Biology subjects

White, H. S.

Publications and source records attributed to White, H. S..

4 recordsLinked to original sources

bioRxiv2025

PAC: A novel translational concordance framework identifies preclinical seizure models with highest predictive validity for clinical focal onset seizures

ABSTRACT/SUMMARYO_ST_ABSObjectiveC_ST_ABSCentral to the development of novel antiseizure medications (ASMs) is testing of anticonvulsant activity in preclinical models. While various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS). MethodsThe Praxis Analysis of Concordance (PAC) framework was implemented to assess the translational concordance between preclinical and clinical ASM response for 32 FDA-approved ASMs. Preclinical ASM responses in historically used seizure models were collected. Protective indices based on reported TD50 and ED50 values were calculated for each ASM in each preclinical model. A weighted scale representing relative anticonvulsant effect was used to grade preclinical ASM response for each seizure model. Data depth was further scored based on the number of evaluated ASMs with publicly available data. Established reports of clinical ASM use in patients with FOS were similarly evaluated and a weighted scale representing prescribing patterns and perceived efficacy used to grade clinical ASM response for each indication. To assess the predictive validity of preclinical models, a unified translational scoring matrix was developed to assign a concordance score spanning the spectrum of complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were summed and normalized to generate a global translational concordance score. ResultsThe preclinical models with the highest translational concordance and greatest data depth for FOS were rodent maximal electroshock seizure (MES), mouse audiogenic seizure, mouse 6 Hz (32mA) and rat amygdala kindling. SignificanceThe PAC-FOS framework highlights mouse MES, mouse audiogenic and mouse 6 Hz (32mA) as three acute seizure models consistently demonstrating high predictive validity for FOS. We provide a pragmatic decision tree approach to support efficient resource utilization for novel ASM discovery for FOS. KEY POINT BOXUsing a newly developed translational scoring matrix, we provide novel insights into the clinical validity of common preclinical seizure models for FOS. O_LIThe PAC-FOS Framework identifies mouse MES, audiogenic and 6-Hz 32 mA as three acute models with greatest predictive validity and versatility for FOS drug discovery. C_LIO_LIWe present a pragmatic approach and decision tree to support efficient use of drug discovery resources and in consideration of the 3Rs of animal ethics. C_LIO_LIThe work presented would allow for faster and more effective screening of ASMs, while potentially reducing future patient exposures to likely ineffective drugs. C_LI

pharmacology and toxicology↗

bioRxiv2023

Diet composition and sterilization modifies intestinal microbiome diversity and burden of Theiler's virus infection-induced acute seizures

ObjectiveCentral nervous system infection with Theilers murine encephalomyelitis virus (TMEV) in C57BL/6J mice can model acquired epileptogenesis. Diet alters the acute seizure incidence in TMEV-infected mice; yet it is unclear whether intestinal dysbiosis may also impact acute or chronic behavioral comorbidities. This study thus assessed the impact of diet sterilization in a specific pathogen-free vivarium on acute seizure presentation, the composition of the gut microbiome, and chronic behavioral comorbidities of epilepsy. MethodsBaseline fecal samples were collected from male C57BL/6J mice (4-5 weeks-old; Jackson Labs) upon arrival. Mice were randomized to either autoclaved (AC) or irradiated (IR) diet (Prolab RMH 3000 - UU diets) or IR (Picolab 5053 - UW IR diet). Mice then underwent intracerebral TMEV or PBS injection three days later. Fecal samples were collected from a subset of mice at infection (Day 0) and Day 7 post-infection. Epilepsy-related working memory deficits and seizure threshold were assessed 6 weeks post-infection. Gut microbiome diversity was determined by 16S rRNA amplicon sequencing of fecal samples. ResultsTMEV-infected mice displayed acute handling-induced seizures, regardless of diet: 28/57 UW IR (49.1%), 30/41 UU IR (73.2%), and 47/77 UU AC (61%) mice displayed seizures. The number of observed seizures significantly differed: UW IR mice had 2.2{+/-}2.8 seizures (mean{+/-}standard deviation), UU IR mice had 3.5{+/-}2.9 seizures, and UU AC mice had 4.4{+/-}3.8 seizures during the 7-day monitoring period. The composition of the gut microbiome significantly differed in TMEV-infected mice fed the UU AC diet, with most measured differences occurring in Gram-positive bacteria. TMEV-infected mice fed the UU AC diet displayed worsened chronic working memory. SignificanceIntestinal dysbiosis evokes stark differences in acute seizure presentation in the TMEV model and vastly influences the trajectory of post-TMEV infection-induced behavioral comorbidities of epilepsy. Our study reveals a novel disease-modifying contribution of intestinal bacterial species after TMEV-induced acute seizures.

neuroscience↗

bioRxiv2021

Continuous Seizure Emergency Evoked in Mice with Pharmacological, Electrographic, and Pathological Features Distinct from Status Epilepticus

ObjectivesBenzodiazepines are the standard of care for the management of sustained seizure emergencies, including status epilepticus (SE) and seizure clusters. Seizure clusters are a variably defined seizure emergency wherein a patient has multiple seizures above a baseline rate, with intervening periods of recovery, distinguishing clusters from SE. While phenotypically distinct, the precise pathophysiological and mechanistic differences between SE and seizure clusters are under studied. Preclinical interrogation is needed to help uncover the behavioral, physiological, and pathological mechanisms associated with seizure emergencies in order to better manage these events in the susceptible individual. MethodsHerein, we characterize a novel model of sustained seizure emergency induced in CF-1 mice through the combined administration of high-dose phenytoin (PHT; 50 mg/kg, i.p.) and pentylenetetrazol (PTZ; 100 mg/kg, s.c.). ResultsIn the present manuscript we describe a mouse model of sustained seizure emergency that is physiologically, pharmacologically, and histologically distinct from SE. Acute administration of PHT 1 hour prior to s.c.PTZ led to significantly more mice with continuous seizure activity (CSA; 73.4%) versus vehicle-pretreated mice (13.8%; p<0.0001). CSA was sensitive to lorazepam and valproic acid when administered at seizure onset, as well as 30-minutes post-seizure onset. Carbamazepine worsened seizure control and post-CSA survival. Mice in CSA exhibited EEG patterns distinct from kainic acid-induced SE and s.c.PTZ alone, clearly differentiating CSA from SE and s.c.PTZ-induced myoclonic seizures. Neuropathological assessment by FluoroJade-C staining of brains collected 24-hours later revealed no neurodegeneration in any mice with CSA, whereas there was widespread neuronal death in brains from KA-SE mice. SignificanceThis study defines a novel mouse model on which to elucidate the mechanistic differences between sustained seizure emergencies (i.e. SE and seizure clusters) to improve discovery of effective clinical interventions and define mechanisms of seizure termination. Key Points BoxO_LISeizure clusters are a variably defined seizure emergency that is sensitive to benzodiazepines, distinct from status epilepticus. C_LIO_LIThe mechanistic differences between seizure clusters and status epilepticus are not well defined. C_LIO_LIWe report a mouse seizure emergency model that is phenotypically, pathologically, and pharmacologically distinct from status epilepticus. C_LIO_LIThis mouse model provides a novel platform on which to further interrogate the mechanisms underlying seizure emergencies. C_LI

neuroscience↗

bioRxiv2020

Development of an Antiepileptogenesis Drug Screening Platform: Effects of Everolimus and Phenobarbital

ObjectiveThe kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. Just as in patients, who develop temporal lobe epilepsy (TLE) following SE, this rat model of KA-induced SE very closely recapitulates many of the clinical and pathological characteristics of human TLE that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (TBI, SE event, viral infection, etc.). Moreover, this rat model of TLE is ideally suited for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. This report details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the onset or severity of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS, or lead to a reduced frequency/severity of SRS. MethodsRats were administered everolimus (2-3 mg/kg, P.O. commencing at 1, 2, or 24-hrs after SE onset) or phenobarbital (60 mg/kg, beginning 1 hr after SE onset). The rats in all studies (n=12/treatment dose/study) were then followed intermittently by video-EEG monitoring; i.e., 2-weeks on/2-weeks off, 2-weeks on epochs to determine latency to onset of SRS, and disease burden following SRS onset. ResultsWhile there were no adverse side effects observed in any of our studies, no treatment conferred a significant disease modifying effect, nor did any agent prevent the presentation of SRS by 6 weeks post-SE onset. ConclusionsWhile neither phenobarbital nor everolimus administered at several time points post-SE onset prevented the development of SRS, we herein demonstrate a moderate-throughput screen for potential antiepileptogenic agents in an etiologically-relevant rodent model of TLE. Key PointsO_LIDisease-modifying therapies are needed to prevent or attenuate the burden of epilepsy in at-risk individuals. C_LIO_LIWe report a moderate-throughput screening protocol to identify disease-modifying agents in a rat post-kainic acid status epilepticus model. C_LIO_LIEverolimus was administered at multiple time points post-status epilepticus with no effect on spontaneous seizures up to 6 weeks later. C_LIO_LIRepeated administration of phenobarbital also did not prevent the development of spontaneous recurrent seizures up to 6 weeks post SE. C_LIO_LIWhile we did not identify any effect of either agent, our approach provides a moderate-throughput screen for antiepileptogenesis. C_LI

neuroscience↗