# Circumventing the pharmacokinetic/pharmacodynamic limitations of antioxidant therapy for Parkinson's Disease by nose to brain delivery of N-acetylcysteine

> **NIH NIH R41** · NEURONASAL INC · 2024 · $478,165

## Abstract

Abstract
Parkinson’s Disease (PD) is a neurodegenerative disorder that affects over 1 million U.S. citizens. PD is most
often diagnosed in people over the age of 60, while only 4% of cases of PD are diagnosed before age 50, making
age the biggest risk factor for the development of PD. The four cardinal features of PD include tremor, rigidity,
bradykinesia, and postural instability, often associated with non-motor symptoms including depression, anxiety,
sleep behavior disorders, constipation, loss of sense of smell, and cognitive impairment. The most prominent
PD pathology is degeneration of dopaminergic neurons in the ventrolateral tier of the pars compacta of the
substantia nigra in the midbrain and the formation of α-synuclein cytoplasmic inclusions throughout the brain.
While current medical therapies for PD significantly improve the quality of life of PD patients, none of these
therapies has been convincingly shown to slow or prevent the progression of PD, requiring the development of
treatments that can provide greater neuroprotection. To address these issues, Entobee Therapeutics
proposes to repurpose N-acetylcysteine (NAC), a well-studied, safe, FDA-approved drug, to manage PD.
Given the pathogenetic role of oxidative damage in PD, Entobee hypothesizes that targeted antioxidant
intervention with NAC may reduce or halt the progressive dopaminergic neurodegeneration associated with
PD. However, the administration of NAC has limitations in both intravenous and oral forms. Thus, Entobee
proposes the creation of a novel intranasal (IN) nose-to-brain (N2B) treatment option to bypass first-pass hepatic
gastrointestinal metabolism and the blood-brain barrier (BBB) for faster outpatient and simple chronic care. The
overall objective of this Phase I project is to identify a safe IN N2B dose of NAC with equivalent or better brain
bioavailability compared to the 50 mg/kg i.v. NAC dose associated with dopaminergic improvement in PD
patients using magnetic resonance spectroscopy to measure NAC-derived GSH in disease-relevant regions of
the brain. This will be accomplished through the following aims: 1) Establish the regional (striatum, midbrain, and
cortex) and temporal (1–6 h and 24 h) single-dose bioavailability profile of 50 mg/kg i.v. NAC in PD patients, 2)
Compare the single-dose bioavailability and safety profiles of 200 mg and 400 mg IN N2B NAC versus 50 mg/kg
i.v. NAC bioavailability profile in PD patients, 3) Confirm the single-dose safety and tolerability of an equally
bioavailable IN N2B NAC dose in PD patients.

## Key facts

- **NIH application ID:** 10920628
- **Project number:** 1R41AG087860-01
- **Recipient organization:** NEURONASAL INC
- **Principal Investigator:** Douglas Greene
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $478,165
- **Award type:** 1
- **Project period:** 2024-09-25 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920628

## Citation

> US National Institutes of Health, RePORTER application 10920628, Circumventing the pharmacokinetic/pharmacodynamic limitations of antioxidant therapy for Parkinson's Disease by nose to brain delivery of N-acetylcysteine (1R41AG087860-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10920628. Licensed CC0.

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