# Identification of small molecules for neurological complications of HIV and substance abuse comorbidity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $442,914

## Abstract

Summary
 HIV-associated neurocognitive disorders and substance abuse comorbidity remain prevalent despite
combination antiretroviral therapy (cART). The scientific literature as well as gene expression results from our
group suggest a degree of pathogenic similarity and possibly overlap between neurodegeneration in neuroHIV
and Alzheimer’s Disease (AD).
 Trophic factors are beneficial in animal and in vitro models of neuroAIDS. However, neurotrophic factors
and other growth factors are unsuitable neuropharmaceuticals because of their peptidic nature that limits
needed drug-like properties, including oral absorption, plasma stability, and brain penetration. The innovative
hypothesis behind the parent grant is that small molecules can be identified that can reverse trophic deficits
that characterize HANDs and manifest as synaptodendritic and mitochondrial injury and can effectively prevent
or ameliorate cognitive decline in HIV and compulsive drug taking. To test this hypothesis, studies under the
parent grant performed a high-throughput screening campaign (HTS) to identify inducers of a gene regulatory
mechanism that broadly regulates trophic support and mitochondrial biogenesis in key cortical and
hippocampal neuronal populations and that we found to be downregulated in both neuroAIDS and substance
dependence.
 Deficient trophic support involving reduced activity of neurotrophins has also been implicated in AD
neurodegeneration. Consistent with these findings, delivery of neurotrophins proved beneficial in AD animal
models. Here we propose to test the small molecules identified in the parent grant for neuroAIDS in rodent
models of AD as candidate therapeutics to promote improved neuronal trophic support. To this end we will test
the ability of the lead compounds identified to prevent or ameliorate cognitive impairment in two transgenic
rodent models of AD, the McGill-R-Thy1-APP rats (hAβPPswe,ind) and the triple transgenic AD (3xTg-AD)
mice (Tg(APPSwe,tauP301L)1Lfa). We will explore the ability of the new compounds identified under the
parent grant to delay or prevent AD progression and to revert the gene expression signatures associated with
AD in the animal models under study.
 Ultimately, the proposed therapeutic strategy is expected to make neurons more resilient through
improved tropic support by means of small molecules, resulting in reduced neuronal injury and improved
cognitive performance in AD. The parent grant does not propose AD animal models, nor any AD-focused
experiments and the PI has no AD-related funds. The results of the present Administrative Supplement will lay
the foundations for a new R01 proposal aimed at further advancing the development of a series of compounds
currently being established for neuroAIDS for the prevention and treatment of AD.

## Key facts

- **NIH application ID:** 10498564
- **Project number:** 3R01DA046204-05S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,914
- **Award type:** 3
- **Project period:** 2018-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498564

## Citation

> US National Institutes of Health, RePORTER application 10498564, Identification of small molecules for neurological complications of HIV and substance abuse comorbidity (3R01DA046204-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10498564. Licensed CC0.

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