Date of Award

12-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Tauheed Ishrat, PhD

Committee

Hassan Almoazen, PhD; Tauheed Ishrat, PhD; Santosh Kumar, PhD; Dennis Leo, PhD; Michelle Puchowicz, PhD

Keywords

Cell Survival;HIV-1 Infection;Inflammation;Ischemic Stroke;LM11A-31;P75NTR

Abstract

The objective of this research project is to explore the potential therapeutic role of LM11A-31 in both ischemic stroke and human immunodeficiency virus-1 (HIV-1) infection. There are limited treatment options for ischemic stroke, with tissue plasminogen activator (tPA) being the only effective medication and a narrow administration window, which is also accompanied with the high incidence of ischemic stroke in HIV-1 infected individuals. Therefore, it is critical to explore an effective therapeutic agent to address the urgent medical need. LM11A-31 is a p75 neurotrophin receptor (p75NTR) modulator and is orally bioavailable, and it can penetrate the intact blood-brain barrier (BBB). It is in phase II clinical trials for the treatment of mild to moderate Alzheimer’s disease. As p75NTR upregulation has been reported in both ischemic stroke and HIV-1 infection, LM11A-31 could be a potential therapeutic in these disease states. This study illustrated that pharmacological regulation of p75NTR with LM11A-31 or genetic knocking down p75NTR significantly improves the outcome of ischemic stroke in mice through mitigating cerebral infarction, edema, and hemorrhagic transformation. Additionally, this research revealed that modulation of p75NTR attenuates inflammatory and cell apoptosis markers, including NF-B, JNK/RhoA, Akt, GSK3, and Bcl-2/Bax. P75NTR modulation also improved the neurobehavioral function of animals, which were assessed using Catwalk analysis. This research also demonstrated that LM11A-31 improves HIV-1 pathogenesis in U1 macrophages via reducing viral replication, cytotoxicity, and pro-inflammatory markers, which was comparable to the positive control darunavir. Furthermore, LM11A-31 did not alter the protein level of Akt, Beclin-1, and oxidative stress enzymes, including SOD-1 and catalase. Overall, this study provides new insights into the efficacy of LM11A-31 in treating both ischemic stroke and HIV-1 infection. HIV-1-infected individuals are more suspectable to develop cerebrovascular diseases, including ischemic stroke, than non-infected individuals. Due to the limited ability of antiretroviral drugs to cross the BBB and achieve therapeutic concentration, LM11A-31 is a promising treatment for reducing HIV-1 pathogenesis, including neuroHIV-1, and cerebrovascular events. Further research is needed to investigate the safety and efficacy of LM11A-31 in dual animal models of ischemic stroke and HIV-1 infection before progressing to clinical trials.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0002-2672-394X

DOI

10.21007/etd.cghs.2023.0638

Additional Files
2023-033-Mirzahosseini-DOA.pdf (209 kB)
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