preprints.org > medicine and pharmacology > pharmacology and toxicology > doi: 10.20944/preprints202302.0173.v1

Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 8 February 2023 / Approved: 10 February 2023 / Online: 10 February 2023 (02:31:56 CET)

This article proposes the use of intranasal rifampin as a means to improve protein homeostasis and disaggregate misfolded proteins in the age-related neurodegenerative proteinopathies. Alzheimer’s disease, Parkinson’s disease, multi-system atrophy, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease are all, at the core, proteinopathies. Although these diseases varying greatly in the specific disease-associated proteins, anatomic sites of the abnormal protein deposition and clinical presentations, what they have in common is disruption of normal “housekeeping” functions related to protein homeostasis, proteostasis. The prospect of pharmacologically augmenting autophagic capacity with a known drug repurposed to improve proteostasis is attractive; to accomplish these ends with an inexpensive drug with relative ease of delivery adds to the attractiveness. Rifampin can be delivered to the brain via the intranasal route. Rifampin has been used for decades primarily against mycobacterial infection; it has been given with intravenous, oral, intrathecal and topical routes including as eyedrops and nasal spray. Rifampin disaggregates toxic oligomers in vitro; given intranasally, rifampin improves memory and clears pathologic proteins in animal models of the proteinopathies. Rifampin acts as both a gatekeeper and a housekeeper against the abnormal proteins of these diseases. This article suggests the merit of a clinical trial with intranasal rifampin to boost protein homeostasis in the most common age-related neurodegenerative proteinopathy, Alzheimer’s disease. The primary outcome of such a trial is change in risk of Alzheimer’s pathology as measured by plasma-based amyloid peptide 42/40 testing pretreatment and follow-up testing after 6 months of intranasal rifampin.

ifampin; proteinopathies; permeability glycoprotein; intranasal; bi-directional; Alzheimer’s; Parkinson’s; Lewy body dementia; multiple system atrophy; huntington’s; amyotrophic lateral sclerosis/frontotemporal dementia spectrum

Medicine and Pharmacology, Pharmacology and Toxicology

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