pilocarpine / Generic mfg. - LARVOL DELTA

Cuproptosis and Immune Microenvironment Interplay in Temporal Lobe Epilepsy: Identification of Key Molecular Signatures and Therapeutic Targets. (PubMed, J Inflamm Res) - "Experimental validation in a pilocarpine-induced TLE mouse model confirmed gene expression changes via Western blot and immunohistochemistry...The CRG-based subtyping offers novel disease classification, while CD44, PDE5A, and TUBA1A emerge as therapeutic targets to mitigate copper-mediated neurotoxicity. These findings reposition cuproptosis as a key pathway in epilepsy, providing a roadmap for precision therapy in drug-resistant TLE."

Journal • CNS Disorders • Epilepsy • Inflammation • PDE5A • TUBA1A

Altered Glut4, IRAP, and Brain Insulin Signaling in a Mouse Model of Epilepsy and Contributions to Glucose Transport in Neurons and Astrocytes. (PubMed, J Neurochem) - "This study aimed to characterize the expression of Glut1, Glut3, Glut4, and key regulators of Glut4 trafficking in the chronic stage of the mouse pilocarpine epilepsy model...Contributions of Glut4 and IRAP to 3H-2-deoxyglucose uptake were quantified in primary mouse neurons and astrocytes...This is the first report showing increased astrocytic Glut4 expression in a rodent epilepsy model. Along with the finding of significant contributions of Glut4 and IRAP to glucose uptake in neurons, our work points to IRAP inhibitors as new pharmacological approaches improving neuronal energy supply to prevent seizure generation in epilepsy."

Journal • Preclinical • CNS Disorders • Epilepsy • FAP • GFAP • SLC2A1 • SLC2A3 • SLC2A4

Metformin Alleviates Cognitive Impairment in Chronic-Phase Epileptic Rats by Modulating the TLR4/MyD88/NF-κB Pathway and Gut Flora Composition. (PubMed, Mol Neurobiol) - "This study used the pilocarpine-induced chronic epilepsy model to mimic the pathological process of epilepsy-related cognitive impairment. Further mechanistic studies involving proteomics and ELISA testing showed that metformin treatment inhibited the TLR4/MyD88/NF-κB pathway and alleviated systemic inflammation in epileptic rats. As can be seen, metformin therapy's amelioration of cognitive impairment in epilepsy may be facilitated by the gut microbiota, with the underlying mechanism potentially involving the suppression of TLR4/MyD88/NF-κB signaling and the mitigation of inflammation."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation • MYD88 • TLR4

Dynamic astrocytic complement C3 activation in the epileptic hippocampus. (PubMed, Front Neurol) - "Using a novel floxed C3-IRES-Tdtomato knock-in mouse line, we identified sustained C3 overexpression mainly in reactive astrocytes within the hippocampal stratum lacunosum-moleculare. This activation emerged 3 days after pilocarpine-induced status epilepticus, progressively extended to the CA1 region by 3 weeks, and highlighted region- and stage-specific dysregulation of C3 during epileptogenesis."

Journal • CNS Disorders • Epilepsy • Inflammation

Taste and Smell Disorders in Children and Young Adults With Cystic Fibrosis and Primary Ciliary Dyskinesia-A Prospective Comparative Study. (PubMed, Pediatr Pulmonol) - "Taste disorders in CF are mostly attributed to difficulties tasting salty and are associated with elevated sweat chloride, probably caused by increased salivary salt following CFTR dysfunction in salivary glands rather than in the nerve cells. Smell disorders, however, remain a significant issue, particularly in PCD."

Clinical • Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases

Store-operated Ca2+ entry mediated by STIM1 and STIM2 regulates salivary secretion and KCa channels in salivary gland. (PubMed, Biochem Biophys Res Commun) - "Epithelium-specific conditional knockout mice for Stim1 and Stim2 (Stim1/2 cKO) were generated, and pilocarpine-stimulated salivary secretions in Stim1/2 cKO mice and control mice (Stim1/2fl/fl) were measured...In these cells, the initial release of Ca2+ from ER stores was comparable between genotypes following carbachol stimulation...The gene expression levels of KCa1.1 and KCa3.1 remained unchanged; however, KCa channel activity was significantly diminished in Stim1/2 cKO cells, similar to the effects of KCa channel inhibitors. These findings indicate that the loss of SOCE decreases the [Ca2+]i and intracellular Ca2+ signals required for salivary secretion, possibly through the ORAI1 channel, in turn reducing KCa channel activation."

Journal • STIM1

Protective effects of clinical anticholinergic and anticholinesterase agents against Bungarus multicinctus venom and neurotoxin-rich snake venoms. (PubMed, PLoS Negl Trop Dis) - "This study investigated the protective effects of clinically standard anticholinergic and anticholinesterase agents-scopolamine, neostigmine methylsulfate, bethanechol chloride, pilocarpine hydrochloride, and atropine sulfate-against different bungarotoxins and wide distribution neurotoxin-rich crude snake venoms (B. Upon confirming victims were bitten by B. multicinctus, administering atropine sulfate or neostigmine methylsulfate as emergency treatment might provide supplementary benefits for subsequent care. Importantly, the administration of clinic used drugs does not interfere with the efficacy of B. multicinctus antivenin in later treating stages."

Journal

Identification of Benzenesulfonamide-Containing Thiazolidine-2,4-Dione Derivatives as Novel Carbonic Anhydrase II and VII Inhibitors with Anti-Epileptic Activity. (PubMed, J Med Chem) - "Among these, 6b, 6c, 6e, and 6g exhibited remarkable inhibitory efficacy toward hCA II (KI values of 4.1, 47.8, 9.6, and 6.9 nM, respectively) and hCA VII (KI values of 9.4, 3.6, 41.6, and 98.3 nM, respectively), and selectivity over hCA I. 6c was found to significantly reduce seizure severity and susceptibility, delay seizure onset, and lower seizure intensity in in vivo study of pilocarpine (PIL)-induced seizure model...According to mechanistic research, 6c increased expression of KCC2 in the hippocampus, maintained neuronal integrity, and reduced mTOR activity. Molecular docking clarified 6c interactions with hCA II and hCA VII."

Journal • CNS Disorders • Epilepsy

E4BP4-Driven Circadian SLC6A1 Expression Governs Tiagabine Chronoefficacy in Temporal Lobe Epilepsy. (PubMed, Mol Neurobiol) - "Tiagabine markedly attenuated seizure severity and progression in both acute and chronic models of pilocarpine-induced TLE...Further, our findings indicated that E4BP4-driven circadian oscillations in SLC6A1 expression regulated the efficacy of tiagabine in a circadian time-dependent manner. These results advocated for chronotherapeutic optimization of tiagabine dosing schedules to align with endogenous SLC6A1 rhythms, offering a promising avenue for precision medicine in the management of TLE."

Journal • CNS Disorders • Epilepsy

Experimental models of epilepsy: A comprehensive review of mechanisms, translational relevance, and future directions. (PubMed, Vet World) - "Ethical considerations, including the principles of replacement, reduction, and refinement, are also emphasized. By integrating classical models with emerging technologies, this review provides a comprehensive framework to guide future research aimed at improving therapeutic strategies and bridging the gap between pre-clinical and clinical epilepsy research."

Journal • Review • CNS Disorders • Epilepsy

Uncovering CD248, MMP28, and SLC16A10 in primary Sjögren's disease: a machine learning-driven SHAP approach for CD4+ T cell-associated biomarker discovery. (PubMed, Clin Exp Rheumatol) - "Our bioinformatic study identifies CD248, MMP28 and SLC16A10 as candidate biomarkers and therapeutic targets for SjD, with their dysregulation specifically enriched in CD4+ T cell subsets, unveiling a previously underappreciated mechanism in SjD pathogenesis. naive and memory CD4+ T cells emerge as key contributors to inflammatory cascades, with azathioprine, leflunomide, methotrexate, hydroxychloroquine, iguratimod, pilocarpine, and cevimeline predicted to bind potently to these targets. This integrative multi-omics framework, combining machine learning, SHAP, and molecular docking, presents a promising approach for autoimmune disease diagnostics and early therapeutic intervention, although future experimental validation is essential to confirm its translational potential."

Biomarker • Journal • Immunology • Sjogren's Syndrome • MMP28

The Role and Therapeutic Targeting of Diazepam Binding Inhibitor (DBI/ACBP) in Epilepsy and Glioma (SNO 2025) - "In the chronic pilocarpine model of epilepsy, intrathecal administration of Ntx-DBI eliminates seizure-induced mortality (0%; n=10) relative to the Ntx-nontargeting control (Ntx-NTC) (30%; n=10; p=0.03) and reduced spontaneous seizures (Ntx-DBI: 33%; n=3 vs Ntx-NTC: 100%; n=5; p=0.03). Mechanistically, Ntx-DBI inhibits fatty acid oxidation and promotes catastrophic lipid peroxidation, driving GBM cell death. In conclusion, DBI plays a dual role in epileptogenesis and gliomagenesis, and when targeted, blocks seizure activity, and increases survival across glioma models."

Brain Cancer • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Metabolic Disorders • Solid Tumor

The Role of HIF-1α/BNIP3 Pathway in Hippocampal Neuronal Autophagy in Epilepsy. (PubMed, Mol Neurobiol) - "This investigation aimed to examine and further validate hypoxia-inducible factor (HIF)-1α/BNIP3 signaling in the Hip neuronal Apg in a lithium chloride-pilocarpine (LiCl-Pilo)-induced EP rat model...Inhibition of HIF-1α upregulated HIF-1α/BNIP3-modulated Apg and attenuated Hip neuron damage and mitochondrial damage induced by LiCl-Pilo-induced EP. Collectively, these outcomes suggest that HIF-1α/BNIP3 signaling might be involved in neuronal damage by mediating Hip Apg, thereby regulating epileptic seizures."

Journal • CNS Disorders • Epilepsy • HIF1A

Type 2 Diabetes Mellitus Exacerbates Brain Injury After Status Epilepticus in Rats. (PubMed, Brain Sci) - "Our findings suggest that T2DM is associated with greater seizure severity and increased brain injury following SE."

Journal • Preclinical • CNS Disorders • Diabetes • Epilepsy • Metabolic Disorders • Type 2 Diabetes Mellitus • Vascular Neurology

Sex-Dependent Effects of Prenatal Stress on Seizure Susceptibility and Neurodegeneration in Neonatal Rats. (PubMed, Brain Sci) - "Maternal restraint stress produced only mild, sex-dependent effects on neonatal seizure susceptibility, affecting males but not females, suggesting a limited yet selective influence of prenatal stress on early brain vulnerability."

Journal • Preclinical • CNS Disorders • Epilepsy

Interneuron Theta Phase Locking Controls Seizure Susceptibility (AES 2025) - "Thus, here we directly test the hypothesis that inhibitory theta phase locking can bidirectionally control seizure susceptibility in control and epileptic mice. To test this hypothesis, we developed a low-latency closed-loop optogenetic system (PhaSER) to bidirectionally control inhibitory phase locking to theta in head-fixed control and pilocarpine-treated epileptic mice navigating a virtual track... These data suggest that theta phase locking of PV+ interneuron spiking plays an important and causal role in seizure susceptibility. Gaining deeper insights into the impacts of inhibitory theta phase locking will reveal the potential of oscillation-driven stimulation as an effective epilepsy therapeutic, and the direct influence that specific interneurons' theta phase locking holds over network-wide activity."

CNS Disorders • Epilepsy

Sex-Specific Neuroimmune and Behavioral Responses During Epileptogenesis in Rats (AES 2025) - "Therefore, this study aims to characterize immune responses along with behavioral deficits following SE in adult male and female rats. Adult male and female rats underwent pilocarpine-induced SE (300 mg/kg, i.p.) for 1 hour, interrupted with diazepam (10 mg/kg, i.p.); controls received saline. SE induced sex-specific metabolic (weight), behavioral, and immune responses. Females experienced sustained weight gain and increased locomotor activity, while males showed reduced anxiety-like behavior. Both sexes exhibited decreased hippocampal cytokine levels and elevated complement C3b, indicating shared immune dysregulation."

Preclinical • CNS Disorders • Epilepsy • Inflammation • Psychiatry • CSF2 • IFNG • IL10 • IL2 • IL5 • TNFA

DISC1 as a Modulator of Glial Responses and Potential Target in Post-SE Epileptogenesis (AES 2025) - "Our prior work in pilocarpine-induced epilepsy models revealed significant DISC1 downregulation and spatial proximity to astrocytes in the hippocampal hilus... Following SE, glial responses transition from early astrocyte activation to late-stage microglial predominance. The initial DISC1 downregulation and subsequent DISC1+/Iba1+ overlap suggest a regulatory role for DISC1 in microglial phagocytic activity, identifying it as a potential therapeutic target in epileptogenesis."

CNS Disorders • Epilepsy • Psychiatry • Schizophrenia • CA3 • GFAP

Inhibition of 12/15-Lipoxygenase after Status Epilepticus Alleviates Neuroinflammation and Mitigates Behavioral Deficits (AES 2025) - "Using a mouse pilocarpine model of SE, we evaluated the acute effects of ML351 on proinflammatory cytokines, neuronal death, and reactive gliosis in the hippocampus 24 h after SE onset...Treatment with ML351 (50 mg/kg, i.p.) after SE was interrupted by diazepam (10 mg/kg, i.p.) markedly decreased proinflammatory cytokines and reactive gliosis in the hippocampus and widely prevented neuronal injuries in the hippocampal regions CA1, CA3, and dentate hilus. These new findings suggest that 12/15-LOX inhibition, even when administered two hours after SE onset, can alleviate neuroinflammation, protect hippocampal neurons, and prevent long-term behavioral deficits. Therefore, targeting 12/15-LOX might provide an adjunctive strategy, together with the current anti-seizure medications (ASMs), to mitigate neurobehavioral comorbidities associated with prolonged seizures."

CNS Disorders • Epilepsy • Inflammation • Psychiatry • ALOX15 • CA3 • LOX

Microglial TREM2 Mediates Sex-Specific Immune Responses During Status Epilepticus (AES 2025) - "Seizure severity, EEG spectral power, and mTOR activation were similar across genotypes and sexes, suggesting that pilocarpine induced a consistent seizure burden in all mice. However, SE-induced IL-6 increases occurred only in WT-SE males, suggesting sex-specific acute inflammatory responses and a male-specific role for TREM2 in IL-6 regulation. These findings suggest that in males, TREM2 may primarily modulate immune signaling, particularly IL-6, rather than directly influencing seizure severity following acute chemoconvulsant exposure."

CNS Disorders • Epilepsy • Inflammation • IL1B • IL6 • TNFA

Status Epilepticus Alters the Function of Brain Derived Extracellular Vesicles (AES 2025) - "To address this, we examined the functional properties of BDEVs following status epilepticus (SE) in the pilocarpine mouse model of MTLE... SE-BDEVs showed dysregulation in their ability to regulate gene expression in both N2a and BV2 cells. Notably, the increased regulation of genes related to the production of cytokines by SE-BDEVs suggests they have pro-inflammatory properties. As increased inflammation is known to the pathogenetic after SE, it is possible that BDEVs contribute to these processes and impact epileptogenesis."

CNS Disorders • Epilepsy • Inflammation • TGFB1

Prostaglandin-E2 Receptor, EP2 Antagonist Mitigates Spontaneous Seizure Burden long-after Status Epilepticus in Mice (AES 2025) - "30 minutes later, pilocarpine HCl (280 mg/kg) was i.p. injected to induce status epilepticus (SE) for 1 hour, followed by diazepam (10 mg/kg) to interrupt SE. This study reveals the critical link between neuroinflammation and long-term spontaneous epileptogenesis, and a proof-of-concept that EP2 receptor antagonism may be a novel therapeutic strategy for reducing seizure burden long after-SE."

Preclinical • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation • PLAAT3

Distinct Roles of mTORC1 and mTORC2 in Regulating Inhibitory Synaptic Input After Status Epilepticus (AES 2025) - "Given that PV+ basket cells mediate critical perisomatic inhibition of dentate granule cells (DGCs), we investigated how conditional, cell-autonomous deletion of Raptor or Rictor from DGCs influences PV-mediated inhibitory synaptic input after status epilepticus (SE). Raptorfl/fl or Rictorfl/fl mice carrying a tdTomato reporter underwent pilocarpine-induced SE or saline treatment... Raptor deletion selectively reduced the size—but not density—of PV+ perisomatic terminals on DGCs, suggesting preserved synapse number but weakened inhibitory strength. This could impair feedback inhibition and enhance DGC excitability. In contrast, Rictor deletion had no measurable effect on inhibitory contact."

CNS Disorders • Epilepsy

Knockout of Spp1/OPN Aggravates Seizure Susceptibility via Blood-Brain Barrier Dysfunction in a Pilocarpine-Induced Murine Model (AES 2025) - "These findings demonstrate that Spp1/OPN deficiency exacerbates epileptogenesis through impairing BBB resilience and amplifying neuroinflammatory signaling. OPN emerges as a critical modulator of neuroimmune crosstalk, suggesting its therapeutic potential for targeting BBB-centric epilepsy pathogenesis."

Preclinical • CNS Disorders • Epilepsy • Inflammation • CD31 • IL23A • ITGAX • OCLN • PECAM1 • SPP1

IL-33/ST2 Axis Contributes to Seizure-Induced Brain Inflammation and Damage (AES 2025) - "Using a drug-like compound, we investigated the effects of ST2 inhibition in mouse models of LPS-provoked neuroinflammation and pilocarpine-induced SE. LPS was able to induce IL-33 in microglia but not in astrocytes... These findings establish the IL-33/ST2 axis in glial cells as a key contributor to SE-triggered neuroinflammation, which is believed to exacerbate brain damage and promote acquired epileptogenesis. Targeting ST2 receptor by our novel, brain-penetrant inhibitors might represent a new strategy to reduce neuroinflammation and long-term sequelae after precipitating events like SE, thereby providing a potential disease-modifying treatment for epilepsy."

CNS Disorders • Epilepsy • Inflammation • Vascular Neurology • IL33