Dose-response assessment of neuroactive botanical extracts and their bioactive constituents using microelectrode array (MEA) recordings in rat primary cortical cultures

Use of botanicals is increasing. While often considered as safe, neuromodulatory effects have been demonstrated previously. Establish the neuroactive potential of 13 botanical extracts. For 8 of these, we made a direct comparison with their major constituent. We used microelectrode array (MEA) recordings of primary rat cortical cultures to evaluate dose-response relationships on neuronal network function <i>in vitro</i>. Exposure to extracts from milk thistle, usnea, green tea, aristolochia, and ephedra mildly inhibited neuronal activity with distinct neuronal activity phenotypes. Extracts of tripterygium, yohimbe, kratom, and kava strongly inhibited neuronal activity. Despite differences in the degree of inhibition, all inhibitory extracts show No Observed Effect Levels (NOELs) of 1–5 µg/mL. Exposure to aconite, blue cohosh, goldenseal and oleander induced specific activity phenotypes characterized by hyperexcitation and/or intensification of (network) burst activity. While the extracts exhibit a narrow effective dose range, the extracts from aconite, goldenseal and oleander are most potent with NOELs of 0.25–0.5 µg/mL. Silybin B (milk thistle), epigallocatechin gallate (green tea), yohimbine (yohimbe), dihydrokavain (kava), mitragynine (kratom), aconitine (aconite), berberine (goldenseal) and oleandrin (oleander) were tested to investigate if the distinct neuronal activity phenotypes, indicative for the presence of multiple modes of action, are due to the known bioactive constituents of the extracts. For most constituents the activity phenotype is comparable to the extract, although the extract generally has a higher potency. Botanical extracts and constituents evoke diverse activity phenotypes, highlighting the complexity of hazard characterization of botanicals.