Blood–Brain Barrier Permeability Study of Potential Neuroprotective Compounds Recovered From Plants and Agri-Food by-Products

Abstract

Plants and agri-food by-products represent a wide and renewable source of bioactive compounds with neuroprotective properties. In this research, various green extraction techniques were employed to recover bioactive molecules from Kalanchoe daigremontiana (kalanchoe), epicarp of Cyphomandra betacea (tamarillo), and cooperage woods from Robinia pseudoacacia (acacia) and Nothofagus pumilio (lenga), as well as a reference extract (positive control) from Rosmarinus officinalis L. (rosemary). The neuroprotective capacity of these plant extracts was evaluated in a set of in vitro assays, including enzymatic [acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and lipoxygenase (LOX)] and antioxidant [ABTS, and reactive oxygen and nitrogen species (ROS and RNS)] bioactivity tests. Extracts were also submitted to a parallel artificial membrane permeability assay mimicking the blood–brain barrier (PAMPA-BBB) and to two cell viability assays in HK-2 and SH-SY5Y cell lines. Comprehensive phytochemical profiling based on liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) analysis showed enriched content of phenolic and terpenoid compounds in the target extracts. Moreover, in vitro bioactivity tests showed promising neuroprotective capacity, particularly for supercritical-fluid extraction (SFE) extract from acacia (ABTS IC50 = 0.11 μg ml−1; ROS IC50 = 1.56 μg ml−1; AChE IC50 = 4.23 μg ml−1; BChE IC50 = 1.20 μg ml−1; and LOX IC50 = 4.37 μg ml−1), whereas PAMPA-BBB assays revealed high perfusion capacity of some representative compounds, such as phenolic acids or flavonoids. Regarding cytotoxic assays, tamarillo and rosemary SFE extracts can be considered as non-toxic, acacia SFE extract and lenga pressurized liquid extraction (PLE) extract as mild-cytotoxic, and kalanchoe as highly toxic extracts. The obtained results demonstrate the great potential of the studied biomass extracts to be transformed into valuable food additives, food supplements, or nutraceuticals with promising neuroprotective properties.

By-Product Extracts from Castanea sativa Counteract Hallmarks of Neuroinflammation in a Microglial Model

“…Recently, an artificial membrane permeability assay (PAMPA-BBB) was adopted to assess the blood-brain barrier penetration of pharmacologically active natural products and plant extracts. The study by Sanchez-Martinez et al [ 55 ] reported the PAMPA-BBB potential penetrability of 113 different compounds extracted from different plant matrices, among which isorhamnetin, kaempferol and quinic acid (present also in our chestnut extracts) resulted able to cross the blood–brain barrier potential, provided that the molecular structure does not contain sugars moieties. Other factors are responsible for the poor availability of flavonoids in vivo, such as their metabolic and microbial transformation, as reported in [ 56 , 57 ].…”

Natural Products as Modulators of Nrf2 Signaling Pathway in Neuroprotection

“…Currently, efforts are underway to identify new plant sources with potential neuroprotective properties. This includes trials to assess their efficacy by evaluating their ability to penetrate the BBB [ 141 ]. Moreover, efforts are underway to improve the delivery of natural products with low BBB permeability, such as curcumin, through the use of nanoparticles [ 142 ] or the direct synthesis of chemically modified analogs with improved permeability [ 143 ].…”

Dietary (Poly)phenols and Cognitive Decline: A Systematic Review and Meta‐Analysis of Observational Studies

“…[ 68 ] Phenolic acids demonstrated a combination of antioxidant and anti‐inflammatory properties through a variety of pathways, including mitogen‐activated protein kinase (MAPK) and NF‐κB signaling pathways and inhibition of pro‐inflammatory cytokines production, such as TNF‐α, IL‐6, and IL‐1, reducing COX‐2 and iNOS, and stimulating the release of neurotrophic factors. [ 68 ] The hypothesized neuroprotective effects of phenolic acids also include their capacity to inhibit the anti‐aggregation of the proteins implicated in the pathogenesis of various neurodegenerative diseases, including dementia and Alzheimer's disease. [ 69 ] Current observational data are still scarce to draft any conclusions, but the general findings are promising, and further studies are encouraged on these groups of molecules and their major dietary sources to elucidate whether they may play a role in preventing cognitive decline.…”

“…[67] From a mechanistic point of view, phenolic acids demonstrate an excellent capacity to pass through the blood-brain barrier and exert potential direct activity on the human brain. [68] Phenolic acids demonstrated a combination of antioxidant and antiinflammatory properties through a variety of pathways, including mitogen-activated protein kinase (MAPK) and NF-𝜅B signaling pathways and inhibition of pro-inflammatory cytokines production, such as TNF-𝛼, IL-6, and IL-1, reducing COX-2 and iNOS, and stimulating the release of neurotrophic factors. [68] The hypothesized neuroprotective effects of phenolic acids also include their capacity to inhibit the anti-aggregation of the proteins implicated in the pathogenesis of various neurodegenerative diseases, including dementia and Alzheimer's disease.…”