About

Cameron S. Metcalf, Ph.D., is a Research Assistant Professor of Pharmacology and Toxicology and the Associate Director of the Anticonvulsant Drug Development Program at the University of Utah. He has extensive experience in preclinical drug development for epilepsy, contributing significantly to the development and implementation of several rodent epilepsy models that are now part of the screening workflow for the NIH/NINDS Epilepsy Therapy Screening Program. The University of Utah has served as the Contract Site for this NIH program since its inception in 1975, and Dr. Metcalf currently serves as a Co-Investigator for this award. His work has been instrumental in advancing drug development efforts for lead compounds from multiple pharmaceutical companies, with products at various stages of preclinical and clinical development. Prior to his current role, Dr. Metcalf was a Senior Scientist and Project Manager at NeuroAdjuvants, Inc., where he focused on drug screening and development for epilepsy and pain indications using modified neuropeptide analogs. He is the author of more than 35 peer-reviewed publications and has served as an editorial board member and ad-hoc reviewer for several scientific journals.

Research topics

• Medicine
• Pharmacology
• Internal medicine
• Anesthesia
• Psychiatry
• Neuroscience
• Chemistry
• Pediatrics
• Engineering ethics
• Pathology
• Finance
• Biology
• Engineering
• Business
• Psychology

Selected publications

• In silico and in vivo studies reveal that Theiler's murine encephalomyelitis virus induces upregulation of miR-155-5p in the hippocampus

  Neurobiology of Disease · 2026-02-16

  articleOpen accessSenior authorCorresponding

  MicroRNAs (miRNAs) are perceived as master regulators of gene expression in the cells. Their involvement has been demonstrated in the etiopathogenesis of many neurological disorders, including central nervous system (CNS) infection, neuroinflammation, seizures and epilepsy. Here, we evaluated the role of miRNAs in the Theiler's murine encephalomyelitis virus (TMEV) model. Using in silico modeling, we indicated miRNAs potentially associated with the regulation of the largest number of differentially expressed (DE) genes in the TMEV model. Next, we developed TMEV model with a tissue collection at Days 7 and 10 post infection (PI). We performed qPCR to identify the miRNAs of interest. Finally, we conducted bioinformatic analyses of the affected miRNAs to characterize biological processes and the most significant interactions among DE genes. The expression of miR-155-5p was significantly increased in the hippocampi of the TMEV-infected mice at Days 7 and 10 PI, showing approximately 60-fold upregulation. We also observed enhanced expression of miR-17-5p in response to viral infection at both Days 7 and 10 PI. The expression of miR-34a-5p and miR-15a-5p was elevated at Day 10 PI. Enrichment analysis associated miR-155-5p and miR-17-5p pathways with apoptosis, microglial activity regulator TYROBP (tyrosine kinase binding protein), interleukin 2 and 5 signaling. Among downregulated miR-155-5p targets, interleukin 1β was identified as gene with the highest number of interactions with other DE genes. Our findings indicate that miR-155-5p and its targets, are promising candidates for future functional studies aimed to improving both, treatment and diagnosis of virus-induced complications like seizures. • MicroRNAs are key regulators of gene expression in mammalian cells. • The role of miRNAs was assessed in the TMEV model for CNS virus-induced seizures. • miR-155-5p and miR-17-5p levels increased in hippocampi of TMEV mice at Days 7 and 10 PI. • Pathway analysis linked miR-155-5p and miR-17-5p to apoptosis, TYROBP, IL-2, and IL-5 signaling. • miR-155-5p and its targets are promising for functional studies on virus-induced complications.

  PublisherDOI

• Epilepsy Therapy Screening From 1975 to 2026 and Beyond: Merging Established and New Approaches to Develop Novel Therapies

  Epiliepsy currents/Epilepsy currents · 2026-04-20

  articleOpen access1st authorCorresponding

  Antiepileptic Drug Development: II. Anticonvulsant Drug Screening Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Epilepsia . 1978 Aug;19(4):409-28. doi:10.1111/j.1528-1157.1978.tb04507.x. PMID: 699894 By means of the maximal electroshock seizure test, the subcutaneous pentylenetetrazol seizure threshold test, and the Rotorod minimal neurotoxicity test, the Anticonvulsant Screening Project has evaluated the activity of 1,495 experimental compounds accessioned in the first 2 years. A three-screen protocol for appraising these compounds has proved reliable, fast, and inexpensive. Preliminary data show that 430 of these compounds have good anticonvulsant activity. Completed evaluations of 352 identified 16 that have anticonvulsant activity at doses less than 75 mg/kg and protective indices greater than 5.0.

  PublisherDOI

• Multiomic Analyses Reveal Brainstem Metabolic Changes in a Mouse Model of Dravet Syndrome

  Cells · 2025-12-30

  articleOpen accessSenior authorCorresponding

  Dravet Syndrome (DS) is a severe genetic epileptic encephalopathy caused by mutations in the SCN1A gene that encodes the voltage-gated sodium channel (NaV1.1) subunit alpha. DS is characterized by intractable seizures, progressive developmental delay, cognitive impairment, and high mortality due to sudden unexpected death in epilepsy (SUDEP). SUDEP is mediated by respiratory dysfunction, but the exact molecular underpinnings are unclear. Though hippocampal metabolic alterations have been reported in DS mice, such changes in brain regions controlling breathing have not been studied. We used Scn1aA1783V/WT DS mice to study temporal alterations in the brain metabolome, including analysis of brainstem and forebrain regions. Glycolytic and pentose phosphate pathway intermediates were significantly elevated in the brainstem of DS mice during the period of enhanced susceptibility to mortality (post-natal days P20–30). In older P40–P50 mice, mitochondrial aconitate and the antioxidant glutathione were significantly elevated in the brainstem. Single-nuclei RNA sequencing (snRNA seq) and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, and protein translation, as well as reorganization of protein kinase-mediated pathways that are specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice.

  PublisherOA PDFDOI

• Emerging Therapy Opportunities for Progressive Myoclonus in Epilepsy

  Epiliepsy currents/Epilepsy currents · 2025-03-18

  articleOpen access1st authorCorresponding

  Original Article Abstract: Original Article Citation: Feng H, Clatot J, Kaneko K, Flores-Mendez M, Wengert ER, Koutcher C, Hoddeson E, Lopez E, Lee D, Arias L, Liang Q, Zhang X, Somarowthu A, Covarrubias M, Gunthorpe MJ, Large CH, Akizu N, Goldberg EM. Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy. Cell Reports Medicine , Volume 5, Issue 2, 2024, 101389. The recurrent variant KCNC1 -p.Arg320His causes progressive myoclonus epilepsy type 7 (EPM7), defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. AKv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.

  PublisherOA PDFDOI

• Discovery of novel hybrid pyrrolidin-2-one derivatives exhibiting potent antiseizure and antinociceptive effects in preclinical models

  Biomedicine & Pharmacotherapy · 2025-11-01

  articleOpen access

  In the present study, a series of novel derivatives based on the pyrrolidin-2-one scaffold were designed using a framework combination approach, synthesized, and comprehensively evaluated through in vitro and in vivo assays conducted on Swiss albino male mice. The obtained hybrid molecules demonstrated potent and broad-spectrum antiseizure activity in key preclinical seizure models. Following intraperitoneal (i.p.) administration, compound (R)-9, identified as the lead molecule, provided robust protection across all tested seizure paradigms, with ED₅₀ values of 64.3 mg/kg (maximal electroshock test), 26.3 mg/kg (6 Hz, 32 mA), and 37.8 mg/kg (6 Hz, 44 mA). In addition, (R)-9 was active in the pentylenetetrazole (PTZ)-induced kindling model as well as in spontaneous electrographic bursting, an in vitro model of pharmacoresistant seizure-like activity at a concentration of 120 μM. Moreover, it significantly increased seizure threshold in the ivPTZ test. Importantly, (R)-9 also exhibited strong antinociceptive properties. No adverse effects on motor coordination and grip strength were observed at effective doses. Pharmacokinetic profiling and in vitro ADME-Tox evaluation showed satisfying drug-like characteristics of (R)-9, including metabolic stability in human liver microsomes, interaction with cytochrome P450 enzymes and hepatotoxicity (HepG2 cell line). In vitro binding and functional assays suggest a multimodal mechanism of action. Besides its TRPV1 antagonistic activity, (R)-9 effectively inhibited voltage-gated sodium channels at a concentration of 50 μM in electrophysiological studies. Collectively, these findings support the further preclinical development of (R)-9 as a promising candidate for the treatment of epilepsy and pain-related disorders.

  PublisherDOI

• Development of a preclinical testing platform for clinically relevant therapy for Dravet syndrome

  Epilepsia · 2025-06-30 · 3 citations

  articleOpen access

  Abstract Objective Patients with drug‐resistant epilepsy, including Dravet syndrome, are frequently prescribed multiple antiseizure medications. Nevertheless, people with Dravet syndrome often have inadequate seizure control, and there is an ongoing unmet clinical need to identify novel therapeutics. As a proof‐of‐principle study to further validate and characterize the Scn1a A1783V/WT mouse model and identify a drug‐testing paradigm with face, construct, and predictive validity, we assessed the efficacy of subchronic administration of stiripentol add‐on to clobazam and valproic acid at clinically relevant doses using the Scn1a A1783V/WT mouse model. Methods Following a 14‐day treatment, we evaluated the efficacy of stiripentol add‐on to clobazam and valproic acid using hyperthermia‐induced ( n = 6) and video‐electroencephalography (EEG) monitoring of spontaneous seizure tests ( n = 13). Valproic acid was delivered via osmotic minipump, whereas stiripentol and clobazam were administered via food pellets delivered through automatic feeders. Bioanalytical assays were performed to evaluate drug concentrations in plasma and brain using liquid chromatography–tandem mass spectrometry. Results Stiripentol, clobazam, N ‐desmethylclobazam, and valproic acid all yielded plasma concentrations within the therapeutic plasma concentration range for humans. Stiripentol added to clobazam and valproic acid significantly elevated the seizing temperatures in the hyperthermia‐induced seizure assay (** p = 0.0018; Log‐rank test). Clobazam, valproic acid, and stiripentol co‐administration significantly reduced spontaneous seizure frequency compared to clobazam and valproic acid combined (*** p = 0.0003, Mann–Whitney test). Significance This research lays the groundwork for exploring effective add‐on compounds to clobazam and valproic acid in treating Dravet syndrome. The study further highlights the utility of the Scn1a A1783V/WT mice in discovering therapies for Dravet syndrome–associated pharmacoresistant seizures.

  PublisherOA PDFDOI

• Seizures elicited by transcorneal 6 Hz stimulation in developing rats

  PLoS ONE · 2025-01-03 · 1 citations

  articleOpen accessCorresponding

  Seizures elicited by corneal 6-Hz stimulation are widely acknowledged as a model of temporal lobe seizures. Despite the intensive research in rodents, no studies hint at this model in developing animals. We focused on seven age groups of both male and female rats. Biphasic pulses with 0.3 ms duration and current intensities from 20 to 80 mA were applied transcorneally for 3 s to calculate threshold intensities for individual age groups. Threshold stimulation intensity necessary for elicitation of clonic seizures was highly age- and sex-dependent. The highest threshold was observed in the youngest (15-day-old) group then it decreased to the age of 25 days and increased again up to adulthood. The threshold current tended to be lower in females of all age groups. The incidence of convulsive seizures increased with stimulation intensity up to postnatal day 25 in either sex. In rats of 31 days old and older convulsions occurred irregularly regardless of the stimulation current and sex. For subsequent analysis, the animals were categorized into two groups: juveniles, aged 15 to 25 days, and adolescents/adults, aged 31 days and older. Our statistical analyses revealed an increased risk of convulsions after the stimulation with higher intensities in juvenile but not adolescent/adult rats. Females tended to be more sensitive to the stimulation with lower currents than males. Seizure severity was higher in females 18- to 25-day old compared to males of the same age and the seizure duration increased with stimulation intensities in juvenile but not adolescent/adult animals. The data extend the use of the rat 6 Hz model to immature animals and may be useful as a model of pediatric temporal lobe seizures.

  PublisherOA PDFDOI

• Preclinical common data elements: a practical guide for use in epilepsy research

  Epilepsy & Behavior · 2025-10-09 · 1 citations

  articleSenior author
  PublisherDOI

• A companion to the preclinical common data elements for rigor, reproducibility and transparency in basic and translational epilepsy research. A report of the <scp>TASK3</scp>‐<scp>WG1A</scp>: Pharmacology Working Group of the <scp>ILAE</scp>/<scp>AES</scp> Joint Translational Task Force

  Epilepsia Open · 2025-06-26 · 1 citations

  articleOpen access

  Rigorous and transparent procedures in preclinical epilepsy research studies are important to permit assessing the reproducibility of their findings and derisk their translation into the clinic. The General Pharmacology Working Group of the ILAE/AES Task Force (TASK3-WG1A) developed common data elements (CDEs) addressing rigor and transparency and organized the CDEs into a case report form (CRF) to provide guidance on study planning, conduct, analysis, and reporting. CDEs specifying the type of study, use of inclusion-exclusion criteria, quantitative methods, randomization, blinding, and masking were developed and defined. This companion paper provides additional information and interpretation on the use of the rigor and transparency CDEs to assist preclinical investigators. Adoption of these CDEs and CRF will enhance data quality and transparent reporting to improve the reuse of preclinical data sets and the successful translation of preclinical epilepsy research. The materials provided in the form of CDEs, CRF, and this companion paper can be used in the research community for training purposes and to promote more rigorous conduct and transparent reporting of basic and translational epilepsy research. PLAIN LANGUAGE SUMMARY: The purpose of the Common Data Elements described in this companion paper is to improve the rigor, reproducibility, and transparency of basic and translational epilepsy research studies. Enhancing these important elements of preclinical epilepsy research will facilitate data sharing and comparisons between research laboratories and potentially the reliability of translating preclinical research findings to clinical studies that reduce the burden of disease for individuals with epilepsy.

  PublisherOA PDFDOI

• AIR Hunger—Why Amygdala Seizures Suppress Breathing

  Epiliepsy currents/Epilepsy currents · 2024-02-06 · 1 citations

  letterOpen access1st authorCorresponding

  [Box: see text]

  PublisherOA PDFDOI

Frequent coauthors

• Karen S. Wilcox

  University of Utah

  33 shared

• H. Steve White

  University of Washington

  20 shared

• Peter J. West

  University of Utah

  16 shared

• Misty D. Smith

  University of Utah

  15 shared

• Brian D. Klein

  National Institutes of Health

  12 shared

• Kristina Johnson

  Harvard University

  10 shared

• Steven L. Bealer

  University of Utah

  10 shared

• Grzegorz Bułaj

  University of Utah

  9 shared

Labs

• Metcalf LabPI

  Focusing on epilepsy, pain, and neurology research in the PharmTox department

Education

• PhD, Pharmacology & Toxicology

  University of Utah

  2008