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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 -
IScience Apr 2024To investigate the phosphorylation-based signaling and protein changes occurring early in epileptogenesis, the hippocampi of mice treated with pilocarpine were examined...
To investigate the phosphorylation-based signaling and protein changes occurring early in epileptogenesis, the hippocampi of mice treated with pilocarpine were examined by quantitative mass spectrometry at 4 and 24 h post-status epilepticus at vast depth. Hundreds of posttranscriptional regulatory proteins were the major early targets of increased phosphorylation. At 24 h, many protein level changes were detected and the phosphoproteome continued to be perturbed. The major targets of decreased phosphorylation at 4 and 24 h were a subset of postsynaptic density scaffold proteins, ion channels, and neurotransmitter receptors. Many proteins targeted by dephosphorylation at 4 h also had decreased protein abundance at 24 h, indicating a phosphatase-mediated weakening of synapses. Increased translation was indicated by protein changes at 24 h. These observations, and many additional indicators within this multiomic resource, suggest that early epileptogenesis is characterized by signaling that stimulates both growth and a homeostatic response that weakens excitability.
PubMed: 38600976
DOI: 10.1016/j.isci.2024.109534 -
Journal of Clinical Medicine Feb 2024Presbyopia is an age-related ocular condition, typically affecting individuals aged over 40 years, characterized by a gradual and irreversible decline in the eye's...
Presbyopia is an age-related ocular condition, typically affecting individuals aged over 40 years, characterized by a gradual and irreversible decline in the eye's ability to focus on nearby objects. Correction methods for presbyopia encompass the use of corrective lenses, surgical interventions (corneal or lens based), and, more recently, the FDA-approved topical administration of 1.25% pilocarpine. While prior research has demonstrated the efficacy of daily pilocarpine eye drop application in enhancing near visual acuity by increasing the depth of focus leveraging the pinhole effect, limited knowledge exists regarding its influence on visual acuity under varying conditions of contrast and ambient luminance. This study aims to investigate the impact of these variables on visual acuity, employing the VA-CAL test, among 11 emmetropic and 11 presbyopic volunteers who reported subjective difficulties with near vision. This study includes evaluations under natural conditions with a pinhole occluder (diameter of 2 mm), and subsequent administration of 1% pilocarpine (Pilomann, Bausch + Lomb, Laval, Canada). The VA-CAL results demonstrate the expected, statistically significant effects of contrast and ambient luminance on visual acuity in both emmetropic and presbyopic volunteers. Furthermore, in emmetropic individuals, the application of pilocarpine resulted in a statistically significant reduction in visual acuity. In contrast, presbyopes did not exhibit statistically significant differences in the visual acuity space under either the pinhole or pilocarpine conditions when compared to natural conditions. The pharmacological treatment of presbyopia with pilocarpine eye drops, intended to enhance near vision, does not adversely affect visual acuity in presbyopes. This suggests that pilocarpine may offer a viable alternative for individuals averse to wearing corrective eyewear.
PubMed: 38592033
DOI: 10.3390/jcm13051209 -
Acta Neurobiologiae Experimentalis Mar 2024Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the...
Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8‑hydroxy‑2‑deoxyguanosine (8‑OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium‑pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8‑OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8‑OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.
Topics: Male; Rats; Animals; Levetiracetam; Epilepsy, Temporal Lobe; Piracetam; Antioxidants; Glutathione Disulfide; Hydrogen Peroxide; Rats, Wistar; Anticonvulsants; Epilepsy; Glutathione; Oxidation-Reduction
PubMed: 38587324
DOI: 10.55782/ane-2024-2537 -
Journal of Current Glaucoma Practice 2024Combined endocyclophotocoagulation and phacoemulsification (ECP/Phaco) are uncommonly associated with complications. We present the first case of a rare complication...
AIM AND BACKGROUND
Combined endocyclophotocoagulation and phacoemulsification (ECP/Phaco) are uncommonly associated with complications. We present the first case of a rare complication following ECP/Phaco.
CASE DESCRIPTION
A 72-year-old patient with dense nuclear sclerotic cataracts and primary open-angle glaucoma (POAG) underwent bilateral surgery uneventfully. He experienced a brief episode of postoperative elevated intraocular pressure (IOP), but only one eye with a lower baseline IOP developed a dilated pupil. No pupillary response was observed after applying 4% pilocarpine. The fixed mydriasis persisted without reaction to light or near stimulus, and the best-corrected vision (BCVA) was 20/30 in the affected eye.
CONCLUSION
This case reports a possible rare complication when undergoing ECP/Phaco therapy. The pathogenesis of Urrets-Zavalia syndrome is unknown, but we hypothesized that eyes with more pronounced increases in IOP from baseline may be more susceptible to ischemic injury to the pupillary sphincter, resulting in a chronically dilated pupil.
CLINICAL SIGNIFICANCE
Even a modest transient rise in postoperative IOP in a glaucomatous eye with normal baseline IOP could result in a chronically dilated pupil.
HOW TO CITE THIS ARTICLE
Cheng AMS, Vedula GG, Kubal AA, Urrets-Zavalia Syndrome of Unresolving Mydriasis Following Endocyclophotocoagulation Combined with Phacoemulsification. J Curr Glaucoma Pract 2024;18(1):28-30.
PubMed: 38585167
DOI: 10.5005/jp-journals-10078-1431 -
European Archives of... Jul 2024This study aims to investigate the efficacy of lower dose pilocarpine in alleviating late dry mouth symptoms in head and neck cancer patients received radiotherapy.
Does lower dose pilocarpine have a role in radiation-induced xerostomia in the modern radiotherapy era? A single-center experience based on patient-reported outcome measures.
PURPOSE
This study aims to investigate the efficacy of lower dose pilocarpine in alleviating late dry mouth symptoms in head and neck cancer patients received radiotherapy.
METHODS
Eighteen head and neck cancer patients experiencing persistent dry mouth were enrolled in this study. All participants started pilocarpine treatment a median of 6 months post-radiotherapy. Initially, patients received pilocarpine at 5 mg/day, with a gradual increase to the recommended dose of 15 mg/day. A Patient-Reported Outcome Measurement (PROMs) questionnaire assessed symptoms' severity related to hyposalivation.
RESULTS
All patients reported symptomatic dry mouth above grade 2 before starting the medication. Pilocarpine treatment continued based on patients' self-assessment, with a median duration of 12 months (range, 3-36 months). The median daily maintenance dose was 10 mg (range, 5 to 20 mg). Total PROMs scores significantly decreased following medication, from 13 points (range 7-18 points) to 7 points (range 4-13 points) (p = 0.001). Significant improvements were observed in questions related to dry mouth (p < 0.001), water intake during eating (p = 0.01), carrying water (p = 0.01), taste (p < 0.001), and water intake during speech (p < 0.001). Initial and maintenance doses of pilocarpine were lower, and the duration of pilocarpine usage was shorter in patients treated with intensity-modulated radiation therapy compared to conformal radiotherapy (12 months vs. 25 months, p = 0.04).
CONCLUSION
Pilocarpine may be considered at doses lower for late-term dry mouth. With modern radiotherapy techniques effectively preserving the parotid gland, short-term use may be recommended in these patients. Future studies may enhance the development of a more robust patient selection criteria model.
Topics: Humans; Xerostomia; Pilocarpine; Male; Female; Middle Aged; Patient Reported Outcome Measures; Head and Neck Neoplasms; Aged; Muscarinic Agonists; Radiation Injuries; Adult; Treatment Outcome
PubMed: 38573515
DOI: 10.1007/s00405-024-08616-x -
Neuropharmacology Jun 2024The prospective involvement of the Wnt/β-catenin signaling pathway in epilepsy, with the proposed therapeutic uses of its modulators, has been suggested; however,...
The prospective involvement of the Wnt/β-catenin signaling pathway in epilepsy, with the proposed therapeutic uses of its modulators, has been suggested; however, comprehensive knowledge in this regard is currently limited. Despite postulations about the pathway's significance and treatment potential, a systematic investigation is required to better understand its implications in chronic epilepsy. We investigated the role of key proteins like β-catenin, GSK-3β, and their modulators sulindac and 6-BIO, in Wnt/β-catenin pathway during chronic phase of temporal lobe epilepsy. We also evaluated the role of modulators in seizure score, seizure frequency and neurobehavioral parameters in temporal lobe epilepsy. We developed status epilepticus model using lithium-pilocarpine. The assessment of neurobehavioral parameters was done followed by histopathological examination and immunohistochemistry staining of hippocampus as well as RT-qPCR and western blotting to analyse gene and protein expression. In SE rats, seizure score and frequency were significantly high compared to control rats, with notable changes in neurobehavioral parameters and neuronal damage observed in hippocampus. Our study also revealed a substantial upregulation of the Wnt/β-catenin pathway in chronic epilepsy, as evidenced by gene and protein expression studies. Sulindac emerged as a potent modulator, reducing seizure score, frequency, neuronal damage, apoptosis, and downregulating the Wnt/β-catenin pathway when compared to 6-BIO. Our findings emphasize the potential of GSK-3β and β-catenin as promising drug targets for chronic temporal lobe epilepsy, offering valuable treatment options for chronic epilepsy. The promising outcomes with sulindac encourages further exploration in clinical trials to assess its therapeutic potential.
Topics: Rats; Animals; Wnt Signaling Pathway; Sulindac; beta Catenin; Epilepsy, Temporal Lobe; Glycogen Synthase Kinase 3 beta; Prospective Studies; Status Epilepticus
PubMed: 38570067
DOI: 10.1016/j.neuropharm.2024.109931 -
BioRxiv : the Preprint Server For... Mar 2024Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To...
Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous electrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.
PubMed: 38559224
DOI: 10.1101/2024.03.12.584697 -
Cureus Feb 2024Sjögren's syndrome is a chronic, inflammatory autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands. Notably, the rehabilitation of...
Sjögren's syndrome is a chronic, inflammatory autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands. Notably, the rehabilitation of partially edentulous patients with Sjögren's syndrome is limited by the scarce availability of studies that could inform therapeutic modalities and potential challenges during clinical procedures. This case report aimed to present the oral rehabilitation of a patient with Sjögren's syndrome who received fixed partial dentures (FPDs). A 28-year-old female patient sought treatment to restore her missing teeth. She was diagnosed with Sjögren's syndrome by a rheumatologist adhering to the revised version of the European criteria proposed by the American-European Consensus Group and was on a medication regimen including prednisolone, hydroxychloroquine, pantoprazole, pilocarpine, and tear substitutes to manage her condition. The final treatment plan consisted of extractions, management of gingivitis, post-and-core restorations, and a 2 mm vertical dimension increase with the placement of 15 porcelain-fused-to-metal (PFM) crowns and 4 short-span bridges. The patient underwent regular clinical and radiographic evaluations every 3 months since June 2020. Throughout this period, the fixed prostheses, teeth, and periodontal tissues demonstrated remarkable stability and exhibited no complications. This three-year case study provides evidence that meticulous planning and clinical execution can facilitate successful oral rehabilitation in young edentulous patients with Sjögren's syndrome. Tooth-supported fixed prostheses can effectively restore oral function and aesthetic appeal in these individuals, provided they undergo more frequent dental examinations than the general population and maintain a cooperative attitude throughout the treatment process.
PubMed: 38558652
DOI: 10.7759/cureus.55148 -
Epilepsy Research May 2024The hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN1) is predominantly located in key regions associated with epilepsy, such as the neocortex and...
BACKGROUND
The hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN1) is predominantly located in key regions associated with epilepsy, such as the neocortex and hippocampus. Under normal physiological conditions, HCN1 plays a crucial role in the excitatory and inhibitory regulation of neuronal networks. In temporal lobe epilepsy, the expression of HCN1 is decreased in the hippocampi of both animal models and patients. However, whether HCN1 expression changes during epileptogenesis preceding spontaneous seizures remains unclear.
OBJECTIVE
The aim of this study was to determine whether the expression of HCN1 is altered during the epileptic prodromal phase, thereby providing evidence for its role in epileptogenesis.
METHODS
We utilized a cobalt wire-induced rat epilepsy model to observe changes in HCN1 during epileptogenesis and epilepsy. Additionally, we also compared HCN1 alterations in epileptogenic tissues between cobalt wire- and pilocarpine-induced epilepsy rat models. Long-term video EEG recordings were used to confirm seizures development. Transcriptional changes, translation, and distribution of HCN1 were assessed using high-throughput transcriptome sequencing, total protein extraction, membrane and cytoplasmic protein fractionation, western blotting, immunohistochemistry, and immunofluorescence techniques.
RESULTS
In the cobalt wire-induced rat epilepsy model during the epileptogenesis phase, total HCN1 mRNA and protein levels were downregulated. Specifically, the membrane expression of HCN1 was decreased, whereas cytoplasmic HCN1 expression showed no significant change. The distribution of HCN1 in the distal dendrites of neurons decreased. During the epilepsy period, similar HCN1 alterations were observed in the neocortex of rats with cobalt wire-induced epilepsy and hippocampus of rats with lithium pilocarpine-induced epilepsy, including downregulation of mRNA levels, decreased total protein expression, decreased membrane expression, and decreased distal dendrite expression.
CONCLUSIONS
Alterations in HCN1 expression and distribution are involved in epileptogenesis beyond their association with seizure occurrence. Similarities in HCN1 alterations observed in epileptogenesis-related tissues from different models suggest a shared pathophysiological pathway in epileptogenesis involving HCN1 dysregulation. Therefore, the upregulation of HCN1 expression in neurons, maintenance of the HCN1 membrane, and distal dendrite distribution in neurons may represent promising disease-modifying strategies in epilepsy.
Topics: Animals; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Male; Epilepsy; Rats, Sprague-Dawley; Rats; Hippocampus; Disease Models, Animal; Potassium Channels; Pilocarpine; Cobalt; Electroencephalography; Neurons; Neocortex
PubMed: 38555654
DOI: 10.1016/j.eplepsyres.2024.107355