A big concern of our society is to efficiently delay the onset of neurodegenerative diseases, which are progressively rising in incidence. The paradigm that a diet rich in the phenolics is beneficial to brain health has reached the public. However, their mechanistic actions in brain functions remain to be seen, particularly since the nature of those acting in the brain remains overlooked. LIMBO’s project addresses this gap by identifying candidate compounds that can support development of effective strategies to delay neurodegeneration. We have been analysing the potential of dietary phenolics in both prevention and treatment of neuroinflammation. We are focused on the low molecular weight (poly)phenol metabolites (LMWPM) derived from dietary phenolics and study their brain permeability and effects in both established and unknown response pathways of microglia cells either alone or when communicating with other brain cells.
The project’s 3 main objectives are:
- Identify LMWPM in brain and screen their capability to attenuate microglia-mediated neuroinflammation
- Elucidate the molecular mechanisms mediating the effects of LMWPM in brain cells undergoing inflammation
- Attain an integrated perception of dietary phenolics effects in mice models of neuroinflammation and Parkinson’s disease.
We listed all described LMWPM and reviewed the molecular mechanisms underlying their effects in the brain and their specific role on neuroinflammation identifying the gaps. We also gather the sparse data available for the brain bioavailability of these LMWPM including evidence of crossing blood brain barrier in silico, in vitro and in vivo. Based on this we updated our library with all described LMWPM either acquiring commercially or by synthesis.
To get a comprehensive overview of LMWPM neuroprotective effects towards neuroinflammation we screen their anti-neuroinflammatory properties to protect microglia cells from a strong inflammatory insult by monitoring the release of pro-inflammatory cytokines and neurotoxic factors. Kinetics and dose response of their protective effects using near-physiological conditions of both concentration and residence time for each metabolite was established.
The brain permeability of all LMWPM was evaluated in silico and for the 3 compounds with higher activity, its brain permeability was confirmed in vivo. Compounds were injected intravenously at post-absorption physiological levels. Brain extracts were analysed for detection of the LMWPM and their end-route metabolites by untargeted metabolomics.
We aim to use specific LMWPM to study new routes of their metabolism inside the brain and push our knowledge on the neuroactive molecular mechanisms of the novel end-route metabolites. LIMBo will provide valuable scientific insights for future implementation of healthy brain diets and the potential use of phenolic metabolites as prodrugs.
ERC-2018-Starting grant (N° 804229) PI- Cláudia N Santos