal models and human subjects, a comprehensive comparative analysis of Posiphen's pharmacokinetics across studies remains elusive. Here, we address this gap by examining the metabolic profiles of Posiphen and its breakdown into two primary metabolites-N1 and N8-across species by measuring their concentrations in plasma, brain, and CSF using the LC-MS/MS method. While all three compounds effectively inhibit neurotoxic proteins, the N1 metabolite is associated with adverse effects. Our findings reveal the species-specific behavior of Posiphen, with both Posiphen and N8 being predominant in various species, while N1 remains a minor constituent, supporting the drug's safety. Moreover, in plasma, Posiphen consistently showed fast clearance of all metabolites within 8 h in animal models and in human subjects, whereas in CSF or brain, the compound has an extended half-life of over 12 h. Combining all our human data and analyzing them by population pharmacokinetics showed that there are no differences between healthy volunteers, Alzheimer's, and Parkinson's patients. It also showed that Posiphen is absorbed and metabolized in a similar fashion across all animal species and human groups tested. These observations have critical implications for understanding the drug's safety, therapeutic effect, and clinical translation.
Topics: Humans; Animals; Rats; Dogs; Mice; Male; Species Specificity; Tandem Mass Spectrometry; Brain; Rats, Sprague-Dawley; Neuroprotective Agents; Female
PubMed: 38785991
DOI: 10.3390/biom14050582 -
Biomolecules Apr 2024This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its... (Review)
Review
This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.
Topics: Brain-Derived Neurotrophic Factor; Humans; Nociception; Pain; Animals; Neuronal Plasticity
PubMed: 38785946
DOI: 10.3390/biom14050539 -
Experimental Neurology Aug 2024Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately,...
Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately, clinical use of DOX is limited due to adverse off-target effects resulting in fatigue, respiratory muscle weakness and dyspnea. The diaphragm is the primary muscle of inspiration and respiratory insufficiency is likely the result of both muscle weakness and neural impairment. However, the contribution of neuropathology to DOX-induced respiratory muscle dysfunction is unclear. We hypothesized that diaphragm weakness following acute DOX exposure is associated with neurotoxicity and that exercise preconditioning is sufficient to improve diaphragm muscle contractility by maintaining neuromuscular integrity. Adult female Sprague-Dawley rats were randomized into four experimental groups: 1) sedentary-saline, 2) sedentary-DOX, 3) exercise-saline or 4) exercise-DOX. Endurance exercise preconditioning consisted of treadmill running for 1 h/day at 30 m/min for 10 days. Twenty-four hours after the last bout of exercise, animals were treated with DOX (20 mg/kg, I.P.) or saline (equal volume). Our results demonstrate that 48-h following DOX administration diaphragm muscle specific force is reduced in sedentary-DOX rats in response to both phrenic nerve and direct diaphragm stimulation. Importantly, endurance exercise preconditioning in DOX-treated rats attenuated the decrease in diaphragm contractile function, reduced neuromuscular transmission failure and altered phrenic nerve morphology. These changes were associated with an exercise-induced reduction in circulating biomarkers of inflammation, nerve injury and reformation. Therefore, the results are consistent with exercise preconditioning as an effective way of reducing respiratory impairment via preservation of phrenic-diaphragm neuromuscular conduction.
Topics: Animals; Diaphragm; Rats, Sprague-Dawley; Doxorubicin; Female; Rats; Physical Conditioning, Animal; Antibiotics, Antineoplastic; Synaptic Transmission; Phrenic Nerve; Muscle Contraction; Neuromuscular Junction
PubMed: 38782352
DOI: 10.1016/j.expneurol.2024.114818 -
BMC Musculoskeletal Disorders May 2024Osteoporosis (OP), the "silent epidemic" of our century, poses a significant challenge to public health, predominantly affecting postmenopausal women and the elderly. It...
Integration of bioinformatics and machine learning approaches for the validation of pyrimidine metabolism-related genes and their implications in immunotherapy for osteoporosis.
BACKGROUND
Osteoporosis (OP), the "silent epidemic" of our century, poses a significant challenge to public health, predominantly affecting postmenopausal women and the elderly. It evolves from mild symptoms to pronounced severity, stabilizing eventually. Unique among OP's characteristics is the altered metabolic profile of affected cells, particularly in pyrimidine metabolism (PyM), a crucial pathway for nucleotide turnover and pyrimidine decomposition. While metabolic adaptation is acknowledged as a therapeutic target in various diseases, the specific role of PyM genes (PyMGs) in OP's molecular response remains to be clarified.
METHODS
In pursuit of elucidating and authenticating PyMGs relevant to OP, we embarked on a comprehensive bioinformatics exploration. This entailed the integration of Weighted Gene Co-expression Network Analysis (WGCNA) with a curated list of 37 candidate PyMGs, followed by the examination of their biological functions and pathways via Gene Set Variation Analysis (GSVA). The Least Absolute Shrinkage and Selection Operator (LASSO) technique was harnessed to identify crucial hub genes. We evaluated the diagnostic prowess of five PyMGs in OP detection and explored their correlation with OP's clinical traits, further validating their expression profiles through independent datasets (GSE2208, GSE7158, GSE56815, and GSE35956).
RESULTS
Our analytical rigor unveiled five PyMGs-IGKC, TMEM187, RPS11, IGLL3P, and GOLGA8N-with significant ties to OP. A deeper dive into their biological functions highlighted their roles in estrogen response modulation, cytosolic calcium ion concentration regulation, and GABAergic synaptic transmission. Remarkably, these PyMGs emerged as potent diagnostic biomarkers for OP, distinguishing affected individuals with substantial accuracy.
CONCLUSIONS
This investigation brings to light five PyMGs intricately associated with OP, heralding new avenues for biomarker discovery and providing insights into its pathophysiological underpinnings. These findings not only deepen our comprehension of OP's complexity but also herald the advent of more refined diagnostic and therapeutic modalities.
Topics: Humans; Pyrimidines; Machine Learning; Computational Biology; Osteoporosis; Female; Immunotherapy; Gene Expression Profiling; Aged; Gene Regulatory Networks
PubMed: 38778304
DOI: 10.1186/s12891-024-07512-z -
ENeuro Jun 2024Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most...
Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most previous studies of homeostatic readjustment to complete activity silencing in rodent forebrain have examined changes after 2 d of deprivation, but it is known that longer periods of deprivation can produce adverse effects. To better understand the mechanisms underlying these effects and to address how presynaptic as well as postsynaptic compartments change during homeostatic plasticity, we subjected mouse cortical slice cultures to a more severe 5 d deprivation paradigm. We developed and validated a computational framework to measure the number and morphology of presynaptic and postsynaptic compartments from super-resolution light microscopy images of dense cortical tissue. Using these tools, combined with electrophysiological miniature excitatory postsynaptic current measurements, and synaptic imaging at the electron microscopy level, we assessed the functional and morphological results of prolonged deprivation. Excitatory synapses were strengthened both presynaptically and postsynaptically. Surprisingly, we also observed a decrement in the density of excitatory synapses, both as measured from colocalized staining of pre- and postsynaptic proteins in tissue and from the number of dendritic spines. Overall, our results suggest that cortical networks deprived of activity progressively move toward a smaller population of stronger synapses.
Topics: Animals; Neuronal Plasticity; Synapses; Neocortex; Excitatory Postsynaptic Potentials; Mice, Inbred C57BL; Sensory Deprivation; Male; Mice; Female; Dendritic Spines
PubMed: 38777611
DOI: 10.1523/ENEURO.0366-23.2024 -
Nature Communications May 2024Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity...
Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.
Topics: Animals; Astrocytes; AlkB Homolog 5, RNA Demethylase; Mice; Humans; Depressive Disorder, Major; Male; Mice, Knockout; Female; Disease Models, Animal; Mice, Inbred C57BL; Neurons; Stress, Psychological; Adenosine; Excitatory Amino Acid Transporter 2; Behavior, Animal; Prefrontal Cortex; Depression; Adult; Synaptic Transmission; Middle Aged
PubMed: 38773146
DOI: 10.1038/s41467-024-48730-2 -
BioRxiv : the Preprint Server For... May 2024Exposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the...
Exposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the effects of chronic nicotine exposure during a critical developmental period on the functional expression of nicotinic acetylcholine receptors (nAChRs), glutamatergic synaptic transmission, and auditory processing in the mouse auditory brainstem. We evaluated the functionality of nAChRs at a central synapse and explored the impact of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABR) in mice. Our findings revealed developmentally regulated changes in nAChR expression in the medial nucleus of the trapezoid body (MNTB) neurons and presynaptic Calyx of Held terminals. PNE was associated with enhanced acetylcholine-evoked postsynaptic currents and compromised glutamatergic neurotransmission, highlighting the critical role of nAChR activity in the early stages of auditory synaptic development. Additionally, PNE resulted in elevated ABR thresholds and diminished peak amplitudes, suggesting significant impairment in central auditory processing without cochlear dysfunction. This study provides novel insights into the synaptic disturbances that contribute to auditory deficits resulting from chronic prenatal nicotine exposure, underlining potential targets for therapeutic intervention.
PubMed: 38765998
DOI: 10.1101/2024.05.08.592930 -
The Journal of Headache and Pain May 2024Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional...
BACKGROUND
Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood.
METHODS
The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats.
RESULTS
The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application.
CONCLUSIONS
Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
Topics: Animals; Migraine Disorders; Calcitonin Gene-Related Peptide; Rats, Sprague-Dawley; Cerebral Cortex; Anxiety; Rats; Male; Disease Models, Animal; Adenylyl Cyclases; Receptors, N-Methyl-D-Aspartate
PubMed: 38760739
DOI: 10.1186/s10194-024-01778-3 -
Toxicology Letters Jun 2024Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of...
Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.
Topics: Receptors, Nicotinic; Animals; Male; Nerve Agents; Rats, Wistar; Rats; Organophosphate Poisoning; Diaphragm; Structure-Activity Relationship; Pyridinium Compounds; Muscle Contraction; Neuromuscular Junction; Binding Sites
PubMed: 38759939
DOI: 10.1016/j.toxlet.2024.05.011