Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: : the missing link in pharmacodynamic studies

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship

Evaluation an aqueous extract of irradiated and non irradiated of Orthosiphon aristatus on zebrafish embryo (Danio rerio) through acute toxicity assay

Background: Orthosiphon aristatus has been usually related to be powerful in curing many illnesses inclusive of post-partum remedy, anti-influence, rheumatism and stopping osteoporosis as a result of menopause. Objectives: Thus, this study was designed to differentiate the toxicity effect of non-irradiated and irradiated Orthosiphon aristatus at different dosage of 3, 6, 9 and 12 kilogray (kGy) on zebrafish embryo. Method: Survival rate, hatching rate, heart beat rate and scoliosis were observed and date were analysed using SPSS 25.00 windows. Result: The lethal dose (LC50) of non-irradiated Orthosiphon aristatus is 381.81 μg/mL compare to irradiated extract at 3 % is (371.27 μg/mL), 6 % (311.03 μg/mL), 9 % (160.72 μg/mL) and 12 % (140.18 μg/mL). Hatchability of zebrafish embryo for Orthosiphon aristatus extract decrease in the higher dosage of irradiated sample compared to non-irradiated sample. No presence of scoliosis was observed in all dosage of irradiated and non-irradiated of Orthosiphon aristatus. The heartbeat of zebrafish embryo treated with irradiated Orthosiphon aristatus specifically 12 % show decrease at 250 μg/mL concentration. Remaining dosage of irradiated and non-irradiated Orthosiphon aristatus show average heartbeat around 120-160 bpm. Conclusion: As conclusion, irradiated and non-irradiated of Orthosiphon aristatus is safe to be consumed due to its pharmaceutical effect but it still exhibited mild toxicity effect on zebrafish embryo

Evaluation of acute toxicity of an aqueous extract of irradiated Labisia pumila on zebrafish embryo (Danio Rerio)

This research aimed to compare the toxicity effect of non-irradiated and irradiated Labisia pumila at a different dosage of 3, 6, 9 and 12 kilogray (kGy). Different irradiated dosages of L.pumila were prepared using Cobalt-60 gamma irradiation and the acute toxicity were assessed through zebrafish (Danio rerio) embryo. The survival rate, hatching rate, heartbeat rate and scoliosis were observed. Data were analyzed using SPSS 25.0 windows. The lethal dose (LC50) value was calculated. The LC50 value of non- irradiated extract L. pumila is 125 μg/ml compared to irradiated extract is 62.5 μg/ml respectively. Hatchability of zebrafish of L.pumila extract reduce in the higher concentration for non-irradiated sample at 250 μg/ml and for irradiated sample at 125 μg/ml. Presence of scoliosis not observed in all concentration for irradiated and non-irradiated sample. The heartbeat of zebrafish embryo treated with irradiated L. pumila extract (0–62.5 μg/ml) was within the normal range (120–180 bpm for all doses), but at higher concentrations (125 μg/ml) the heartbeat differs from normal ranges for all the doses. From this time forward, irradiated and non-irradiated of this plant was safe to be consumed due to its pharmaceutical effect but it still exhibited mild toxicity effect on zebrafish embryo. The diverse irradiated doses show a change of toxicity level of this plant which higher doses show mild toxicity to the zebrafish embryo compared to low doses exposure

The effects of Clitoria ternatea extract on zebrafish model of Alzheimer’s disease : a neurobehavioural study

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is currently affecting 40-50 million people worldwide. It is generally recognized from its main symptom dementia, in which the patient undergoes a progressive decline in their cognitive memory. Recent studies have shown that medicinal plants such as Clitoria ternatea equipped with antioxidant properties has high potential in treating AD. The study was conducted using zebrafish model of AD induced with aluminium chloride for 28 days. The treatment dose of C. ternatea extract (4.34 mg/L) was then given for 14 days. The behaviour of the zebrafish were evaluated through memory testing by using a T-maze test and novel tank diving test. Histological studies were also performed. 50% of the zebrafish tested showed improvement in memory through the T-maze test after treatment with C. ternatea extract. Zebrafish model of AD treated with C. ternatea extract also shows a decrease in anxiety in the novel tank diving test. A significant increase of purkinje cells were also observed from the histological study after treatment with C. ternatea extract. Nucleus elongation of oligodendrocytes from zebrafish model of AD induced with aluminium chloride were improved when treated with the C. ternatea extract. In conclusion, it was found that C. ternatea extract exhibits strong potential for treating zebrafish model of AD induced with aluminium chloride