# Novel presynaptic agents to prevent glutamate-induced neural injury

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2024 · $313,433

## Abstract

Temporal lobe epilepsy is the most common form of focal (partial) or location related epilepsy. It
affects about 60 percent of all people with epilepsy and can occur at any age. The kainic acid model of
temporal lobe epilepsy has greatly contributed to the understanding of the molecular, cellular and
pharmacological mechanisms underlying epileptogenesis. This model presents with neuropathological features
that are seen in patients with temporal lobe epilepsy. There are many potential causes, and often the exact
cause is unknown. Excessive presynaptic glutamate (Glu) release causes excessive stimulation of NMDA
receptors that is implicated in many CNS disorders that result in acute and chronic neurodegeneration
including epilepsy. Mechanisms to reduce excessive synaptic Glu release under these conditions could
potentially prevent/reduce excitotoxic damage to vulnerable hippocampal neurons. Current treatment options
to prevent excessive Glu release are limited and most post-synaptic interventions in human studies have been
disappointing because of poor efficacy or unacceptable side effects. Under normal conditions, maintenance of
synaptic cytoplasmic Glu levels (~2mM) required for vesicular filling is via α-ketoglutarate-derived Glu
synthesis. The scientific premise for the proposed project is that glutamine (Gln) is a precursor for Glu
synthesis under high synaptic activity because under increased excitatory activity Gln is imported into axon
terminals from glia where it is synthesized. Hence, Na+-dependent Gln import into neurons from glia to
replenish synaptic cytoplasmic Glu stores under high synaptic activity is a potential novel target to prevent
excessive Glu release under excitotoxic conditions. We have recently discovered a neuronal activity-regulated
Gln transporter expressed in excitatory synapses that is potently inhibited by riluzole, a benzothiazole
compound that is believed to inhibit excessive Glu release from synapses. A critical barrier to progress in
understanding the presynaptic mechanisms involved in excessive Glu release has been the lack of molecular
information about the transporter that mediates K+-stimulated, activity-regulated Gln import into excitatory
synapses. In addition, the role of activity-regulated Gln transport in synapses to support excessive Glu release
and neural injury has not been revealed and potential therapeutic agents that target activity-regulated Gln
transport in synapses and that are neuroprotective, more selective, brain penetrant, with fewer side effects
than riluzole have not been developed. This project has important implications in advancing basic
understanding of the neurobiology of excessive synaptic release of Glu, Glu/Gln cycling between neuronal and
glial synapses, and Glu-induced neuronal excitotoxicity. Resolution of this missing link of the role for activity-regulated Gln transport in synaptic Glu synthesis in hippocampal neurons provide the basis for studies in in
vitro and in vivo model...

## Key facts

- **NIH application ID:** 10756170
- **Project number:** 5R01NS113955-05
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** JEFFREY D ERICKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $313,433
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756170

## Citation

> US National Institutes of Health, RePORTER application 10756170, Novel presynaptic agents to prevent glutamate-induced neural injury (5R01NS113955-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10756170. Licensed CC0.

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