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Neurobiology of Disease Mar 2023Status epilepticus (SE) is a life-threatening medical emergency with significant morbidity and mortality. SE is associated with a robust and sustained increase in serum...
Status epilepticus (SE) is a life-threatening medical emergency with significant morbidity and mortality. SE is associated with a robust and sustained increase in serum glucocorticoids, reaching concentrations sufficient to activate the dense population of glucocorticoid receptors (GRs) expressed among hippocampal excitatory neurons. Glucocorticoid exposure can increase hippocampal neuron excitability; however, whether activation of hippocampal GRs during SE exacerbates seizure severity remains unknown. To test this, a viral strategy was used to delete GRs from a subset of hippocampal excitatory neurons in adult male and female mice, producing hippocampal GR knockdown mice. Two weeks after GR knockdown, mice were challenged with the convulsant drug pilocarpine to induce SE. GR knockdown had opposing effects on early vs late seizure behaviors, with sex influencing responses. For both male and female mice, the onset of mild behavioral seizures was accelerated by GR knockdown. In contrast, GR knockdown delayed the onset of more severe convulsive seizures and death in male mice. Concordantly, GR knockdown also blunted the SE-induced rise in serum corticosterone in male mice. GR knockdown did not alter survival times or serum corticosterone in females. To assess whether loss of GR affected susceptibility to SE-induced cell death, within-animal analyses were conducted comparing local GR knockdown rates to local cell loss. GR knockdown did not affect the degree of localized neuronal loss, suggesting cell-intrinsic GR signaling neither protects nor sensitizes neurons to acute SE-induced death. Overall, the findings reveal that hippocampal GRs exert an anti-convulsant role in both males and females in the early stages of SE, followed by a switch to a pro-convulsive role for males only. Findings reveal an unexpected complexity in the interaction between hippocampal GR activation and the progression of SE.
Topics: Mice; Male; Female; Animals; Receptors, Glucocorticoid; Corticosterone; Status Epilepticus; Hippocampus; Seizures; Glucocorticoids; Pilocarpine; Convulsants
PubMed: 36702319
DOI: 10.1016/j.nbd.2023.106014 -
ACS Pharmacology & Translational Science Sep 2022Ionic liquid pilocarpine analog [Pilo-OEG]Cl, the first-of-its-kind ionic liquid antiglaucoma drug candidate, is synthesized and reported. To synthesize [Pilo-OEG]Cl,...
Ionic liquid pilocarpine analog [Pilo-OEG]Cl, the first-of-its-kind ionic liquid antiglaucoma drug candidate, is synthesized and reported. To synthesize [Pilo-OEG]Cl, pilocarpine was reacted with the oligo-polyethylene glycol chloride, 2-[2-(2-chloroethoxy)ethoxy] ethanol, to form an ionic liquid molecule with an imidazole cation and a chloride anion. The chemical structure of [Pilo-OEG]Cl was confirmed with H NMR spectroscopy. Compared with pilocarpine (Pilo) and pilocarpine hydrochloride (PiloHCl), [Pilo-OEG]Cl has improved structural stability according to pH measurements and LC-MS analysis. The corneal permeability coefficient of [Pilo-OEG]Cl is 2-fold higher than that of Pilo and 8-fold higher than that of PiloHCl. [Pilo-OEG]Cl does not show apparent toxicity to human corneal epithelial cells over a broad range of concentrations up to 50 mM. The in vivo efficacy of PiloHCl and [Pilo-OEG]Cl was tested in normotensive adult Brown Norway female rats. [Pilo-OEG]Cl is found to be more potent than PiloHCl in lowering the intraocular pressure (IOP). [Pilo-OEG]Cl is more cytocompatible than PiloHCl based on the in vitro ELISA and hemolysis tests and in vivo histological analysis. Taken together, [Pilo-OEG]Cl has enhanced stability, corneal permeability, better IOP-lowering efficacy, and improved biocompatibility, thus making it a promising new drug candidate for antiglaucoma therapy. Transforming old antiglaucoma drugs to pharmaceutically active ionic liquids represents an innovative approach to developing glaucoma medications.
PubMed: 36110370
DOI: 10.1021/acsptsci.2c00024 -
Frontiers in Cellular Neuroscience 2023A variety of clinical observations and studies in animal models of temporal lobe epilepsy (TLE) reveal dysfunction of blood-brain barrier (BBB) during seizures. It is...
A variety of clinical observations and studies in animal models of temporal lobe epilepsy (TLE) reveal dysfunction of blood-brain barrier (BBB) during seizures. It is accompanied by shifts in ionic composition, imbalance in transmitters and metabolic products, extravasation of blood plasma proteins in the interstitial fluid, causing further abnormal neuronal activity. A significant amount of blood components capable of causing seizures get through the BBB due to its disruption. And only thrombin has been demonstrated to generate early-onset seizures. Using the whole-cell recordings from the single hippocampal neurons we recently showed the induction of epileptiform firing activity immediately after the addition of thrombin to the blood plasma ionic media. In the present work, we mimic some effects of BBB disruption to examine the effect of modified blood plasma artificial cerebrospinal fluid (ACSF) on the excitability of hippocampal neurons and the role of serum protein thrombin in seizure susceptibility. Comparative analysis of model conditions simulating BBB dysfunction was performed using the lithium-pilocarpine model of TLE, which most clearly reflects the BBB disruption in the acute stage. Our results demonstrate the particular role of thrombin in seizure-onset in conditions of BBB disruption.
PubMed: 36970419
DOI: 10.3389/fncel.2023.1101006 -
Molecules (Basel, Switzerland) Nov 2021Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to...
Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly ( < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.
Topics: Animals; Anticonvulsants; Chondroitin Sulfates; Male; Mice; Molecular Docking Simulation; Neuroprotective Agents; Oxidative Stress; Pentylenetetrazole; Pilocarpine; Seizures; Status Epilepticus; Valproic Acid
PubMed: 34833865
DOI: 10.3390/molecules26226773 -
Journal of Ophthalmology 2022To compare the clinical outcomes of the different treatments for acute primary angle closure (APAC).
PURPOSE
To compare the clinical outcomes of the different treatments for acute primary angle closure (APAC).
METHODS
We retrospectively reviewed the clinical charts of 87 eyes of 87 patients undergoing treatment for APAC. We investigated the best spectacle-corrected visual acuity (BSCVA), intraocular pressure (IOP), corneal endothelial cell density (ECD), and secondary interventions after each treatment.
RESULTS
The pretreated IOP was 56.4 ± 9.0 mmHg. As the first treatment for APAC, all eyes underwent topical 2% pilocarpine and systemic mannitol administration. Subsequent laser iridotomy (LI) and lensectomy were necessary in 29 eyes (33%) and 35 eyes (40%), respectively. Bullous keratopathy developed in 1 eye (1%), and following glaucoma surgery was required in 7 eyes (8%). The BSCVA at the final follow-up was 0.16 ± 0.53 and 0.01 ± 0.20 logMAR (Mann-Whitney test, =0.149), the IOP was 12.8 ± 2.6, and 12.6 ± 2.9 mmHg (=0.860), and the ECD was 2295.9 ± 658.2 and 2244.1 ± 622.0 cells/mm (=0.735) in the LI and lensectomy groups, respectively.
CONCLUSIONS
Approximately 26% of eyes with APAC were resolved after the initial medical treatment, and subsequent surgical treatments, such as LI and lensectomy, were required in 33% and 40% of eyes, respectively. We found no significant differences in the BSCVA, the IOP, or the ECD among LI and lensectomy treatment groups.
PubMed: 35677621
DOI: 10.1155/2022/6959479 -
Epilepsia Apr 2022As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability....
OBJECTIVE
As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine-treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility.
METHODS
We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator.
RESULTS
JW-65 showed adequate half-life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalographic monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner.
SIGNIFICANCE
These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof-of-concept study establishes TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.
Topics: Animals; Disease Models, Animal; Mice; Pentylenetetrazole; Pilocarpine; Pyrazoles; Seizures
PubMed: 35179226
DOI: 10.1111/epi.17190 -
Journal of Medical Case Reports Mar 2024This case report is applicable to the field of ophthalmology because there is a paucity of medical literature related to the clinical presentation, diagnosis, and...
BACKGROUND
This case report is applicable to the field of ophthalmology because there is a paucity of medical literature related to the clinical presentation, diagnosis, and management of uveal effusion syndrome. This is an urgent concern because there are severe complications associated with this disease, including non-rhegmatogenous retinal detachment, angle closure glaucoma, and possible blindness. This report will fill clinical knowledge gaps using a patient example.
CASE PRESENTATION
A 68-year-old white male with multiple cardiovascular risk factors initially presented to the Eye Institute Urgent Care Clinic with new onset visual symptoms, including eye pain, eye lid swelling, redness, and tearing of his left eye. He had experienced a foreign body sensation in the left eye and bilateral floaters weeks prior to his presentation. The patient was examined, and vision was 20/30 in both eyes, and intraocular pressure was 46 in the right eye and 36 in the left eye. After initial assessment, including compression gonioscopy, intermittent angle closure glaucoma was suspected. He received oral diamox 500 mg, one drop of alphagan in both eyes, one drop of latanoprost in both eyes, one drop of dorzolamide in both eyes, and one drop of 2% pilocarpine in both eyes. There was only slight response in intraocular pressure. Owing to the bilateral angle closure, he underwent laser peripheral iridotomy to decrease intraocular pressure and open the angle that was found closed on gonioscopy. The patient was discharged on oral and topical glaucoma drops and scheduled for the glaucoma clinic. When he presented for follow-up in the glaucoma clinic, he was evaluated and noted to have bilateral narrow angles and intraocular pressure in the mid-twenties. A brightness scan (B-scan) was performed and was noted to have bilateral choroidal effusions, confirmed by Optos fundus photos. He was started on prednisone at 60 mg once per day (QD) with taper, continuation of oral and topical glaucoma medications, and a retina evaluation. Evaluation with a retina specialist showed resolving choroidal effusion in the left eye. He continued the prednisone taper as well as glaucoma drops as prescribed. Follow-up in the glaucoma clinic revealed a grade 3 open angle. He continued the prednisone taper, cosopt twice per day in both eyes, and discontinued brimonidine. The magnetic resonance imaging (MRI) that was performed showed results that were remarkable. No hemorrhage or mass was present. Follow-up with the retina specialist found that the choroidal effusions had resolved completely.
CONCLUSION
This case report emphasizes the value in early detection, keen diagnostic evaluation, and cross-collaboration between multiple ophthalmology specialists to optimize healthcare outcomes for patients with uveal effusion syndrome.
Topics: Humans; Male; Aged; Glaucoma, Angle-Closure; Prednisone; Uveal Effusion Syndrome; Intraocular Pressure; Eye; Brimonidine Tartrate
PubMed: 38509616
DOI: 10.1186/s13256-024-04496-1 -
Planta Medica May 2024Plants are an incredible source of metabolites showing a wide range of biological activities. Among these, there are the alkaloids, which have been exploited for medical... (Review)
Review
Plants are an incredible source of metabolites showing a wide range of biological activities. Among these, there are the alkaloids, which have been exploited for medical purposes since ancient times. Nowadays, many plant-derived alkaloids are the main components of drugs used as therapy for different human diseases. This review deals with providing an overview of the alkaloids used to treat eye diseases, describing the historical outline, the plants from which they are extracted, and the clinical and molecular data supporting their therapeutic activity. Among the different alkaloids that have found application in medicine so far, atropine and pilocarpine are the most characterized ones. Conversely, caffeine and berberine have been proposed for the treatment of different eye disorders, but further studies are still necessary to fully understand their clinical value. Lastly, the alkaloid used for managing hypertension, reserpine, has been recently identified as a potential drug for ameliorating retinal disorders. Other important aspects discussed in this review are different solutions for alkaloid production. Given that the industrial production of many of the plant-derived alkaloids still relies on extraction from plants, and the chemical synthesis can be highly expensive and poorly efficient, alternative methods need to be found. Biotechnologies offer a multitude of possibilities to overcome these issues, spanning from genetic engineering to synthetic biology for microorganisms and bioreactors for plant cell cultures. However, further efforts are needed to completely satisfy the pharmaceutical demand.
Topics: Humans; Alkaloids; Eye Diseases; Atropine; Pilocarpine; Plants, Medicinal; Caffeine; Plant Extracts; Reserpine
PubMed: 38452806
DOI: 10.1055/a-2283-2350 -
International Journal of Molecular... Jan 2024In humans and animal models, temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal networks, gliosis, neuroinflammation, and loss of...
In the Rat Hippocampus, Pilocarpine-Induced Status Epilepticus Is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ, and Collagen IV in Endothelial Cells and Pericytes of the Blood-Brain Barrier.
In humans and animal models, temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal networks, gliosis, neuroinflammation, and loss of integrity of the blood-brain barrier (BBB). More than 30% of epilepsies remain intractable, and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new therapeutic strategies. In this work, we induced status epilepticus in rats through injection of the proconvulsant drug pilocarpine, which leads to TLE. Using RT-qPCR, double immunohistochemistry, and confocal imaging, we studied the regulation of reactive glia and vascular markers at different time points of epileptogenesis (latent phase-3, 7, and 14 days; chronic phase-1 and 3 months). In the hippocampus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neuroinflammatory status. We report for the first time the concomitant induction of the specific proteins CD31, PDGFRβ, and ColIV-which peak at the same time points as inflammation-in the endothelial cells, pericytes, and basement membrane of the BBB. The altered expression of these proteins occurs early in TLE, during the latent phase, suggesting that they could be associated with the early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.
Topics: Animals; Humans; Rats; Blood-Brain Barrier; Collagen; Disease Models, Animal; Endothelial Cells; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Neuroglia; Pericytes; Pilocarpine; Rats, Sprague-Dawley; Status Epilepticus; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Platelet-Derived Growth Factor; Receptor, Platelet-Derived Growth Factor beta
PubMed: 38338969
DOI: 10.3390/ijms25031693 -
Journal of Pharmacy & Bioallied Sciences Aug 2020The aim of this study was to evaluate effectiveness of bethanechol and pilocarpine among xerostomic denture wearers.
AIM
The aim of this study was to evaluate effectiveness of bethanechol and pilocarpine among xerostomic denture wearers.
MATERIALS AND METHODS
This study was conducted in 60 complete denture wearers of both genders. For assessment of salivary flow, resting saliva and stimulated saliva were collected. Patients were split into two groups consisting of 30 patients each. Pilocarpine was given to patients in group I and patients in group II received bethanechol. Salivary flow was measured at baseline, after 2 weeks, and after 4 weeks.
RESULTS
The mean whole resting saliva in patients of group I was 0.61 mg/mL and in that of group II was 0.65 mg/mL. The mean whole stimulated saliva in patients of group I was 1.35 mg/mL and in group II it was 1.51 mg/mL. The mean whole resting saliva after 2 weeks in patients of group I was 0.83 mg/mL and in group II was 0.92 mg/mL. Whole stimulated saliva in patients of group I was 1.67 mg/mL, and in patients of group II it was 1.86 mg/mL. The difference noted was significant ( < 0.05). The mean whole resting saliva after 4 weeks in patients of group I was 1.23 mg/mL and in that of group II was 1.43 mg/mL. Whole stimulated saliva in patients of group I was 1.98 mg/mL and in patients of group II it was 2.04 mg/mL.
CONCLUSION
Authors found that both agents were effective in increasing salivary secretions. However, pilocarpine is a more effective sialagogue as compared to bethanechol in completely edentulous patients with xerostomia.
PubMed: 33149490
DOI: 10.4103/jpbs.JPBS_111_20