# Validation of a novel animal model of post-traumatic epilepsy

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2022 · —

## Abstract

PTE (posttraumatic epilepsy) has been identified by the VA as a priority area for
research. Current medical therapy for this condition is inadequate. No anticonvulsant has yet
been demonstrated to be specifically effective against PTE. The animal model used for
screening anticonvulsants (AEDs) greatly influences which compounds are identified. One
consequence is that standard animal models seem to consistently identify compounds with
similar actions. Since there is no good PTE animal model, AEDs especially effective for PTE
have not been identified. Evidence of the benefits of novel animal models is the identification of
levetiracetam (Keppra), currently the most prescribe drug for epilepsy. The more standard
animal models had failed to identify its antiepileptic activity. Current PTE animal models such as
lateral fluid percussion and controlled cortical impact are not practical for screening AEDs
because the timing of seizures cannot be controlled.
 We have developed a model of penetration injury induced epilepsy. It is a variation on the
theme of Dave Prince’s partial cortical isolation PTE model. The current model solves two critical
weakness of the cortical undercutting model by utilizing the simpler anatomy of the
hippocampus. First, sectioning the Schaffer Collateral that connect the CA3 and CA1 region of
the rat hippocampus can create a region that predominantly contains reactive presynaptic
changes (i.e. aberrant synaptic reorganization) and a region that contain postsynaptic changes
(deafferentation induced dendritic hyperexcitability). This segregation of reactive mechanisms
cannot be achieved in the cortex. Consequently, it makes it possible to more easily dissect the
underlying complex mechanisms of PTE. Secondly, sectioning of the Schaffer Collateral does
NOT block the spread of seizure from the seizure focus, as is the case with the cortical
undercutting model. Thus, behavioral seizures can be observed. A third advantage from a drug
discovery perspective is that, similar to the kindling model, seizures can be reliably evoked by a
weak triggering electrical stimulus. This is operationally important for drug screening. One
cannot wait for a seizure to occur when screening drugs. A useful animal model has to produce
seizures on demand. In preliminary studies we have gathered compelling evidence that this
novel PTE animal model can reliably produce behavioral and electrographic limbic seizures on
demand.
 At this moment a compelling and unusual opportunity exists for a successful rational drug
development. A novel therapeutic target for PTE, dendritic SK2 channels, has been identified. A
novel animal model of PTE possessing the latter dysfunction has been developed. And a class of
SK2 enhancers that can reverse that dysfunction has been discovered. We seek to make the
most from the confluence of these discoveries and the opportunity they offer.

## Key facts

- **NIH application ID:** 10477237
- **Project number:** 5I01BX004973-03
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Cha-Min Tang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477237

## Citation

> US National Institutes of Health, RePORTER application 10477237, Validation of a novel animal model of post-traumatic epilepsy (5I01BX004973-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477237. Licensed CC0.

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