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Cureus Mar 2024Overlap syndrome is a clinical challenge and brings together a wide range of treatment options for the treating physician. Addressing each and every complaint of the...
Overlap syndrome is a clinical challenge and brings together a wide range of treatment options for the treating physician. Addressing each and every complaint of the patient is crucial. A 50-year-old female patient presented with skin thickening, blackening, and hyperkeratosis; dysphagia; joint pain; features of myopathy; Raynaud's phenomenon; and dry mouth. Inflammatory markers were raised along with a positive antinuclear antibody (ANA) with Golgi apparatus pattern, anti-Sjögren's-syndrome-related antigen A (anti-SSA)/Ro60 3+, anti-SSA/Ro52 3+, and anti-PM/Scl 2+ antibodies that suggested overlap syndrome. Although the patient had no respiratory complaints, a unique interstitial lung disease (ILD) pattern was noted during the evaluation. Skin manifestations were puzzling, but the histopathology analyses of skin biopsies taken from two different sites revealed distinguishing features of cutaneous lupus and dermatomyositis. Treatment with hydroxychloroquine, pilocarpine, nifedipine, methotrexate, and topical tacrolimus produced a dramatic improvement in the clinical features. This case highlights subtle and florid features of different autoimmune diseases. The hyperkeratotic skin changes were the most striking feature, but the whole evaluation process unveiled many rare presentations of known autoimmune conditions that can open doors to new areas of our understanding toward connective tissue diseases (CTDs). Our case report demonstrates significant heterogeneity in the ANA patterns, ILD patterns, clinical manifestations, and treatment approaches.
PubMed: 38646215
DOI: 10.7759/cureus.56531 -
Proceedings of the National Academy of... Apr 2024The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical...
The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs.
Topics: Rats; Humans; Animals; Pilocarpine; Autoimmunity; Epilepsy; Seizures; Brain; Disease Models, Animal; Methylazoxymethanol Acetate
PubMed: 38635635
DOI: 10.1073/pnas.2319607121 -
Neurotherapeutics : the Journal of the... Apr 2024Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role...
Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role of lysosomal dysfunction in epilepsy, which can lead to the accumulation of toxic substrates and impaired autophagy in neurons. Our focus is on phosphodiesterase-4 (PDE4), an enzyme that plays a crucial role in regulating intracellular cyclic adenosine monophosphate (cAMP) levels by converting it into adenosine monophosphate (AMP). In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses. We hypothesized that amlexanox, an anti-inflammatory drug and non-selective PDE4 inhibitor, could offer neuroprotection by addressing lysosomal dysfunction and mitigating neuroinflammation, ultimately preventing neuronal death in epileptic conditions. Our research utilized a pilocarpine-induced epilepsy animal model to investigate amlexanox's potential benefits. Administered intraperitoneally at a dose of 100 mg/kg daily following the onset of a seizure, we monitored its effects on lysosomal function, inflammation, neuronal death, and cognitive performance in the brain. Tissue samples from various brain regions were collected at predetermined intervals for a comprehensive analysis. The study's results were significant. Amlexanox effectively improved lysosomal function, which we attribute to the modulation of zinc's influx into the lysosomes, subsequently enhancing autophagic processes and decreasing the release of inflammatory factors. Notably, this led to the attenuation of neuronal death in the hippocampal region. Additionally, cognitive function, assessed through the modified neurological severity score (mNSS) and the Barnes maze test, showed substantial improvements after treatment with amlexanox. These promising outcomes indicate that amlexanox has potential as a therapeutic agent in the treatment of epilepsy and related brain disorders. Its ability to combat lysosomal dysfunction and neuroinflammation positions it as a potential neuroprotective intervention. While these findings are encouraging, further research and clinical trials are essential to fully explore and validate the therapeutic efficacy of amlexanox in epilepsy management.
PubMed: 38631990
DOI: 10.1016/j.neurot.2024.e00357 -
International Journal of Developmental... Jun 2024According to experimental and clinical studies, status epilepticus (SE) causes neurodegenerative morphological changes not only in the hippocampus and other limbic... (Comparative Study)
Comparative Study
According to experimental and clinical studies, status epilepticus (SE) causes neurodegenerative morphological changes not only in the hippocampus and other limbic structures, it also affects the thalamus and the neocortex. In addition, several studies reported atrophy, metabolic changes, and neuronal degeneration in the dorsal striatum. The literature lacks studies investigating potential neuronal damage in the ventral component of the striatopallidal complex (ventral striatum [VS] and ventral pallidum) in SE experimentations. To better understand the development of neuronal damage in the striatopallidal complex associated with SE, the detected neuronal degeneration in the compartments of the VS, namely, the nucleus accumbens (NAc) and the olfactory tubercle (OT), was analyzed. The experiments were performed on Wistar rats at age of 25-day-old pups and 3-month-old adult animals. Lithium-pilocarpine model of SE was used. Lithium chloride (3 mmol/kg, ip) was injected 24 h before administering pilocarpine (40 mg/kg, ip). This presented study demonstrates the variability of post SE neuronal damage in 25-day-old pups in comparison with 3-month-old adult rats. The NAc exhibited small to moderate number of Fluoro-Jade B (FJB)-positive neurons detected 4 and 8 h post SE intervals. The number of degenerated neurons in the shell subdivision of the NAc significantly increased at survival interval of 12 h after the SE. FJB-positive neurons were evidently more prominent occupying the whole anteroposterior and mediolateral extent of the nucleus at longer survival intervals of 24 and 48 h after the SE. This was also the case in the bordering vicinity between the shell and the core compartments but with clusters of degenerating cells. The severity of damage of the shell subdivision of the NAc reached its peak at an interval of 24 h post SE. Isolated FJB-positive neurons were detected in the ventral peripheral part of the core compartment. Degenerated neurons persisted in the shell subdivision of the NAc 1 week after SE. However, the quantity of cell damage had significantly reduced in comparison with the aforementioned shorter intervals. The third layer of the OT exhibited more degenerated neurons than the second layer. The FJB-positive cells in the young animals were higher than in the adult animals. The morphology of those cells was identical in the two age groups except in the OT.
Topics: Animals; Status Epilepticus; Rats; Rats, Wistar; Male; Nerve Degeneration; Ventral Striatum; Neurons; Animals, Newborn; Pilocarpine; Disease Models, Animal; Lithium Chloride; Age Factors; Fluoresceins
PubMed: 38631684
DOI: 10.1002/jdn.10331 -
ACS Chemical Neuroscience May 2024The development of antiepileptic drugs is still a long process. In this study, heparin-modified superparamagnetic iron oxide nanoparticles (UFH-SPIONs) were prepared,...
Heparin-Modified Superparamagnetic Iron Oxide Nanoparticles Suppress Lithium Chloride/Pilocarpine-Induced Temporal Lobe Epilepsy in Rats through Attenuation of Inflammation and Oxidative Stress.
The development of antiepileptic drugs is still a long process. In this study, heparin-modified superparamagnetic iron oxide nanoparticles (UFH-SPIONs) were prepared, and their antiepileptic effect and underlying mechanism were investigated. UFH-SPIONs are stable, homogeneous nanosystems with antioxidant enzyme activity that are able to cross the blood-brain barrier (BBB) and enriched in hippocampal epileptogenic foci. The pretreatment with UFH-SPIONs effectively prolonged the onset of seizures and reduced seizure severity after lithium/pilocarpine (LP)-induced seizures in rats. The pretreatment with UFH-SPIONs significantly decreased the expression of inflammatory factors in hippocampal tissues, including IL-6, IL-1β, and TNF-α. LP-induced oxidative stress in hippocampal tissues was in turn reduced upon pretreatment with UFH-SPIONs, as evidenced by an increase in the levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and a decrease in the level of lipid peroxidation (MDA). Moreover, the LP-induced upregulation of apoptotic cells was decreased upon pretreatment with UFH-SPIONs. Together, these observations suggest that the pretreatment with UFH-SPIONs ameliorates LP-induced seizures and downregulates the inflammatory response and oxidative stress, which exerts neuronal protection during epilepsy.
Topics: Animals; Oxidative Stress; Pilocarpine; Rats; Male; Magnetic Iron Oxide Nanoparticles; Epilepsy, Temporal Lobe; Lithium Chloride; Heparin; Inflammation; Rats, Sprague-Dawley; Hippocampus; Anticonvulsants
PubMed: 38630556
DOI: 10.1021/acschemneuro.4c00188 -
Naunyn-Schmiedeberg's Archives of... Apr 2024Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter...
Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter the structure and functioning of the brain, resulting in diverse manifestations. Antiepileptic drugs (AEDs) can be very effective in 30% of patients in controlling seizures. Several factors contribute to this: drug resistance, individual variability, side effects, complexity of epilepsy, incomplete understanding, comorbidities, drug interactions, and no adherence to treatment. Therefore, research into new AEDs is important for several reasons such as improved efficacy, reduced side effects, expanded treatment options, treatment for drug-resistant epilepsy, improved safety profiles, targeted therapies, and innovation and progress. Animal models serve as crucial biological tools for comprehending neuronal damage and aiding in the discovery of more effective new AEDs. The utilization of antioxidant agents that act on the central nervous system may serve as a supplementary approach in the secondary prevention of epilepsy, both in laboratory animals and potentially in humans. Chlorogenic acid (CGA) is a significant compound, widely prevalent in numerous medicinal and food plants, exhibiting an extensive spectrum of biological activities such as neuroprotection, antioxidant, anti-inflammatory, and analgesic effects, among others. In this research, we assessed the neuroprotective effects of commercially available CGA in Wistar rats submitted to lithium-pilocarpine-induced status epilepticus (SE) model. After 72-h induction of SE, rats received thiopental and were treated for three consecutive days (1, 2, and 3 doses). Next, brains were collected and studied histologically for viable cells in the hippocampus with staining for cresyl-violet (Nissl staining) and for degenerating cells with Fluoro-Jade C (FJC) staining. Moreover, to evaluate oxidative stress, the presence of malondialdehyde (MDA) and superoxide dismutase (SOD) was quantified. Rats administered with CGA (30 mg/kg) demonstrated a significant decrease of 59% in the number of hippocampal cell loss in the CA3, and of 48% in the hilus layers after SE. A significant reduction of 75% in the cell loss in the CA3, shown by FJC+ staining, was also observed with the administration of CGA (30 mg/kg). Furthermore, significant decreases of 49% in MDA production and 72% in the activity of SOD were seen, when compared to animals subjected to SE that received vehicle. This study introduces a novel finding: the administration of CGA at a dosage of 30 mg/kg effectively reduced oxidative stress induced by lithium-pilocarpine, with its effects lasting until the peak of neural damage 72 h following the onset of SE. Overall, the research and development of new AEDs are essential for advancing epilepsy treatment, improving patient outcomes, and ultimately enhancing the quality of life for individuals living with epilepsy.
PubMed: 38625552
DOI: 10.1007/s00210-024-03080-0 -
Journal of Oral Biosciences Jun 2024Local anesthetics act on G protein-coupled receptors (GPCRs); thus, their potential as allosteric modulators of GPCRs has attracted attention. Intracellular signaling...
OBJECTIVES
Local anesthetics act on G protein-coupled receptors (GPCRs); thus, their potential as allosteric modulators of GPCRs has attracted attention. Intracellular signaling via GPCRs involves both G-protein- and β-arrestin-mediated pathways. To determine the effects of local anesthetics on muscarinic acetylcholine receptors (mAChR), a family of GPCRs, we analyzed the effects of local anesthetics on mAChR-mediated Ca responses and formation of receptor-β-arrestin complexes in the HSY human parotid cell line.
METHODS
Ca responses were monitored by fura-2 spectrofluorimetry. Ligand-induced interactions between mAChR and β-arrestin were examined using a β-arrestin GPCR assay kit.
RESULTS
Lidocaine reduced mAChR-mediated Ca responses but did not change the intracellular Ca concentration in non-stimulated cells. The membrane-impermeant lidocaine analog QX314 and procaine inhibited mAChR-mediated Ca responses, with EC values of 48.0 and 20.4 μM, respectively, for 50 μM carbachol-stimulated Ca responses. In the absence of extracellular Ca, the pretreatment of cells with QX314 reduced carbachol-induced Ca release, indicating that QX314 reduced Ca release from intracellular stores. Lidocaine and QX314 did not affect store-operated Ca entry as they did not alter the thapsigargin-induced Ca response. QX314 and procaine reduced the carbachol-mediated recruitment of β-arrestin, and administration of procaine suppressed pilocarpine-induced salivary secretion in mice.
CONCLUSION
Local anesthetics, including QX314, act on mAChR to reduce carbachol-induced Ca release from intracellular stores and the recruitment of β-arrestin. These findings support the notion that local anesthetics and their derivatives are starting points for the development of functional allosteric modulators of mAChR.
Topics: Humans; Anesthetics, Local; beta-Arrestins; Calcium; Receptors, Muscarinic; Animals; Mice; Parotid Gland; Lidocaine; Cell Line; Carbachol; Calcium Signaling; Procaine
PubMed: 38614428
DOI: 10.1016/j.job.2024.04.002 -
Journal of AOAC International Apr 2024To study the ultra-trace simultaneous determination of drugs, the colorimetric method in combination with chemometrics can be used.
Colorimetric Concurrent Determination of Ultra-Trace Amounts of Pilocarpine and Timolol as anti-Glaucoma Drugs in Binary Mixtures Using a Multivariate Calibration Approach Based on the Aggregation of Gold Nanoparticles.
BACKGROUND
To study the ultra-trace simultaneous determination of drugs, the colorimetric method in combination with chemometrics can be used.
OBJECTIVE
In this study, a simple, rapid, and sensitive UV-Vis spectrophotometric method using gold nanoparticles (AuNPs) was introduced for the simultaneous determination of ultra-trace amounts of Pilocarpine (PIL) and Timolol (TIM) in binary mixtures and biological sample.
METHODS
AuNPs interacted with components and the aggregation mode of NPs occurred and finally, the color change of the solution (red to gray) was observed with the naked eye without the most modern and expensive instruments. The characterization of AuNPs was evaluated by transmission electron microscopy (TEM) and dynamic light scattering (DLS).
RESULTS
The validation of the colorimetric way was studied in the concentration range of 100-800 and 100-600 μg/L with good linearity equal to 0.9772 and 0.9891 for PIL and TIM, respectively. The limit of detection (LOD) was found to be 165.00 and 92.40 μg/L, where the limit of quantitation (LOQ) was 500.00 and 280.00 μg/L for PIL and TIM, respectively. The effect of some factors such as interaction time, the concentration of components, and the volume of buffer on absorbance was investigated. Partial least squares (PLS) as an efficient multivariate calibration method was combined with colorimetry for the simultaneous determination of PIL and TIM in binary mixtures. The optimum number of latent variables was selected by k-fold cross-validation based on minimum mean square error prediction (MSEP) and the number of components equal to 1 with MSEP of 1.085 and 0.763 was considered for PIL and TIM, respectively. The mean recovery was obtained at 100.20% and 101.55% for PIL and TIM, respectively.
CONCLUSION
The colorimetric method can be introduced as a proper option for the simultaneous determination of components in pharmaceutical formulations and other samples.
HIGHLIGHTS
A colorimetric method using AuNPs was proposed.PLS method was coupled with a colorimetric method for the ultra-trace simultaneous estimation of PIL and TIM in binary mixtures.Ultra-trace amounts of PIL and TIM were also determined in biological sample.The proposed method is simple, fast and less expensive than chromatography methods.
PubMed: 38608200
DOI: 10.1093/jaoacint/qsae030 -
Medicine Apr 2024This report presents a unique case of a patient diagnosed with Primary Sjögren's syndrome and a relatively rare traditional Chinese medicine pattern, known as the...
RATIONALE
This report presents a unique case of a patient diagnosed with Primary Sjögren's syndrome and a relatively rare traditional Chinese medicine pattern, known as the combined cold and heat pattern and cold-dampness syndrome. The patient's condition was successfully managed using Chinese herbal medicine, specifically the modified Da-Chai-Hu decoction and Linggui Zhugan decoction.
PATIENT CONCERNS
A 56-year-old woman had chronic dry eye and mouth for over 10 years. She was initially managed with traditional Chinese herbal medicine (TCHM) prescriptions, including the Zengye decoction, but the therapeutic effects were unsatisfactory. As the disease progressed, she was diagnosed with an anxiety disorder due to symptoms of vexation and insomnia. Treatment with alprazolam and venlafaxine failed to alleviate these symptoms. Recently, her general condition gradually worsened, with symptoms including a bitter taste in her mouth, dizziness, hot flashes, chills, poor appetite, chest discomfort, and constipation.
DIAGNOSES
After a series of examinations, including a Schirmer test and labial gland biopsy, she was diagnosed with Sjögren's syndrome.
INTERVENTIONS
Despite regular treatment with pilocarpine, sodium hyaluronate eye drops, venlafaxine, and alprazolam, the dry mouth symptoms intensified. Consequently, she sought further intervention through the TCHM.
OUTCOMES
After 8 weeks of treatment with the modified Da-Chai-Hu decoction and Linggui Zhugan decoction, she reported a significant improvement in her dryness-related symptoms and sleep quality.
LESSONS
This case report demonstrates that TCHM can effectively treat Primary Sjögren's syndrome, and should be considered for broader applications. Furthermore, this underscores the importance of tailoring treatment formulas to patients by identifying their specific syndrome differentiation in a clinical setting.
Topics: Humans; Female; Middle Aged; Alprazolam; Drugs, Chinese Herbal; Medicine, Chinese Traditional; Sjogren's Syndrome; Venlafaxine Hydrochloride
PubMed: 38608118
DOI: 10.1097/MD.0000000000037744 -
Clinical Science (London, England :... May 2024Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of individuals worldwide. Despite extensive research, the underlying...
Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of individuals worldwide. Despite extensive research, the underlying mechanisms leading to epileptogenesis, the process by which a normal brain develops epilepsy, remain elusive. We, here, explored the immune system and spleen responses triggered by pilocarpine-induced status epilepticus (SE) focusing on their role in the epileptogenesis that follows SE. Initial examination of spleen histopathology revealed transient disorganization of white pulp, in animals subjected to SE. This disorganization, attributed to immune activation, peaked at 1-day post-SE (1DPSE) but returned to control levels at 3DPSE. Alterations in peripheral blood lymphocyte populations, demonstrated a decrease following SE, accompanied by a reduction in CD3+ T-lymphocytes. Further investigations uncovered an increased abundance of T-lymphocytes in the piriform cortex and choroid plexus at 3DPSE, suggesting a specific mobilization toward the Central Nervous System. Notably, splenectomy mitigated brain reactive astrogliosis, neuroinflammation, and macrophage infiltration post-SE, particularly in the hippocampus and piriform cortex. Additionally, splenectomized animals exhibited reduced lymphatic follicle size in the deep cervical lymph nodes. Most significantly, splenectomy correlated with improved neuronal survival, substantiated by decreased neuronal loss and reduced degenerating neurons in the piriform cortex and hippocampal CA2-3 post-SE. Overall, these findings underscore the pivotal role of the spleen in orchestrating immune responses and neuroinflammation following pilocarpine-induced SE, implicating the peripheral immune system as a potential therapeutic target for mitigating neuronal degeneration in epilepsy.
Topics: Pilocarpine; Animals; Status Epilepticus; Spleen; Male; Neuroinflammatory Diseases; Splenectomy; Rats, Sprague-Dawley; Hippocampus; Disease Models, Animal; T-Lymphocytes; Piriform Cortex; Neurons
PubMed: 38602323
DOI: 10.1042/CS20231621