Synergistic Inhibition of Glycinergic Transmission In Vitro and In Vivo by Flavonoids and Strychnine

Author(s): Raafat K, Breitinger U, Mahran L, Ayoub N, Breitinger HG


The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signaling in spinal cord, brain stem, and higher central nervous system regions. The flavonoids quercetin and genistein have been identified previously as promising GlyR antagonists in vitro, but their detailed mechanism of action was not known. Here, inhibition of recombinant human α1 GlyRs in HEK 293 cells by genistein, quercetin, and strychnine was studied using whole-cell recording techniques. The interaction of several inhibitors applied alone or in combination was analyzed using a minimum mechanism of receptor activation and inhibition. Receptor inhibition in vivo was studied in a mouse model of strychnine toxicity. Genistein, quercetin, and strychnine were noncompetitive GlyR inhibitors. The inhibitory potency of one flavonoid (either genistein or quercetin) was not affected by simultaneous application of the other, suggesting that both flavonoids target the same site on the receptor. In combination with strychnine, flavonoid inhibition was augmented, indicating that strychnine binds to a position on the receptor physically distant from the flavonoid site. Potentiation of strychnine inhibition by flavonoids was also observed in vivo, where harmless doses of flavonoids enhanced strychnine toxicity in mice. Thus, in vitro and in vivo studies demonstrated a true synergism between flavonoids and strychnine for GlyR inhibition. The mechanism-based approach used here allows a rapid analysis of the effects of single drugs versus drug combinations.

Similar Articles

Antidiabetic potential of Butea monosperma in rats

Author(s): Somani R, Kasture S, Singhai AK

Plants as source of drugs

Author(s): Rates SM

Hypoglycemic activity of Salvia fruticosa Mill

Author(s): Perfumi M, Arnold N, Tacconi R

Flavonoids from Centaurea clementei

Author(s):  I Gonzalez Collado, FA Macias, GM Massanet, F Rodriguez Luis

A new flavonoid glycoside from Centaurea horrida

Author(s): Flamini G, Bulleri C, Morelli I, Manunta A

Medicinal plants with hypoglycemic activity

Author(s): Atta-Ur-Rahman, Zaman K

Physicochemical and functional properties of barley ß-glucan as affected by different extraction procedures

Author(s): Asif Ahmad, Faqir Muhammad Anjum, Tahir Zahoor, Haq Nawaz, Ahmad Din

The juice of fresh leaves of Catharanthus roseus Linn

Author(s): Nammi S, Boini MK, Lodagala SD, Behara RB

Protective effects of Origanum majorana L

Author(s): Karim M Raafat, Hasan Jassar, Maha Aboul-Ela, Abdalla El-Lakany

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice

Author(s): Ulugol A, Oltulu C, Gunduz O, Citak C, Carrara R, et al.

Effects of in vivo antioxidant enzyme activities of myrtle oil in normoglycaemic and alloxan diabetic rabbits

Author(s): Sepici-Dincel A, Açikgöz S, Cevik C, Sengelen M, Yesilada E