Molecular characterization of neuroprotective activities of plant based products could revive their utilization and lead discovery of new drug candidates for brain diseases

A plethora of flora in nature, a gift to the mankind, contain diverse products with both preventive and therapeutic benefits against diseases as well as an array of bioactive nutrients enhancing human health. While herbal preparations and natural products were utilized extensively as a “first line of treatment/prevention”, particularly in rural population of Asia and other parts of the world, a declining trend was observed during the later years of the last century, primarily driven by a combination of factors including a large scale urbanization of the population as well as lack of molecular studies to fully conform these herbal preparations to the standards of drug testing, safety, and efficacy. While the trend is fortunately changing in the recent years and as per a recent estimate herbal products now constitute about 20% of international pharmacological industry. Ramesh et al.,[1] in this issue examine the bio-active ingredients and their mechanism of action in enhancing brain health and potential exploitation of such molecular understanding in neurodegenerative disease therapeutics. The study not only provides proof-of-principle for new drug targets for Alzheimer's disease (AD) and other debilitating, yet untreatable neurodegenerative diseases, but also highlights the need for more such in-depth mechanistic investigation of such products of natural origin with traditionally known health benefits.

Medicinal plant extracts have been known to be particularly beneficial towards gradually progressing human diseases involving extremely complex and multiple/heterogeneous etiopathologies such as diseases of the human brain, including AD and other neurodegenerative diseases. As a result, it may be unlikely that AD may be mitigated by drug acting on a single specific target. Accumulated evidence suggests that naturally occurring phyto-compounds, such as polyphenolic antioxidants found in herbs and plant products, may potentially hinder neurodegeneration and improve memory and cognitive function. Currently, two of the presently approved drugs for AD are based on natural products (galantamine and the physostigmine-derivative rivastigmine) and many plants are now under investigation as a potential source of new drugs.[2] In fact, more than sixteen plant species, including Ginseng, Celastrus paniculatus, Centella asiatica, Curcuma longa, Ginkgo biloba, Huperzia serrata, Lycoris radiate, Galanthus nivalis, Magnolia officinalis, Polygala tenuifolia, Salvia lavandulaefolia, Salvia miltiorrhiza, Coptis chinensis, Crocus sativus, Evodia rutaecarpa, Sanguisorba officinalis, Veratrum grandiflorum and Picrorhiza kurvoa, may be potential sources of neuroprotective active extracts.[3] However, the principle bioactive compound (s) in these plant products and/or molecular mechanisms behind their curative/preventive effects are very poorly understood, which is a roadblock to convince the more educated urban population about their benefits and to exploit these for the discovery of new drug targets. Supporting the argument, a recent study[4] showed that redox-active copper which accumulates in many neurodegenerative disease affected human brain regions, inhibits repair of genome damage by oxidizing cysteine residues in repair-initiating NEIL enzymes. Thus reversing this inhibitory effect not only requires a metal chelator, but also reducing, or natural compound like curcumin with dual activities.[5]

Ramesh et al.[1] in this issue characterized active ingredients and biological action of leaf extracts of two plants, namely, C. crista and C. asiatica widely used to treat brain related diseases in India. The authors attribute their neuroprotective function to anti-oxidant and anti-inflammatory activities due to the presence of high level of gallic and ferulic acid in their leaf extract. The anti-inflammatory activity was achieved by their ability to inhibit 5-lipoxygenase in the brain. They had previously reported inhibition of amyloid fibril formation and dis-aggregation of the pre-formed fibrils by C. crista.[6,7] It is generally accepted that the primary pathology in AD involves oxidative stress, chronic inflammation and amyloid aggregation along with other secondary pathologies including genome damage and repair failure. Thus the study not only provides a proof-of-principle for AD prevention/therapy which would require a combination of anti-oxidant, anti-inflammatory and anti-amyloidogenic activity. While more extensive in-cell studies and reliable clinical data are required to take these forward to drug discovery, the study is in the right direction toward such an overarching effort with an emphasis on search for novel natural products that has multi-target directed ligands such as anti-amyloidogenic, antioxidant and anti-inflammatory molecules. This is necessary to combat multi-factorial pathology in AD and I believe, could revive their utilization and pave the way for discovery of new drug candidates for yet untreatable brain diseases.