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Frontiers in Neurology 2024Patients with epilepsy are prone to cognitive decline, depression, anxiety and other behavioral disorders. Cognitive comorbidities are particularly common and...
Patients with epilepsy are prone to cognitive decline, depression, anxiety and other behavioral disorders. Cognitive comorbidities are particularly common and well-characterized in people with temporal lobe epilepsy, while inconsistently addressed in epileptic animals. Therefore, the aim of this study was to ascertain whether there is good evidence of cognitive comorbidities in animal models of epilepsy, in particular in the rat pilocarpine model of temporal lobe epilepsy. We searched the literature published between 1990 and 2023. The association of spontaneous recurrent seizures induced by pilocarpine with cognitive alterations has been evaluated by using various tests: contextual fear conditioning (CFC), novel object recognition (NOR), radial and T-maze, Morris water maze (MWM) and their variants. Combination of results was difficult because of differences in methodological standards, in number of animals employed, and in outcome measures. Taken together, however, the analysis confirmed that pilocarpine-induced epilepsy has an effect on cognition in rats, and supports the notion that this is a valid model for assessment of cognitive temporal lobe epilepsy comorbidities in preclinical research.
PubMed: 38872822
DOI: 10.3389/fneur.2024.1392977 -
Annals of Medicine and Surgery (2012) Jun 2024This article discusses the prevalence and impact of pharmacologically-induced mydriasis, a condition where the pupil becomes excessively dilated due to certain drugs. It... (Review)
Review
This article discusses the prevalence and impact of pharmacologically-induced mydriasis, a condition where the pupil becomes excessively dilated due to certain drugs. It highlights the challenges faced by medical professionals in dealing with this condition and the limitations of current treatments, like pilocarpine and dapiprazole, which come with systemic side effects and specific contraindications, limiting their regular use. The article introduces Ryzumvi, a novel ophthalmic solution approved by the US FDA, which effectively reverses mydriasis caused by adrenergic agonists and antimuscarinic drugs. The article provides insights into its mechanism of action, clinical efficacy, pharmacokinetics, safety, and tolerance based on extensive clinical trials. It emphasizes its rapid onset of action and effectiveness in restoring pupils to their initial size. It also underlines the potential for expanded applications, including in pediatric patients, solidifying its importance in the field of ophthalmology. Furthermore, Ryzumvi represents a promising advancement in managing pharmacologically-induced mydriasis, offering swift and effective relief while highlighting the importance of adhering to safety precautions and the continuous research and development efforts in ophthalmology to comprehensively address vision-related disorders and enhance patient outcomes.
PubMed: 38846833
DOI: 10.1097/MS9.0000000000002058 -
Turkish Journal of Medical Sciences 2023Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of...
Propofol mitigates brain injury and oxidative stress, and enhances GABAA receptor α1 subunit expression in a rat model of lithium chloride-pilocarpine induced status epilepticus.
BACKGROUND/AIM
Propofol is a positive allosteric modulator of GABAA receptor (GABAAR) and has potent antioxidant activity. The aim of this study was to investigate the effect of propofol on damage to the cerebral cortex and hippocampus in a lithium chloride (LiCl)-pilocarpine animal model of status epilepticus (SE).
MATERIALS AND METHODS
Adult male Sprague Dawley rats were injected with LiCl-pilocarpine to induce SE. They were then randomized and injected 30 min later with vehicle saline (SE+saline), propofol (SE+PPF, 50 mg/kg), Diazepam (SE+DZP, 10 mg/kg), Scopolamine (SE+SCOP, 10 mg/kg), or MK-801 (SE+MK-801, 2 mg/kg). Another group of rats received saline only and served as the naïve control (BLK). The levels of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) in the serum, cortex and hippocampus were analyzed 2 and 24 h posttreatment. The degree of tissue damage in the cortex and hippocampus of individual rats was assessed 24 h posttreatment, together with expression of the GABAAR α1 subunit.
RESULTS
The propofol group showed reduced levels of tissue damage in the cerebral cortex and hippocampus, decreased levels of MDA, and increased levels of GSH compared to the SE+saline group. No changes in SOD level were observed in serum and tissue samples from the cortex and hippocampus of SE+saline rats. Immunohistochemistry and Western blot assays showed that propofol treatment significantly increased the expression of GABAR α1 subunit in the cortical and hippocampal tissues of SE rats.
CONCLUSION
Propofol treatment protected against SE-induced tissue injury in the cortex and hippocampus of rats. This was due at least in part to its antioxidant activity and to its induction of GABAAR α1 subunit expression in the brain.
Topics: Animals; Propofol; Receptors, GABA-A; Status Epilepticus; Pilocarpine; Male; Rats, Sprague-Dawley; Lithium Chloride; Oxidative Stress; Rats; Disease Models, Animal; Hippocampus; Brain Injuries; Malondialdehyde; Cerebral Cortex
PubMed: 38813010
DOI: 10.55730/1300-0144.5670 -
CNS Neuroscience & Therapeutics May 2024Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was...
AIMS
Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF.
METHODS
An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF.
RESULTS
Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction.
SIGNIFICANCE
SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.
Topics: Animals; Rats; Apoptosis Inducing Factor; Male; Nerve Tissue Proteins; Disease Models, Animal; Rats, Sprague-Dawley; Drug Resistant Epilepsy; Membrane Glycoproteins; Hippocampus; Anticonvulsants
PubMed: 38801174
DOI: 10.1111/cns.14778 -
Biomedicines May 2024Reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) is a commonly used tool for gene expression analysis. The selection of stably...
Reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) is a commonly used tool for gene expression analysis. The selection of stably expressed reference genes is required for accurate normalization. The aim of this study was to identify the optimal reference genes for RT-qPCR normalization in various brain regions of rats at different stages of the lithium-pilocarpine model of acquired epilepsy. We tested the expression stability of nine housekeeping genes commonly used as reference genes in brain research: , , , , , , , , and . Based on four standard algorithms (geNorm, NormFinder, BestKeeper, and comparative delta-Ct), we found that after pilocarpine-induced status epilepticus, the stability of the tested reference genes varied significantly between brain regions and depended on time after epileptogenesis induction (3 and 7 days in the latent phase, and 2 months in the chronic phase of the model). and were the most stable, while , , and demonstrated the lowest stability in the analyzed brain areas. We revealed time- and region-specific changes in the mRNA expression of the housekeeping genes , , , , , , and These changes were more pronounced in the hippocampal region during the latent phase of the model and are thought to be related to epileptogenesis. Thus, RT-qPCR analysis of mRNA expression in acquired epilepsy models requires careful selection of reference genes depending on the brain region and time of analysis. For the time course study of epileptogenesis in the rat lithium-pilocarpine model, we recommend the use of the and genes.
PubMed: 38791067
DOI: 10.3390/biomedicines12051100 -
Frontiers in Neurology 2024Temporal lobe epilepsy (TLE) is a prevalent refractory partial epilepsy seen in clinical practice, with most cases originating from the hippocampus and being...
OBJECTIVE
Temporal lobe epilepsy (TLE) is a prevalent refractory partial epilepsy seen in clinical practice, with most cases originating from the hippocampus and being characterized by impaired learning and memory. Oxidative stress plays a direct role in the development of epilepsy and neurodegeneration while promoting cognitive dysfunction. Previous research indicates that benzyl isothiocyanate (BITC) has antioxidative stress properties and contributes to neuroprotection. In this study, we aimed to investigate the neuroprotective effect of BITC on a lithium-pilocarpine-induced temporal lobe epileptic mice model.
METHODS
We conducted Intellicage learning tests, Morris water maze, open field test, and step-down-type passive avoidance tests, respectively. In addition, body weight and brain-to-body ratio were calculated. Nissl staining, real-time quantitative PCR detection of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase quinone 1(NQO1) were performed. Content of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) were determined.
RESULTS
Our results demonstrate that BITC enhances cognitive function and motor ability in mice, as determined by Intellicage learning tests, Morris water maze, open field test, and step-down-type passive avoidance tests, respectively. Epilepsy leads to the loss of neurons in the CA3 region, while BITC treatment plays a positive role in neuroprotection, especially in the cortex. In comparison to the control group, the EP group exhibited decreased transcription levels of HO-1 and NQO1, alongside reduced GSH-Px activity, while MDA content was elevated. Conversely, the BITC treatment group, when compared to the EP group, showed enhanced transcription levels of Nrf2, HO-1, and NQO1, along with increased GSH-Px activity, and a decrease in MDA content.
CONCLUSION
In summary, our study provides evidence that BITC can improve cognitive impairments in pilocarpine-induced epileptic mice, demonstrating significant antioxidant effects and neuroprotective properties. This highlights its potential as a phytochemical for managing the sequelae of epilepsy.
PubMed: 38715687
DOI: 10.3389/fneur.2024.1330102 -
BMC Chemistry May 2024In the investigation of active ingredients from natural products, current technologies relying on drug-target affinity recognition analysis face significant challenges....
In the investigation of active ingredients from natural products, current technologies relying on drug-target affinity recognition analysis face significant challenges. This is primarily due to their limited specificity and inability to provide downstream pharmacodynamic information, such as agonistic or antagonistic activity. In this study, a two-point method was developed by immobilizing M3 acetylcholine receptor (M3R) through the combination of the conformation-specific peptide BJ-PRO-13a and the HaloTag trap system. We systematically assessed the specificity of the immobilized M3R using known M3R antagonists (pirenzepine and atropine) and agonists (cevimeline and pilocarpine). By frontal analysis and nonlinear chromatography, the performance of immobilized M3R was evaluated in terms of binding kinetics and thermodynamics of four drugs to the immobilized M3R. Additionally, we successfully identified two M3R antagonists within an extract from Daturae Flos (DF), specifically hyoscyamine and scopolamine. Our findings demonstrate that this immobilization method effectively captures receptor-ligand binding interactions and can discern receptor agonists from antagonists. This innovation enhances the efficiency of receptor chromatography to determine binding-affinity in the development of new drugs, offering promise for the screening and characterization of active compounds, particularly within complex natural products.
PubMed: 38702791
DOI: 10.1186/s13065-024-01198-z -
Antioxidants (Basel, Switzerland) Mar 2024Epilepsy, marked by abnormal and excessive brain neuronal activity, is linked to the activation of L-type voltage-gated calcium channels (LTCCs) in neuronal membranes....
Epilepsy, marked by abnormal and excessive brain neuronal activity, is linked to the activation of L-type voltage-gated calcium channels (LTCCs) in neuronal membranes. LTCCs facilitate the entry of calcium (Ca) and other metal ions, such as zinc (Zn) and magnesium (Mg), into the cytosol. This Ca influx at the presynaptic terminal triggers the release of Zn and glutamate to the postsynaptic terminal. Zn is then transported to the postsynaptic neuron via LTCCs. The resulting Zn accumulation in neurons significantly increases the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, contributing to reactive oxygen species (ROS) generation and neuronal death. Amlodipine (AML), typically used for hypertension and coronary artery disease, works by inhibiting LTCCs. We explored whether AML could mitigate Zn translocation and accumulation in neurons, potentially offering protection against seizure-induced hippocampal neuronal death. We tested this by establishing a rat epilepsy model with pilocarpine and administering AML (10 mg/kg, orally, daily for 7 days) post-epilepsy onset. We assessed cognitive function through behavioral tests and conducted histological analyses for Zn accumulation, oxidative stress, and neuronal death. Our findings show that AML's LTCC inhibition decreased excessive Zn accumulation, reactive oxygen species (ROS) production, and hippocampal neuronal death following seizures. These results suggest amlodipine's potential as a therapeutic agent in seizure management and mitigating seizures' detrimental effects.
PubMed: 38671837
DOI: 10.3390/antiox13040389 -
Ophthalmology and Therapy Jun 2024The phase 3, randomized, vehicle-controlled, 14-day VIRGO study evaluated the efficacy and safety of twice-daily dosing of pilocarpine hydrochloride ophthalmic solution...
INTRODUCTION
The phase 3, randomized, vehicle-controlled, 14-day VIRGO study evaluated the efficacy and safety of twice-daily dosing of pilocarpine hydrochloride ophthalmic solution 1.25% (Pilo) in presbyopia. On VIRGO exit, a companion study was conducted to assess the patient experience with presbyopia and satisfaction with Pilo.
METHODS
Recruited individuals completed the Presbyopia Patient Satisfaction Questionnaire (PPSQ) plus a three-part exit survey, or a live interview. The PPSQ evaluated respondents' experience with Pilo. Survey parts 1 and 2 evaluated experience managing presbyopia before and during VIRGO, respectively; part 3 assessed future possibilities of using Pilo in real-world situations. The interview further informed the interviewees' experience with presbyopia and Pilo. The primary endpoint was responders (%) in each rating category of the PPSQ items 1-7; the secondary endpoints were summary of categorical (survey) and qualitative (interviews) responses.
RESULTS
The PPSQ and survey included 62 participants who received Pilo (N = 28) or vehicle (N = 34) in VIRGO; the interview included ten participants (Pilo, N = 4; vehicle, N = 6). Per the PPSQ, 64.3% of Pilo users reported vision improvement, including 17.9% with complete improvement; ≥ 46.4% were satisfied/very satisfied with their ability to perform daily activities, see up close unaided, and read in dim light. Among vehicle users, these percentages were 35.3%, 0%, and ≤ 23.5%, respectively. In both subgroups, ≥ 67.9% were interested in using Pilo or Pilo and eyeglasses/contact lenses in the future. Per the interview, vehicle users (n = 6/6) found the eyedrop easy to use but none experienced meaningful near-vision improvements, stopped using other correction method(s) part of the day, were satisfied with the eyedrop, preferred it over their previous correction method(s), or would continue using it if prescribed. Conversely, 75% (n = 3/4) of Pilo users responded positively to each of these six criteria.
CONCLUSIONS
Findings validate the VIRGO results and improve our understanding of the patient experience, demonstrating improved vision and satisfaction with Pilo (vs. vehicle) when performing daily activities.
PubMed: 38662193
DOI: 10.1007/s40123-024-00935-w -
Cell Reports May 2024The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows...
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.
Topics: Animals; Male; Mice; Apoptosis; Mice, Inbred C57BL; Neurons; Phosphorylation; Pilocarpine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; Seizures; Status Epilepticus
PubMed: 38656874
DOI: 10.1016/j.celrep.2024.114144