Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

Abstract

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

Polyphenol Rich Ajuga bracteosa Transgenic Regenerants Display Better Pharmacological Potential

“…Inflammation and neurodegeneration are often associated in neurological disorder [37]. Different studies suggest that polyphenols, alkaloids, terpenoids, steroids, and lignans can attenuate the inflamed and damaged BBB thus acting as curative agent against neurovegetative disorders [38,39] Previously, ferulic acid was physiologically detected in the cerebrospinal fluid (CSF) of mice and rat [40,41]. Interestingly, a recent study demonstrated the presence of non-endogenous caffeic acid in the human CSF.…”

A novel in vitro assay model developed to measure both extracellular and intracellular acetylcholine levels for screening cholinergic agents

“…Second, we used doses of drugs and food constituents up to 100 μM or 100 μg/mL because our main objective was to compare the response of intracellular and extracellular ACh. Given the metabolic process and existence of the blood–brain barrier, it is unlikely for some drugs and food constituents evaluated in this study to reach the brain at such doses [ 43 ]. The assay model described here should serve as a preliminary in vitro screen, and further in vivo and clinical studies are needed to clarify whether the candidates selected using this screening model could improve ACh transmission, neural plasticity, and even cognitive function.…”

Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities

“…However, the presence of the BBB severely prevents most drugs such as many polyphenols from entering the brain to exert their effects [386]. Although a large number of studies have shown that some plant polyphenols can cross the BBB and reach the brain to exert a neuroprotective effect, there are still many polyphenols reported having indirect beneficial effects in neurodegenerative diseases [387][388][389]. There is growing evidence of stronger two-way communication between the gut and the brain through the neural, endocrine, and immune systems, called the brain-gut axis [390].…”

“…Recent studies have shown a tight association between dysbiosis of the intestinal flora and several neurodegenerative diseases, such as AD and PD [391]. Therefore, targeting regulation of the intestinal microbiota is an important strategy for the treatment of neurodegenerative diseases [389]. For example, it has been found that curcumin plays a neuroprotective role by affecting intestinal microorganisms [392].…”