Neurogenesis-inducing flavonoids: A structure-activity study

Diseases like Alzheimer's or Parkinson's and also ischemic incidences (“strokes”) are characterized by a loss of neurons due to cell death, resulting in functional deficits. Since the discovery of multi-potent neural stem cells (NSCs) present in the adult human brain (1), considerable interest has arisen in the possibility of regenerative therapies involving exogenous compounds to target differentiation in NSCs.

Searching for natural compounds which can induce neurogenesis to NSCs, prenylflavonoids called our attention, since they can cross the blood-brain barrier (2,3). Hops mostly known from brewing industry, is an abundant source of prenylflavonoids. Accordingly we did an activity-guided fractionation of a commercial hops extract. This fractionation led to a potent neurogenesis-inducing pyranoflavonoid, which showed higher activity than retinoic acid, a well known differentiation factor and other flavonoids known from literature. Moreover, it promoted neurite outgrowth, displayed neuroprotective activity and shows neuronal lineage-specific effects (4).

We identified the structural characteristics responsible for the neurogenesis-inducing effects of prenylflavonoids, comparing the activity of some side chain-open and ring-closed derivates. Testing of derivatives with structural changes to the pyranoring confirmed the importance of this structural characteristic. Furthermore structural changes on A-ring as well as on B-ring of prenylflavonoids showed a specific influence on until now unknown targets.

References:

[1] Gage FH, Science 2000, 287, 14 33

[2] Butterweck V. et al., J. Pharm. Pharmacol. 2007, 59, 549 – 553

[3] Rad M. et al., Brit. J. Clin. Pharmacol. 2006, 62, 288 – 296

[4] Aigner L., Riepl H., Urmann C., 2012 WO2012172090 A1