GABA Agonists from One of the World’s Oldest Plants

Every spring, one horticultural assertion captures my attention with its opalescent flowers, petoliate leaves and robust stipules.

The Magnolia, which denotes any of the 7 genera and 225 species belonging to the family Magnoliaceae, is one of the earth’s oldest plants.  Even after its heavy flowers fall to the ground, after its leaves are shed in the autumnal effluvium, and after its resignation to the New England winter,  the most magnificent inner workings of this tree gracefully proceed.  This is because the true beauty of this tree is the part that people never notice—the bark.

The enzymatic machinery housed in the woody layers is more meticulous than Boticelli’s oevre, more dynamic than the earth’s prevailing winds and more recondite than Goodman and Gilman’s The Pharmacological Basis of Therapeutics.  I have been reminded often of my arcane taste in literature (once I misplaced my Merck Index and a colleague suggested I may have left it at a party).  That aside, as an artist and pharmacologist, few specimens of contiguity between ornamental horticulture and medicinal chemistry could be so elegant.

In Asia, the bark of Magnolia officinalis has been used medicinally since 1083, and 250 prospective medicinal compounds have been reported to date.  The two most well-researched are the phenolic lignans magnolol and honokiol, which feature a biphenyl structure that, coincidentally, occurs in 4.3% of synthetic pharmaceutical drugs.  This is a perfect example of a plant remaining a half-step ahead of human pharmacologic ambition—in this case, the lapse has been 95 million years.

Regardless of botanical or synthetic incidence, the therapeutic power of the biphenyl arises from a defining characteristic of polyphenols—the ability to bind proteins, such as receptors, enzymes and ion channels.  Magnolol and honokiol are particularly competent in binding and activating GABA receptors, the ion channels in the brain that mediate the relaxation and sleep evoked by Xanax and other benzodiazepines [1].  Current research in medicinal chemistry and drug design is using the biphenyls in magnolia as scaffolds to arrive at more potent drugs for anxiety [2].  These efforts have been successful in vitro and in preclinical models.  Taken orally, Magnolia bark extracts are relatively weak activators of GABA, but clinical efficacy has been documented.  A preparation consisting of Magnolia officinalis and Phellodendron amurense (Relora®) has been clinically researched and found to be effective for mild anxiety [3].  Another proprietary blend consisting of Magnolia officinalis and the seed extract of Ziziphus jujube (Seditol®) was found to be effective for insomnia [4].

Mechanistic studies, along with healthy intuition, show that GABA is not the sole conduit of therapeutic effects of Magnolia bark extracts.  Plants always have more than one answer to my simple questions. 

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