Neuroprotective Effects of Direct Peptide Nutraceuticals

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Among the different types of nutraceuticals, direct peptides are especially interesting because they are metabolised rapidly by DPP-4 enzyme and subsequently enter the bloodstream as metabolically active metabolites with multiple beneficial effects including neuroprotection. However, only very few of the circulating metabolites are considered to interact with GLP-1 receptor and therefore exert a direct effect on the inhibition of microglial activation and subsequent neuroprotection.

In this study we investigated the effectiveness of a group of peptide nutraceuticals by testing their ability to modulate glial responses in an Alzheimer’s disease (AD) animal model. The rat hippocampus is an appropriate animal model as it amplifies proinflammatory microenvironments and over-suppresses anti-inflammatory responses. Glial morphology and viability were measured for peptide-injected animals as well as PBS- and reverse-peptide-injected controls to enable correlating glial responses with neuroprotective efficacy.

The DPRA-cys and the kDPRA were both adopted by the OECD in 2021 as alternative test methods for predicting whether chemicals should be assigned to a sensitiser potency class on the basis of their electrophilic reactivity. The DPRA-cys and kDPRA predictions combine results from two in vitro cell-based assays (the mouse local lymph node assay and the human dermal contact irritant assay, both developed in the 1990s) to determine if a chemical is predicted to be a sensitiser.

The DPRA-cys and/or kDPRA are designed to assess the reactivity of chemicals to a synthetic peptide consisting of a cysteine and a lysine unit. The reactivity of a chemical is calculated from the peptide depletion observed after exposure to the chemical and the logkmax values derived from this assay. This approach makes an implicit assumption that the potency of a compound is solely related to its reactivity and that it cannot be determined from any other property such as hydrophobicity. This is not always the case and for example trimellitic anhydride and phthalic anhydride (both acyl transfer agents) their reactivity in the DPRA-cys assay is similar, but their reactivity in the kDPRA assay is quite different and they differ substantially in their overall hydrophobicity.

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