Novel cannabis flavonoid, cannflavin A displays both a hormetic and neuroprotective profile against amyloid β-mediated neurotoxicity in PC12 cells: comparison with geranylated flavonoids, mimulone and diplacone.

Biochemical Pharmacology

“Flavonoids form a diverse class of naturally occurring polyphenols ascribed various biological activities, including inhibition of amyloid β (Aβ) fibrillisation and neurotoxicity of relevance to Alzheimer’s disease.

Cannabis contains a unique subset of prenylated flavonoids, the cannflavins.

While selected conventional flavonoids have demonstrated anti-amyloid and neuroprotective potential, any neuroprotective bioactivity of prenylated flavonoids has not been determined.

We evaluated the in vitro neuroprotective and anti-aggregative properties of the novel geranylated cannabis-derived flavonoid, cannflavin A against Aβ1-42 and compared it to two similarly geranylated flavonoids, mimulone and diplacone, to compare the bioactive properties of these unique flavonoids more broadly.

RESULTS:

Cannflavin A demonstrated intrinsic hormetic effects on cell viability, increasing viability by 40% from 1-10µM but displaying neurotoxicity at higher (>10-100µM) concentrations. Neither mimulone nor diplacone exhibited such a biphasic effect, instead showing only concentration-dependent neurotoxicity, with diplacone the more potent (from >1 µM). However at the lower concentrations (<10µM), cannflavin A increased cell viability by up to 40%, while 10µM cannflavin A inhibited the neurotoxicity elicited by Aβ1-42 (0-2µM), reducing Aβ aggregate adherence to PC-12 cells and associated neurite loss. The neuroprotective effects of cannflavin A were associated with a direct inhibition of Aβ1-42 fibril and aggregate density, evidenced by attenuated ThT fluorescence kinetics and microscopic evidence of both altered and diminished density of Aβ aggregate and fibril morphology via electron microscopy.

CONCLUSIONS:

These findings highlight a concentration-dependent hormetic and neuroprotective role of cannflavin A against Aβ-mediated neurotoxicity, associated with an inhibition of Aβ fibrillisation. The efficacy of the cannabis flavone may itself direct further lead development targeting neurodegeneration in Alzheimer’s disease. However, the geranylated flavonoids generally displayed a comparatively potent neurotoxicity not observed with many conventional flavonoids in vitro.”

https://www.ncbi.nlm.nih.gov/pubmed/31437460

https://www.sciencedirect.com/science/article/abs/pii/S0006295219302990?via%3Dihub

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Cannflavin A and B, prenylated flavones from Cannabis sativa L.

“Two novel prenylated flavones, termed Cannflavin A and B, were isolated from the cannabinoid free ethanolic extract of Cannabis sativa L. Both compounds inhibited prostaglandin E2 production by human rheumatoid synovial cells in culture.”

http://www.ncbi.nlm.nih.gov/pubmed/3754224

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Isolation from Cannabis sativa L. of cannflavin–a novel inhibitor of prostaglandin production.

“The isolation from Cannabis sativa L. of an inhibitor of prostaglandin (PG) E2 production by cultured rheumatoid synovial cells is described. This agent, for which the name Cannflavin has been coined, is distinct from cannabinoids on the basis of isolation procedure, preliminary structural analysis and biological properties. The activity of Cannflavin has been compared with several established anti-inflammatory drugs and the major cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/3859295

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