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Progress in Neurobiology Dec 2023Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although...
Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.
Topics: Humans; Reproducibility of Results; Dentate Gyrus; Neurons; Axons; Status Epilepticus
PubMed: 37898313
DOI: 10.1016/j.pneurobio.2023.102542 -
Frontiers in Pharmacology 2023Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we...
Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we investigated the therapeutic effects of a novel small molecule, NecroX-7, in TLE using both a low [Mg]-induced epileptiform activity model and a mouse model of pilocarpine-induced status epilepticus (SE). NecroX-7 post-treatment enhanced the viability of primary hippocampal neurons exposed to low [Mg] compared to controls in an MTT assay. Application of NecroX-7 after pilocarpine-induced SE also reduced the number of degenerating neurons labelled with Fluoro-Jade B. Immunocytochemistry and immunohistochemistry showed that NecroX-7 post-treatment significantly alleviated ionized calcium-binding adaptor molecule 1 (Iba1) intensity and immunoreactive area, while the attenuation of reactive astrocytosis by glial fibrillary acidic protein (GFAP) staining was observed in cultured hippocampal neurons. However, NecroX-7-mediated morphologic changes of astrocytes were seen in both and models of TLE. Finally, western blot analysis demonstrated that NecroX-7 post-treatment after acute seizures could decrease the expression of mixed lineage kinase domain-like pseudokinase (MLKL) and phosphorylated MLKL (p-MLKL), markers for necroptosis. Taken all together, NecroX-7 has potential as a novel medication for TLE with its neuroprotective, anti-inflammatory, and anti-necroptotic effects.
PubMed: 37601059
DOI: 10.3389/fphar.2023.1187819 -
American Journal of Ophthalmology Sep 2023To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the safety, efficacy, and pharmacokinetics of pilocarpine hydrochloride 1.25% (Pilo hereafter) compared with vehicle when administered bilaterally, twice daily (6 hours apart) for 14 days in participants with presbyopia.
DESIGN
Phase 3, randomized (1:1), controlled, double-masked, multicenter study.
METHODS
Participants (40-55 years of age) had objective and subjective evidence of presbyopia affecting daily activities with mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA) of 20/40 to 20/100. The primary/key secondary endpoint was the proportion of participants gaining ≥3 lines in mesopic/photopic, high-contrast, binocular DCNVA on day 14 (last study visit), hour 9 (3 hours after the second dose), with no more than a 5-letter loss in mesopic/photopic corrected distance visual acuity with the same refractive correction. Key safety measures included treatment-emergent adverse events (TEAEs) and some ocular measurements. Pilocarpine plasma levels were assessed in approximately 10% of enrolled participants.
RESULTS
Overall, 230 participants were randomized to Pilo twice daily (N = 114) and vehicle (N = 116). The proportion of participants achieving the primary and key secondary efficacy endpoints was statistically significantly greater with Pilo twice daily than vehicle, with between-treatment differences of 27.3% (95% CI = 17.3, 37.4) and 26.4% (95% CI = 16.8, 36.0), respectively. The most common TEAE was headache, reported in 10 participants (8.8%, Pilo group) and 4 participants (3.4%, vehicle group). Pilocarpine's accumulation index on day 14 was ≤1.11 after the second dose.
CONCLUSIONS
Near-vision improvements were statistically greater with Pilo twice daily than with vehicle, without compromising distance acuity. The safety profile of Pilo twice daily was consistent with that of Pilo once daily, and systemic accumulation was minimal, supporting twice daily administration.
Topics: Humans; Pilocarpine; Presbyopia; Visual Acuity; Refraction, Ocular; Double-Blind Method
PubMed: 37149245
DOI: 10.1016/j.ajo.2023.05.008 -
Medicine Dec 2023Obesity and diabetes of different types are considered global health risks with rising prevalence. In addition to low-calorie diet and daily exercise, several treatment...
RATIONALE
Obesity and diabetes of different types are considered global health risks with rising prevalence. In addition to low-calorie diet and daily exercise, several treatment options have been introduced to help patient in needs. Semaglutide (Ozempic) is one popular agent, which attracted the attention of both physicians and patients due to its positive outcome in improving glucose control and weight loss. However, no reports on the effect of semaglutide use on the oral cavity and specifically xerostomia are available in the literature. We are reporting 3 cases for patients who were using semaglutide and developed secondary xerostomia.
PATIENT CONCERNS
Three female patients with median age of 34 (range 27-46) presented to the oral medicine clinic with chief complaint of xerostomia. All patients were overweight with a mean body mass index of 35.6 (range 35-37) and have been using semaglutide for weight loss for a mean duration of 11.3 weeks (range 6-16).
DIAGNOSES
All 3 patients had severe dryness in the mouth with minimal frothy saliva with mean modified Schirmer test of 9 mL at 3 minutes (range 8-10 mL). Following exclusion of other possible underlying medical problems, the diagnosis of semaglutide-induced hyposalivation was given to all patients.
INTERVENTIONS
The patients' management varied between discontinuation of the drug, the use of pilocarpine, and conservative symptomatic management.
OUTCOMES
The patients resumed acceptable salivary flow.
LESSONS
We are reporting for the first time hyposalivation associated with the use of semaglutide. Further prospective, larger studies are warranted to confirm these findings.
Topics: Humans; Female; Xerostomia; Glucagon-Like Peptides; Weight Loss
PubMed: 38206684
DOI: 10.1097/MD.0000000000036730 -
Stem Cell Research & Therapy Sep 2023Refractory epilepsy is also known as drug-resistant epilepsy with limited clinical treatment. Benefitting from its safety and easy availability, olfactory mucosa...
BACKGROUND AND AIMS
Refractory epilepsy is also known as drug-resistant epilepsy with limited clinical treatment. Benefitting from its safety and easy availability, olfactory mucosa mesenchymal stem cells (OM-MSCs) are considered a preferable MSC source for clinical application. This study aims to investigate whether OM-MSCs are a promising alternative source for treating refractory epilepsy clinically and uncover the mechanism by OM-MSCs administration on an epileptic mouse model.
METHODS
OM-MSCs were isolated from turbinal and characterized by flow cytometry. Autologous human OM-MSCs treatment on a patient was carried out using intrathecal administration. Epileptic mouse model was established by 1 mg/kg scopolamine and 300 mg/kg pilocarpine treatment (intraperitoneal). Stereotaxic microinjection was employed to deliver the mouse OM-MSCs. Mouse electroencephalograph recording was used to investigate the seizures. Brain structure was evaluated by magnetic resonance imaging (MRI). Immunohistochemical and immunofluorescent staining of GFAP, IBA1, MAP2, TUBB3, OLIG2, CD4, CD25, and FOXP3 was carried out to investigate the neural cells and Treg cells. QRT-PCR and ELISA were performed to determine the cytokines (Il1b, Il6, Tnf, Il10) on mRNA and protein level. Y-maze, the object location test, and novel object recognition test were performed to measure the cognitive function. Footprint test, rotarod test, balance beam test, and grip strength test were conducted to evaluate the locomotive function. Von Frey testing was carried out to assess the mechanical allodynia.
RESULTS
Many beneficial effects of the OM-MSC treatment on disease status, including seizure type, frequency, severity, duration, and cognitive function, and no apparent adverse effects were observed at the 8-year follow-up case. Brain MRI indicated that autologous OM-MSC treatment alleviated brain atrophy in epilepsy patients. A study in an epileptic mouse model revealed that OM-MSC treatment recruited Treg cells to the brain, inhibited inflammation, rebuilt the neural network, and improved the cognitive, locomotive, and perceptive functions of epileptic mice.
CONCLUSIONS
Autologous OM-MSC treatment is efficacious for improving chronic refractory epilepsy, suggesting a future therapeutic candidate for epilepsy.
TRIAL REGISTRATION
The study was registered with Chinese Clinical Trial Registry (ChiCTR2200055357).
Topics: Humans; Animals; Mice; Drug Resistant Epilepsy; Brain; Neural Networks, Computer; Disease Models, Animal; Mesenchymal Stem Cells; Olfactory Mucosa
PubMed: 37674249
DOI: 10.1186/s13287-023-03458-6 -
Journal of Dental Research Feb 2024Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is...
Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is caused by mutations in the claudin-10 gene. However, little is known about the expression pattern and role of claudin-10 in saliva secretion in physical and disease conditions. In the present study, we found that only claudin-10b transcript was expressed in human and mouse submandibular gland (SMG) tissues, and claudin-10 protein was dominantly distributed at the apicolateral membranes of acini in human, rat, and mouse SMGs. Overexpression of claudin-10 significantly reduced transepithelial electrical resistance and increased paracellular transport of dextran and Na in SMG-C6 cells. In C57BL/6 mice, pilocarpine stimulation promoted secretion and cation concentration in saliva in a dose-dependent increase. Assembly of claudin-10 to the most apicolateral portions in acini of SMGs was observed in the lower pilocarpine (1 mg/kg)-treated group, and this phenomenon was much obvious in the higher pilocarpine (10 mg/kg)-treated group. Furthermore, 7-, 14-, and 21-wk-old nonobese diabetic (NOD) and BALB/c mice were used to mimic the progression of hyposalivation in Sjögren syndrome. Intensity of claudin-10 protein was obviously lower in SMGs of 14- and 21-wk-old NOD mice compared with that of age-matched BALB/c mice. In the cultured mouse SMG tissues, interferon-γ (IFN-γ) downregulated claudin-10 expression. In claudin-10-overexpressed SMG-C6 cells, paracellular permeability was decreased. Furthermore, IFN-γ stimulation increased p-STAT1 level, whereas pretreatment with JAK/STAT1 antagonist significantly alleviated the IFN-γ-induced claudin-10 downregulation. These results indicate that claudin-10 functions as a pore-forming component in acinar epithelia of SMGs, assembly of claudin-10 is required for saliva secretion, and downregulation of claudin-10 induces hyposecretion. These findings may provide new clues to novel therapeutic targets on hyposalivation.
Topics: Humans; Mice; Rats; Animals; Submandibular Gland; Pilocarpine; Mice, Inbred C57BL; Claudins; Sjogren's Syndrome; Tight Junctions; Xerostomia; Claudin-4
PubMed: 38058154
DOI: 10.1177/00220345231210547 -
Orphanet Journal of Rare Diseases Jul 2023Primary focal hyperhidrosis (PFH) may be attributed to the up-regulation of the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) in eccrine glands. Plasminogen...
BACKGROUND
Primary focal hyperhidrosis (PFH) may be attributed to the up-regulation of the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) in eccrine glands. Plasminogen activator inhibitor-1 (PAI1, encoded by SERPINE1) is reported to inhibit the expression of CHRNA1, while the role of PAI1 in hyperhidrosis is unknown.
METHODS
Serpine1 KO mice, Serpine1-Tg mice, and wild type BALB/c mice were intraperitoneally injected with pilocarpine hydrochloride to induce PFH. Cisatracurium (CIS, antagonist of CHRNA1) or PAI-039 (small-molecule inhibitor of PAI1) was pre-administrated before the induction of hyperhidrosis. On the other hand, Chrna1-expressing AAV was constructed and administered to Serpine1-Tg mice with hydrochloride stimulation. Hydrochloride-related biomarkers, such as acetylcholine (ACH) in the serum, calcium voltage-gated channel subunit alpha1 C (CACNA1C), and aquaporin 5 (AQP5) in sweat glands of mice were assayed with ELISA, RT-PCR, and Western blot.
RESULTS
The administration of PAI-039 or Pai1 knock-out increased Chrna1 expression, sweat secretion, and hydrochloride-related biomarkers (ACH, CACNA1C, and AQP5) expression. On the other hand, CIS administration diminished the strengthened hyperhidrosis phenotype induced by Pai1 knock-out with decreased sweat gland secretion.
CONCLUSION
PAI1 inhibits CHRNA1-mediated hydrochloride-induced hyperhidrosis, with decreased sweat gland secretion and diminished ACH, AQP5, and CACNA1C expression. These results indicate the potential to utilize PAI1 to alleviate PFH.
Topics: Animals; Mice; Acetylcholine; Aquaporin 5; Biomarkers; Hyperhidrosis; Sweat Glands; Plasminogen Activator Inhibitor 1
PubMed: 37542348
DOI: 10.1186/s13023-023-02808-0 -
Neural Regeneration Research Mar 2024Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory...
Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory functions across multiple neurological diseases, its application in patients with epilepsy remains controversial. Here, we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy. Cognitive assays confirmed the improvement of object and spatial memory after endurance training, and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise. Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons, probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier. In summary, this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.
PubMed: 37721298
DOI: 10.4103/1673-5374.377771 -
Behavioural Brain Research Aug 2023Status epilepticus is a neurological disorder that can result in various neuropathological conditions and presentations. Various studies involving animal models have... (Review)
Review
Status epilepticus is a neurological disorder that can result in various neuropathological conditions and presentations. Various studies involving animal models have been accomplished to understand and replicating its prominent manifestations including characteristics of related clinical cases. Up to these days, there are variety of methods and techniques to be utilized in inducing this disorder that can be chemically or electrically applied which depending on the experimental designs and targets of the studies. In particular, the chemically induced pilocarpine animal model of status epilepticus is a reliable choice which has evolved for 40 years from its initial discovery back in 1983. Although the development of the model can be considered as a remarkable breakthrough in understanding status epilepticus, several aspects of the model have been improved, throughout the years. Among the major issues in developing this model are the morbidity and mortality rates during induction process. Several modifications have been introduced in the process by different studies to tackle the related problems including application of dose fractionation, adaptation of pilocarpine to lithium-pilocarpine model and utilization of various drugs. Despite all challenges and drawbacks, this model has proven its pertinent and relevance with improvements that have been adapted since it was introduced 40 years ago. In this review, we emphasize on the evolution of this animal model from the beginning until now (1983 - 2023) and the related issues that have made this model still a popular choice in status epilepticus studies.
Topics: Animals; Pilocarpine; Electroencephalography; Status Epilepticus; Models, Animal; Disease Models, Animal
PubMed: 37348654
DOI: 10.1016/j.bbr.2023.114551 -
Journal of Ophthalmology 2023To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power...
OBJECTIVE
To evaluate the influence of pilocarpine eyedrops on the ocular biometric parameters and whether these parameter changes affect the intraocular lens (IOL) power calculation in patients with primary angle-closure glaucoma (PACG).
METHODS
Twenty-two PACG patients and fifteen normal subjects were enrolled. Ocular biometric parameters including the axial length (AL), anterior chamber depth (ACD), lens thickness (LT), mean keratometry (Km), and white-to-white distance (WTW) were measured by using a Lenstar LS 900 device before and at least 30 minutes after instillation of 2% pilocarpine eyedrops. Lens position (LP) was calculated, and the IOL power prediction based on the ocular biometric parameters was performed using the Barrett Universal II, Haigis, Hoffer Q, Holladay I, or SRK/T formulas before and after pilocarpine application.
RESULTS
In both PACG and normal groups, pilocarpine eyedrops induced a slight but statistically significant increase in the mean AL (0.01 mm for both groups) and mean LT (0.02 mm and 0.03 mm, respectively) but a significant decrease in the mean ACD (0.03 mm and 0.05 mm, respectively) and mean LP (0.02 mm and 0.04 mm, respectively). No significant changes in the mean Km and WTW were noticed in both groups. In addition, the IOL power calculation revealed insignificant changes before and after the pilocarpine instillation in both groups, regardless of the formula used.
CONCLUSIONS
Pilocarpine eyedrops can induce slight changes in the ocular biometric parameters including the AL, ACD, LT, and LP. However, these parameter changes will not result in a significant difference in IOL power estimation.
PubMed: 37455794
DOI: 10.1155/2023/7680659