Neuroprotective effect of herbal extracts inhibiting soluble epoxide hydrolase (sEH) and cyclooxygenase (COX) against chemotherapy-induced cognitive impairment in mice.

Chemotherapy-induced cognitive impairment (CICI) is a novel clinical condition characterized by memory, learning, and motor function deficits. Oxidative stress and inflammation are potential factors contributing to chemotherapy's adverse effects on the brain. Inhibition of soluble epoxide hydrolase (sEH) has been proven effective in neuroinflammation and reversal of memory impairment. The research aims to evaluate the memory protective effect of sEH inhibitor and dual inhibitor of sEH and COX and compare its impact with herbal extracts with known nootropic activity in an animal model of CICI. In vitro sEH, the inhibitory activity of hydroalcoholic extracts of Sizygium aromaticum, Nigella sativa, and Mesua ferrea was tested on murine and human sEH enzyme as per the protocol, and IC50 was determined. Cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and fluorouracil (5 mg/kg) combination (CMF) were administered intraperitoneally to induce CICI. The known herbal sEH inhibitor, Lepidium meyenii and the dual inhibitor of COX and sEH (PTUPB) were tested for their protective effect in the CICI model. The herbal formulation with known nootropic activity viz Bacopa monnieri and commercial formulation (Mentat) were also used to compare the efficacy in the CICI model. Behavioral parameter such as cognitive function was assessed by Morris Water Maze besides investigating oxidative stress (GSH and LPO) and inflammatory (TNFα, IL-6, BDNF and COX-2) markers in the brain. CMF-induced CICI, which was associated with increased oxidative stress and inflammation in the brain. However, treatment with PTUPB or herbal extracts inhibiting sEH preserved spatial memory via ameliorating oxidative stress and inflammation. S. aromaticum and N. sativa inhibited COX2, but M. Ferrea did not affect COX2 activity. Lepidium meyenii was the least effective, and mentat showed superior activity over Bacopa monnieri in preserving memory. Compared to untreated animals, the mice treated with PTUPB or hydroalcoholic extracts showed a discernible improvement in cognitive function in CICI.

Erectogenic and Aphrodisiac Property of Moringa oleifera: Involvement of Soluble Epoxide Hydrolase Enzyme.

Soluble epoxide hydrolase (sEH) inhibitors have been reported to improve penile erection; therefore, sEH could be useful for management of erectile dysfunction. Methanolic and aqueous extracts of 30 Indian medicinal plants were screened for their sEH inhibition potential. Fifteen extracts showed >50% inhibition when screened at 50 µg/mL in sEH inhibition assay. Methanolic extract of Moringa oleifera Lam. (Moringaceae) seeds (MEMO) was most potent with IC50 1.7 ± 0.1 µg/mL and was selected for in vitro studies on isolated rat corpus cavernosum smooth muscle and in vivo sexual behaviour studies on healthy and diabetic rats. Rats were divided into five groups, each containing six animals and treated orally with either water, vehicle (1% Tween-20), MEMO (45 and 90 mg/kg/day for 21 days), and standard drug, sildenafil (5 mg/kg/day for 7 days). An equal number of female rats were used, and the effect of MEMO and sildenafil was compared with that of vehicle. MEMO significantly relaxed isolated rat corpus cavernosum smooth muscle at 0.1-100 µg/mL in vitro and significantly increased (p < 0.05) sexual activity, intracavernous pressure/mean arterial pressure in normal and diabetic rats. The increase in erectile function of rats by MEMO could be because of its sEH inhibitory activity. Copyright © 2016 John Wiley & Sons, Ltd.

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model.

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7 days)+TPPU (3mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.

Erectogenic and Aphrodisiac Effects of Butea frondosa Koenig ex Roxb. in Rats: Involvement of Enzyme Inhibition.

Butea frondosa Koenig ex Roxb. (BF) is traditionally used to manage male sexual disorders including erectile dysfunction (ED). Methanol extract of BF (bark) inhibited Rho-kinase 2 (ROCK-II) enzyme activity in vitro with an IC50 of 20.29 ± 1.83 µ g/mL. The relaxant effect of methanol extract of BF (MEBF) was studied on phenylephrine precontracted corpus cavernosum smooth muscle (CCSM) isolated from young rats. The effect of MEBF treatment on sexual behaviour of both young (5 month) and aged (24 month) rats was also studied in addition to the influence on smooth muscle, collagen (collagen-I and -III) level in penis, and sperm characteristics of young and aged rats. MEBF relaxed CCSM up to 21.77 ± 2.57% and increased sexual behavior of young and aged rats. This increase in sexual function could be attributed to ROCK-II inhibition and increase in ratio of smooth muscle to collagen level in rat penile tissue. Increased sperm production and decreased defective sperms in young and aged rats corroborate the usefulness of Butea frondosa in male infertility in addition to ED.

Screening for Rho-kinase 2 inhibitory potential of Indian medicinal plants used in management of erectile dysfunction.

THE AIM OF THE STUDY: Activation of Rho-kinase 2 (ROCK-II) results in contraction of corpus cavernosum smooth muscle and ROCK-II inhibitors relax corpus cavernosum in vitro and in vivo hence, plant extracts capable of inhibiting ROCK-II enzyme may be useful in management of erectile dysfunction (ED). The aim of the study was to screen selected Indian medicinal plants, having similar ethnopharmacological use for ROCK-II inhibition. MATERIALS AND METHODS: Some Indian medicinal plants reported as aphrodisiacs in Ayurveda and modern scientific literature were collected, authenticated and extracted. Direct methanol and successive aqueous extracts of these plants were screened for ROCK-II inhibitory activity using HTRF(®)KinEASE™ STK S2 Kit (Cisbio Bioassays). Relaxant effect of potent extract was recorded on isolated rat corpus cavernosum. RESULTS: Methanolic and successive aqueous extracts of 30 plants were screened for ROCK-II inhibition and 15 herbal extracts showed inhibition ranging between 50 and 88% at 50 µg/mL. While IC(50) of Y-27632, a standard ROCK-II inhibitor, was found to be 163.8 ± 1.2 nM. The Methanolic extract of Terminalia chebula (METC) with IC(50) value of 6.09 ± 0.17 µg/mL was found to be most potent and relaxed isolated rat corpus cavernosum significantly (p<0.01). Chebulagic and chebulinic acid of METC were found to inhibit ROCK-II and might be responsible for the inhibitory potential of the extract. The traditional use of plants like Butea frondosa, Syzygium aromaticum, Butea superba, Chlorophytum borivilianum and Mucuna pruriens, as aphrodisiacs and for male sexual disorder (MSD) might be in part due to the ROCK II inhibitory potential of these plants. CONCLUSION: Some of the Indian medicinal plants have ROCK-II inhibitory potential and those deserve further investigation.