Indolepropionamide

IPAM, short for indolepropionamide or indole-3-propionamide, is a small indole amide: indole-3-propionic acid (IPA) with its carboxylic acid group replaced by an amide (PubChem CID 351791). IPA is a tryptophan metabolite made by gut bacteria (Wikoff et al., 2009); IPAM is a separate compound.

PubMed indexes one primary study of IPAM itself, which made it from IPA, reported it as a naturally occurring indole in rat brain, and tested it in rodent brain mitochondria and rotifer cultures (Poeggeler et al., 2010).

Published work relevant to IPAM falls into six areas. The first three cover IPAM itself, all from one 2010 paper by a single laboratory. The last three cover its parent acid, IPA, and synthetic derivatives, labeled as related compounds whose findings do not transfer to IPAM.

IPAM in rat brain: design and detection

The authors added an amide group to IPA to make a more membrane-permeable molecule, then reported HPLC peaks in rat brain matching synthetic IPAM. Baseline levels were below about 100 pg per mg of protein; one hour after an oral L-tryptophan load of 300 mg/kg, brain IPAM measured about 346 pg per mg.

In rats given 0.5 mg/kg IPAM intraperitoneally, brain IPAM reached about 691 pg per mg at 2 hours and 361 at 8 hours, while the same amounts of melatonin or IPA did not raise their own brain levels (Poeggeler et al., 2010). Model: young male Sprague-Dawley rats.

Mitochondria and the respiratory chain

In brain mitochondria from 1-month-old and 20-month-old rats, membrane potential was lower with age, and IPAM, melatonin and IPA at 10 nM each raised it, IPAM the most. IPAM at 10 nM also blunted the collapse of membrane potential caused by doxorubicin, antimycin A and the uncoupler FCCP. In mouse brain mitochondria, IPAM raised complex I and complex IV activity. The authors proposed that IPAM binds the rate-limiting component of complex I, but the ligand displacement data behind that claim were not shown (Poeggeler et al., 2010). Models: isolated rat and mouse brain mitochondria.

Hydroxyl radicals and rotifer cultures

In a cell-free hydroxyl radical system, IPAM was the most potent indole tested and, like IPA, formed no pro-oxidant intermediates. In rat forebrain homogenate, the concentration that halved hydroxyl radical DNA damage was 0.18 µM for IPAM, against 1.4 µM for melatonin and 7.46 µM for IPA.

In cultures of the rotifer Philodina acuticornis odiosa, IPAM at 10 to 30 µM raised mean lifespan from 24.6 days to between 58.5 and 90.5 days, with larger bodies and more offspring (Poeggeler et al., 2010). Groups held 10 or 11 rotifers, and PubMed lists no independent replication. Models: cell-free chemistry, rat brain homogenate, rotifers.

IPA, the gut-microbial parent acid (related compound)

In mice, IPA production depended entirely on gut bacteria: germ-free animals lacked it, and colonization with Clostridium sporogenes established it (Wikoff et al., 2009). A genetic study traced IPA to a reductive tryptophan pathway in C. sporogenes. Disrupting its fldC gene abolished IPA, mice colonized with the wild-type strain had serum IPA near 80 µM against undetectable levels with the mutant, and the screen found further IPA-producing gut bacteria (Dodd et al., 2017). Models: germ-free and gnotobiotic mice, bacterial cultures.

IPA in barrier, antioxidant and mitochondrial models (related compound)

Most of the gut-brain axis and intestinal barrier interest attached to IPAM comes from IPA. In mice, IPA together with indole acted as a pregnane X receptor (PXR) ligand, lowered enterocyte TNF-alpha and raised junctional protein mRNAs, and PXR-deficient mice had a leaky barrier (Venkatesh et al., 2014).

Two of the IPAM authors had earlier reported IPA as a diffusion-rate hydroxyl radical scavenger that limited lipid peroxidation in rat striatum (Poeggeler et al., 1999) and as protective for neurons exposed to amyloid beta (Chyan et al., 1999). In HL-1 cardiomyocytes, acute IPA raised maximal mitochondrial respiration by about 22%, while chronic exposure lowered it by about 19% (Gesper et al., 2021). Models: mice, rat brain tissue, neuronal and cardiomyocyte cultures.