Dissertation
Investigating the neuroprotective effects of naltrexone, a mu-opioid receptor antagonist, in juvenile mouse models of epilepsy
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008448
Abstract
Epilepsy can be generated in many different models which allow us to study new potential therapeutic compounds. Although there are over 40 drugs developed to treat epilepsy, there is still over a third of patients unable to relieve their seizure burden. It was recently identified that naltrexone, a mu opioid receptor (MOR) antagonist, had anticonvulsant properties that could potentially treat those suffering from epilepsy. We further investigated these properties in two different forms of epilepsy models: traumatic brain injury (TBI) and chemoconvulsants.
We began by utilizing a TBI mouse model to develop an automated algorithm able to rapidly quantify EEG data as well as a mode to study the anticonvulsive effects of naltrexone. This novel algorithm was able was able to detect spiking activity, interictal events and electrographic seizures from EEG data faster and more accurately than manual inspection. With the TBI model we were able to demonstrate MOR increases following injury. This soon led to a cascade of increasing inflammation in both the central nervous system (CNS) and periphery based on RT-PCR and serum analysis respectively. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation and neurodegeneration both acutely and chronically. Video EEG was able to demonstrate a higher number of interictal events with 71% of mice developing post-traumatic seizures. The addition of naltrexone ameliorated neuroinflammation, neurodegeneration, white matter microvascular alteration, reduced interictal events and prevented epilepsy altogether.
Following TBI we began working with the chemo convulsant pilocarpine to produce a temporal lobe epilepsy (TLE) model in wildtype (WT) and a constitutive MOR knockout (KO) mice. The single high dose model was able to produce low numbers of interictal events and electrographic seizures which were unaffected by the addition of naltrexone. Lack of an MOR also demonstrated no significant difference. The concentration for a single high dose of pilocarpine was increased to assess mortality but there was no difference between treatment and injury group. Seizure severity was then assessed using graded pilocarpine administration in both WT and MOR KO mice which were reduced with the addition of naltrexone.
Following this, maximal electroshock (MES) was used to assess seizure severity and mortality in both WT and MOR KO mice. Naltrexone was able to reduce seizure severity at low electrical stimulation but there was no difference in mortality. Lastly, mRNA studies demonstrated that a single high dose of pilocarpine was incapable of producing an inflammatory phenotype in WT mice which sheds light on a possible mechanism by which naltrexone prevents epilepsy.
Ultimately, our results illustrate that naltrexone is a promising antiepileptic drug capable of reducing neuroinflammation and epileptogenesis to help further treat epilepsy.
Details
- Title: Subtitle
- Investigating the neuroprotective effects of naltrexone, a mu-opioid receptor antagonist, in juvenile mouse models of epilepsy
- Creators
- Saul Rodriguez
- Contributors
- Alex Bassuk (Advisor)Gordon Buchanan (Committee Member)Joseph Glykys (Committee Member)Levi Sowers (Committee Member)Hanna Stevens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008448
- Publisher
- University of Iowa
- Number of pages
- xiv, 105 pages
- Copyright
- Copyright 2023 Saul Rodriguez
- Language
- English
- Date submitted
- 04/20/2026
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 90-105).
- Public Abstract (ETD)
Currently, there are millions of people suffering from epilepsy with a third unable to attain any form of seizure management. To ameliorate the seizure burden, studies must be done to identify novel therapies to treat their affliction. Here we try to repurpose naltrexone, a muopioid receptor antagonist previously used to treat binge drinking and opioid addiction, into a new therapeutic by testing it against different epilepsy models.
We first began by looking at naltrexone’s effects on epilepsy that developed in mice following a TBI. When looking at the cells in the brain responsible for inflammation, we found that naltrexone was able to reduce their numbers both in the short and long term. We also demonstrated there was less neuronal death and injury when mice were given naltrexone following the TBI. Ultimately there was less epilepsy occurring in the mice given naltrexone compared to the mice that were not.
In a different model where we used a chemical to induce a brain injury and given multiple times, naltrexone was able to reduce the seizure severity in both male and female mice. When the receptor that naltrexone primarily works on was removed, we found naltrexone was still able to reduce the severity of seizures. This indicated that naltrexone worked through a different mechanism than previously thought. Identifying the mechanisms that naltrexone works through will be crucial in developing effective therapies.
Overall, our work has demonstrated that naltrexone could be a potential new treatment for those suffering from epilepsy.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9985176872002771
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