# Altering the development of epilepsy through CB2R activation

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $416,112

## Abstract

PROJECT SUMMARY
Temporal lobe epilepsy (TLE) is the most common form of refractory human epilepsy, and mesial temporal lobe
epilepsy (MTLE) is the most common form of TLE. MTLE is characterized by focal seizures, neuropsychological
deficits, neuroinflammation, and hippocampal alterations that include neuronal loss. MTLE is often refractory to
available antiepileptic drugs (AEDs), creating a need for the development of treatments that can more effectively
mitigate the broad spectrum of clinical features associated with MTLE, while minimizing unwanted side effects.
It is increasingly recognized that dysregulated neuroinflammatory responses can contribute to the pathogenesis
of several forms of epilepsy, including MTLE, and is thus an important consideration in the development of new
drug targets. Cannabinoid 2 receptors (CB2Rs) are receiving increasing attention for their ability to safely confer
anti-inflammatory and neuroprotective properties in models of neurological disorders such as traumatic brain
injury and stroke. While much less research has been conducted on the role of CB2Rs in epilepsy, pre-treatment
with CB2R agonists has been shown to increase resistance to acutely induced seizures in mice. In addition, we
provide Preliminary Data demonstrating that CB2R knockout mice are seizure susceptible, and resistance to
induced seizures in wildtype mice is increased following the administration of EC21a, a novel CB2R positive
allosteric modulator (PAM). Given that reactive gliosis and increased pro-inflammatory cytokine release in MTLE
are important contributors to the development of spontaneous seizures, we hypothesize that that activation of
CB2Rs will effectively ameliorate these inflammatory changes thereby reducing seizure generation and co-
morbid behavioral abnormalities in MTLE. We will test this hypothesis by evaluating and comparing the ability of
two CB2R selective compounds, JWH-133 (a CB2R agonist) and EC21a (a PAM), to reduce inflammation and
neuron loss (Aim 1) and to mitigate the development of spontaneous seizures and behavioral abnormalities (Aim
2) in the intrahippocampal-kainic acid (IH-KA) mouse model of MTLE. We will also compare the effect of early
and delayed treatment initiation. If successful, this proposal will establish the potential of CB2Rs as a novel
therapeutic target for the treatment of MTLE and potentially other forms of epilepsy associated with significant
neuroinflammation.

## Key facts

- **NIH application ID:** 10072354
- **Project number:** 1R21NS117113-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew P Escayg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,112
- **Award type:** 1
- **Project period:** 2020-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072354

## Citation

> US National Institutes of Health, RePORTER application 10072354, Altering the development of epilepsy through CB2R activation (1R21NS117113-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072354. Licensed CC0.

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