Biochemical mechanisms of action of hypericum LI 160 in glial and neuronalcells: Inhibition of neurotransmitter uptake and stimulation of extracellular signal regulated protein kinase

We have investigated biochemical mechanisms that may underlie the antidepre ssant effects of Hypericum Ll 160. We found that LI 160 inhibits uptake of serotonin and norepinephrine in cultures of rat cortical astrocytes. Observ ed differences in the kinetic parameters Km and Vmax as well as in the reco very of uptake after removal of Hypericum indicates that LI 160 does not af fect serotonin and norepinephrine transport in the same manner. This sugges ts that multiple components of the extract can mediate inhibition of these neurotransmitter transporters. Hypericum LI 160 also inhibits serotonin upt ake in neuronal cultures from serotonergic-rich raphe nuclei; concentration -response studies indicate Ll 160 is 25 times more potent in terms of inhib ition of serotonin uptake in neurons than in astrocytes. In addition, Hyper icum LI 160 inhibits norepinephrine uptake in SK-N-SH cells, a human neurob lastoma cell line enriched in norepinephrine transporters. A chemical const ituent of LI 160, hyperforin, is about 10 to 20 times more potent than LI 1 60 in inhibiting neurotransmitter uptake in astrocytes and neuronal cells; this finding is consistent with the observation that hyperforin comprises 5 % of LI 160 extracts. As several weeks are needed to achieve a clinical res ponse with antidepressants, we have also investigated whether Hypericum LI 160 affects biochemical mechanisms that underlie long-term changes such as gene expression. We found that LI 160 stimulates a sustained activation of extracellular signal regulated protein kinase (ERK), a key component of a s ignal transduction pathway involved in gene expression. Taken together, our findings suggest that Hypericum Ll 160 can affect rapidly-acting as well a s slower-developing, long-term biochemical mechanisms related to depressive disorders.