# Therapeutic efficacy of Ibudilast to attenuate inflammation at the synapse

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $190,625

## Abstract

Abstract
Despite earlier studies that have shown the overall impact of inflammation and excitotoxicity induced by HIV and
methamphetamine (meth) in the progression of HIV-Associated Neurocognitive Disorders, a significant gap that
remains is identifying synaptic protein targets including their modulation by therapeutic drugs to ameliorate such
inflammatory responses and glutamate excitotoxicity at the synapse. This R21 proposal focuses on one such
synaptic target phosphatidylethanolamine-binding protein 1 (PEBP1) which we have identified from a previous
study and whose reduced expression by HIV (Tat, gp120) and meth was reversed by treatment with the anti-
inflammatory drug Ibudilast, a phosphodiesterase inhibitor. Based on the synaptic localization of PEBP1, we
tested a more causal effect of knock down of PEBP1 using siRNA on mixed cerebrocortical cultures that
comprise of differentiating neurons and astrocytes. We treated 14 days in vitro (DIV14) mixed cerebrocortical
cultures with siRNA against PEBP1 followed by Tat/meth treatments alone and in combination for 24h. In parallel,
a subset of 24h Tat/meth treated cultures were given ibudilast treatment for 24h. Tat and meth in combination
decreased the expression of the glutamate transporter EAAT2 and a concurrent increase in the vesicular
glutamate transporter 1 (vGLUT1) in the lysates by western blot thus suggesting excitotoxicity. This increase in
glutamate levels corroborated with increase in the levels of the proinflammatory cytokines IL6 and TNF-in the
cell supernatants as determined by ELISA. Interestingly, these effects were attenuated in cultures treated with
Ibudilast for 24h. Based on the well-established dogma of inflammation and excitotoxicity by HIV and meth, we
hypothesize that PEBP1 down regulation by HIV and meth increases inflammation and glutamate toxicity thus
exacerbating synaptodendritic damage which can be reversed by ibudilast treatment. We will examine our
hypothesis in an in vitro model of mixed cerebrocortical cultures complemented by a tractable preclinical animal
model system HIV-Tg rat using biochemical, molecular, imaging and electrophysiological approaches. To
summarize, our studies have identified a potential synaptic protein target and an anti-inflammatory drug with a
therapeutic efficacy to mitigate aberrations associated with its downregulation at the synapse during HIV and
meth induced CNS dysfunction.

## Key facts

- **NIH application ID:** 9904613
- **Project number:** 5R21DA046284-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Gurudutt Pendyala
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2019-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904613

## Citation

> US National Institutes of Health, RePORTER application 9904613, Therapeutic efficacy of Ibudilast to attenuate inflammation at the synapse (5R21DA046284-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9904613. Licensed CC0.

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