Markhamia lutea leaves aqueous and ethanolic extract with curative anti-inflammatory activity attenuates paclitaxel toxicity in rat's intestine.

OBJECTIVES: Markhamia lutea (M. lutea, Bignoniaceae) is mainly found in tropical/neotropical regions of America, Africa and Asia. The plant's leaves, stems or roots are used to treat anaemia, bloody diarrhoea, parasitic and microbial infections. This study evaluates anti-inflammatory properties (in vitro) of Markhamia lutea and their curative effects on paclitaxel-induced intestinal toxicity (in vivo). METHODS: The anti-inflammatory potential of Markhamia lutea was tested over cytokines (TNF-alpha, IL-6, IL-1ß, IL-10), reactive oxygen species (ROS) and enzymes (cyclooxygenase and 5-lipoxygenase). While in vivo, intestinal toxicity was induced for 10 days by oral administration of paclitaxel (3 mg/kg, 0.05 mL). Animals in each group were further treated with aqueous (300 mg/kg) and ethanolic (300 mg/kg) leaves extracts of Markhamia lutea during 7 days and clinical symptoms were recorded, hematological, biochemical and histological analysis were subsequently performed. RESULTS: In vitro, aqueous (250 µg/mL) and ethanolic (250 µg/mL) extracts of Markhamia lutea inhibited the activities of cyclooxygenase 1 (56.67 % and 69.38 %), cyclooxygenase 2 (50.67 % and 62.81 %) and 5-lipoxygenase (77.33 % and 86.00 %). These extracts inhibited the production of intracellular ROS, extracellular ROS and cell proliferation with maximum IC50 of 30.83 µg/mL, 38.67 µg/mL and 19.05 µg/mL respectively for the aqueous extract, then 25.46 µg/mL, 27.64 µg/mL and 7.34 µg/mL respectively for the ethanolic extract. The extracts also inhibited the production of proinflammatory cytokines (TNFα, IL-1ß and IL-6) and stimulated the production of anti-inflammatory cytokines (IL-10). In vivo, after administration of paclitaxel, the aqueous and ethanolic extracts of Markhamia lutea significantly reduced the weight loss, the diarrheal stools and the mass/length intestines ratio of the treated animals compared to the animals of the negative control group. Biochemically, the extracts lead to a significant drop in serum creatinine and alanine aminotransferase levels, followed by a significant increase in alkaline phosphatase. In addition to bringing the haematological parameters back to normal values after disturbance by paclitaxel, the extracts caused tissue regeneration in the treated animals. CONCLUSIONS: In vitro, aqueous and ethanolic extracts of Markhamia lutea showed anti-inflammatory properties (inhibition of COX1, COX2, 5-LOX activities, inhibition of ROS production and cell proliferation); in vivo, the same extracts showed curative properties against intestinal toxicity caused by paclitaxel.

Parthenolide as a potential analgesic in the treatment of paclitaxel-induced neuropathic pain: the rat modeling.

In this study, we determined the therapeutic effect of parthenolide (PTL), the active component of Tanacetum parthenium, on neuropathic pain caused by paclitaxel (PTX), a chemotherapeutic drug frequently used in cancer treatment, at the gene and protein levels. To this end, 6 groups were formed: control, PTX, sham, 1 mg/PTL, 2 mg/kg PTL, and 4 mg/kg PTL. Pain formation was tested by Randall-Selitto analgesiometry and locomotor activity behavioral analysis. Then, PTL treatment was performed for 14 days. After the last dose of PTL was taken, Hcn2, Trpa1, Scn9a, and Kcns1 gene expressions were measured in rat brain (cerebral cortex/CTX) tissues. In addition, changes in the levels of SCN9A and KCNS1 proteins were determined by immunohistochemical analysis. Histopathological hematoxylin-eosin staining was also performed to investigate the effect of PTL in treating tissue damage on neuropathic pain caused by PTX treatment. When the obtained data were analyzed, pain threshold and locomotor activity decreased in PTX and sham groups and increased with PTL treatment. In addition, it was observed that the expression of the Hcn2, Trpa1, and Scn9a genes decreased while the Kcns1 gene expression increased. When protein levels were examined, it was determined that SCN9A protein expression decreased and the KCNS1 protein level increased. It was determined that PTL treatment also improved PTX-induced tissue damage. The results of this study demonstrate that non-opioid PTL is an effective therapeutic agent in the treatment of chemotherapy-induced neuropathic pain, especially when used at a dose of 4 mg/kg acting on sodium and potassium channels.

Polysaccharide from spore of Ganoderma lucidum ameliorates paclitaxel-induced intestinal barrier injury: Apoptosis inhibition by reversing microtubule polymerization.

Side effects of chemotherapy are burning questions for physicians and patients involved in cancers. Ganoderma lucidum is a widely consumed traditional Chinese medicine and edible mushroom with multiple functional properties. The present study aims to investigate the potential of polysaccharides from spore of G. lucidum (SGP) on small intestinal barrier function recovery against paclitaxel (PTX) challenge in a breast cancer mice model and IEC-6 cell line. The 4T1 tumor-bearing mice were treated with PTX together with four-week daily oral administration of SGP. Results indicated that combination of PTX and SGP reversed body weight lost and remolded the histology of small intestine, accompanied with promoted proliferation but suppressed apoptosis in intestinal cells. Intestinal barrier function was enhanced by the combination as indicated by reduced endotoxemia and the up-regulation of tight junction proteins, including Zonula occludens-1 (ZO-1), E-cadherin, ß-catenin and Occludin. The protection of SGP was further confirmed in IEC-6 cells affected by PTX in vitro. The combination treatment prevented PTX-induced apoptosis in IEC-6 by inhibiting microtubule polymerization, and the aforementioned tight junction proteins were also upregulated. These findings suggest a promising protective effect of SGP against small intestinal barrier injury caused by PTX, highlighting its clinical implication against the chemotherapy side effects.

Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons.

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca2+ imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.

DNA damaging effect of paclitaxel in the epididymal sperms as a chemotherapeutic agent and possible remedies to prevent this effect: A study on reproductive potential of male cancer patients of reproductive age.

Cancer is a major public health problem, young cancer patients therefore undergo chemotherapy, and most of them may lose their fertility. DNA damage level provides important clues about the quality and reproductive potential of spermatozoa. In this study, we evaluated the levels of both DNA fragmentation and abnormal DNA integrity in the epididymal sperms of New Zealand rabbit (Oryctolagus cuniculus) after cryopreservation using the terminal deoxyribonucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay and the toluidine blue (TB) staining methods and assessed the effects of paclitaxel, resveratrol, l-glutamine (LG), and basal medium eagle (BME) solution on DNA damage. Paclitaxel induced the levels of both DNA damages in the sperms, but resveratrol ameliorated this effect. LG and BME supplementation to the extender prevented the sperm samples from DNA fragmentation after cryopreservation. Chemotherapy drugs containing paclitaxel can cause the sperm DNA to be damaged, and hence adversely affect the fertility of male cancer patients of reproductive age. The administration of resveratrol together with paclitaxel may ameliorate the DNA damage inducing effect of paclitaxel. Sperm banking and cryopreservation with the appropriate cryoprotectants such as LG and BME prior to cancer treatment can also be suggested to all male cancer patients of reproductive age facing cancer treatment for fertility preservation.

Electroacupuncture enhances antioxidative signal pathway and attenuates neuropathic pain induced by chemotherapeutic paclitaxel.

One of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy for several types of cancers. Our recent study showed that impairment of Nrf2-antioxidant response element (Nrf2-ARE) and upregulation of oxidative signals in the dorsal root ganglion (DRG) of rats with treatment of paclitaxel result in neuropathic pain. The purpose of this study was to examine the beneficial role played by electroacupuncture (EA) in modifying neuropathic pain evoked by paclitaxel via Nrf2-ARE and oxidative mechanisms. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-ARE and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our data showed that paclitaxel increased mechanical and thermal sensitivity and this was accompanied with impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress (i.e. 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). EA treatment largely restored the levels of Nrf2-ARE/SOD and inhibited products of oxidative stress and thereby attenuated mechanical and thermal hypersensitivity induced by paclitaxel. In conclusion, we revealed specific signaling pathways leading to paclitaxel-evoked neuropathic pain, including impairment of Nrf2-ARE and heightened oxidative signals. We further provided evidence for the role of EA in alleviating paclitaxel-neuropathic pain via these molecular mediators.

Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.

Protective Effect of Polysaccharides from Tussilago farfara L. on Bone Marrow Cells and Small Intestinal Epithelium Under Conditions of Polychemotherapy Evaluated by DNA Comet Assay.

Using DNA comet assay we found that polysaccharides from Tussilago farfara L. reduced the intensity of polychemotherapy-induced apoptosis and DNA damage in bone marrow cells and small intestinal epithelium of C57Bl/6 mice, which attested to genoprotective properties of these polysaccharides.

Beneficial effects of Gelsemium-based treatment against paclitaxel-induced painful symptoms.

Chemotherapeutic drugs induce various side effects including painful peripheral neuropathy that represents a major concern. The widely used anticancer drug paclitaxel causes neurological side effects such as burning pain, allodynia, and hyperalgesia. Neuroprotective substances that may effectively counteract paclitaxel-induced neuropathic symptoms are needed. Here, we investigated the potential of Gelsemium sempervirens (GS) to counteract paclitaxel-evoked painful neuropathy in rats. Using the von Frey hair and acetone behavioral tests, we investigated the potential of GS centesimal (C) dilutions 3, 5, and 9C to prevent or to correct paclitaxel-induced cold allodynia and mechanical allodynia/hyperalgesia involved in neuropathic pain. We found that a prophylactic or corrective treatment with GS dilutions prevented or suppressed PAC-evoked cold allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased cold thermal and mechanical pain thresholds of PAC-treated rats. In particular, preventive or corrective treatments with GS dilution 3C counteracted PAC-evoked allodynic and hyperalgesic responses. Also, GS dilution 5C (in a lesser extent than 3C) significantly reduced PAC-induced mechanical allodynia/hyperalgesia while GS dilution 9C was ineffective. PAC-evoked neuropathic symptoms were efficiently reduced after 1 week treatment with GS dilutions 3 or 5C and the beneficial action increased after 2 weeks. GS dilutions, particularly 3C, also counteracted or prevented PAC-induced sciatic nerve axon alterations and decreased the density of intraepidermal nerve fibers. Altogether, these results obtained in the rat preclinical model suggest that GS dilution-based treatment may constitute an interesting option to explore for the long-term management of pain without undesirable effects.

pH- and Enzyme-Sensitive IR820-Paclitaxel Conjugate Self-Assembled Nanovehicles for Near-Infrared Fluorescence Imaging-Guided Chemo-Photothermal Therapy.

The short lifetime and easy quick elimination of the near-infrared (NIR) dye new indocyanine green (IR820) in the body restrict its practical application as a photothermal agent in cancer therapy. Meanwhile, the drawback of poor water solubility of the chemotherapeutic drug paclitaxel (PTX) largely restricts its clinical applications. Herein, we, for the first time, combined IR820 and PTX in an "all-in-one" fluorescence imaging-guided chemo-photothermal therapy (PTT) platform by a rational design of a novel pH- and enzyme-sensitive IR820-PTX conjugate assembly. Specifically, the IR820-PTX conjugate nanoparticles exhibit an extremely high therapeutic agent content (IR820 and PTX, 95.7%). Besides the good stability in bloodstream, the IR820-PTX nanoparticles can target tumors for high accumulation via the enhanced permeation and retention effect. Particularly, our IR820-PTX nanoparticles simultaneously solve the obstacles of PTX poor solubility and the short lifetime of IR820 for cancer therapy. The simultaneous release of the free drug and dye can efficiently kill tumor cells by the combination of PTT and chemotherapy via NIR irradiation. Furthermore, the combined therapy can be imaging-guided by measuring the NIR fluorescence imaging resulting from the IR820 component. Therefore, our rationally designed pH- and enzyme-sensitive IR820-PTX conjugate nanoparticles provide an alternative "all-in-one" option for an efficient combinational dual-therapy and imaging.

Hepatotoxicity induced by paclitaxel interaction with turmeric in association with a microcystin from a contaminated dietary supplement.

A 67-year-old Caucasian male with lung cancer was presented to the Emergency Department with asthenia, anorexia, jaundice and choluria. The patient's lung cancer was being treated medically by a combination of paclitaxel/carboplatin with bi-monthly frequency. The patient was also self-medicating with several natural products, including Chlorella (520 mg/day), Silybum marianum (total of 13.5 mg silymarin/day), zinc sulphate (5.5 mg), selenium (50 µg) and 15 g/day of Curcuma longa. In first chemotherapy cycle no toxicity was observed even he was taking other medications as budesonide and sitagliptin. The toxic events started only after the introduction of the dietary products. Chlorella had contamination with cyanobacteria (Oscillatoriales) and 1.08 µg of cyanotoxin Microcystin-LR (MC-LR) per gram of biomass was found. Patient was consuming ca 0.01 µg MC-LR/kg/day. This case report describes the first known case of paclitaxel toxicity probably related to pharmacokinetic interaction with Turmeric and a contaminated Chlorella supplement resulting in an acute toxic hepatitis and the impact on oncologic patient health.

Primary Afferent-Derived BDNF Contributes Minimally to the Processing of Pain and Itch.

BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. Here, we used targeted, inducible molecular approaches to characterize the expression pattern of primary afferent BDNF and the extent to which it contributes to a variety of pain and itch behaviors. Using a BDNF-LacZ reporter mouse, we found that BDNF is expressed primarily by myelinated primary afferents and has limited overlap with the major peptidergic and non-peptidergic subclasses of nociceptors and pruritoceptors. We also observed extensive neuronal, but not glial, expression in the spinal cord dorsal horn. In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine, and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents.

Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies.

Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment. Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome. Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon. Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy-induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study. Four studies investigating the activation of both cannabinoid receptor-1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A). Pre-clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population.

Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats.

Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L-carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated.

In situ cultured preantral follicles is a useful model to evaluate the effect of anticancer drugs on caprine folliculogenesis.

Despite the increase in the incidence of cancer, the number of women who survive cancer treatment is growing. However, one of the principal results of chemotherapy is premature ovarian failure (POF). The aim of this study was to use the in situ culture preantral follicles as an in vitro model to evaluate the toxicity of two anticancer drugs, doxorubicin (DXR) and paclitaxel (PTX), on the integrity and development of ovarian follicles. Fragments of the ovarian cortex of goats were cultured in vitro for 1 or 7 days in α-MEM(+) supplemented with different concentrations of DXR (0.003, 0.03, or 0.3 µg/mL) and PTX (0.001, 0.01, or 0.1 µg/mL). Analyses were performed before and after culture to evaluate tissue integrity by classical histology, apoptosis by TUNEL assay, DNA laddering kit and the detection of activated caspase 3, and DNA damage by the immune detection of phosphorylated histone H2A.x (H2AXph139). Both DXR and PTX reduced the number of morphologically normal primordial and developing follicles. Positive staining for TUNEL and active caspase 3 was detected in all the samples (P < 0.05). Therefore, we propose the in situ culture of caprine preantral follicles as a useful experimental model for assessing the toxic effects of the chemotherapeutic agents on ovarian folliculogenesis. Microsc. Res. Tech. 79:773-781, 2016. © 2016 Wiley Periodicals, Inc.

Evaluating the relationship between cell viability and volatile organic compound production following DMSO treatment of cultured human cells.

Methylsulfinylmethane (dimethyl sulfoxide; DMSO) is widely used in clinical treatment and bioresearch. Moreover, there is bioconversion between methylsulfanylmethane (dimethyl sulfide; DMS), DMSO, and methylsulfonylmethane (DMSO2) in mammalian metabolism. Due to the real-time detection limits for volatile compounds, most research has focused on DMSO2 as a stable byproduct of DMSO. Therefore, details about the production of DMS as a byproduct of DMSO metabolism remain to be elucidated. Here, we report the characterization of trace-level volatile organic compounds (VOCs) produced following DMSO treatment of cultured human cells using an ultrasensitive vacuum ultraviolet photoionization mass spectrometer (VUV-PIMS). Using this approach, 24 h after DMSO treatment we detected 16.9 and 21 parts per billion by volume (ppbv) DMS in the atmosphere above the cells (headspace) within HeLa and 293T tissue culture flasks, respectively. When simultaneously exposed to 50 nM paclitaxel (PTX), 17.6 and 22.3 ppbv DMS were detected in the headspace of HeLa and 293T culture flasks, respectively. Nevertheless, at doses of PTX more or less than 50 nM, the detectable levels of DMS were reduced to as low as 8.4 ppbv. Our experimental results demonstrate that by co-administering 5 to 10 nM PTX with DMSO, it is possible to moderate the production of DMS considerably. However, at higher doses of PTX, increased apoptosis was observed that likely contributed to higher DMS production by cells.

Antinociceptive effects of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis, and possible involvement of the adenosine system.

Incarvillea sinensis is a Bignoniaceae plant used to treat rheumatism and relieve pain in traditional Chinese medicine. As a major component of I. sinensis, incarvillateine has shown analgesic activity in mice formalin tests. Using a series of animal models, this study further evaluated the effects of incarvillateine against acute, inflammatory, and neuropathic pain. Incarvillateine (10 or 20 mg/kg, i.p.) dose-dependently attenuated acetic acid-induced writhing, but did not affect thermal threshold in the hot plate test. In a Complete Freund's Adjuvant model, incarvillateine inhibited both thermal hyperalgesia and paw edema, and increased interleukin-1ß levels. Additionally, incarvillateine attenuated mechanical allodynia induced by spared nerve injury or paclitaxel, whereas normal mechanical sensation was not affected. Incarvillateine did not affect locomotor activity and time on the rotarod at analgesic doses, and no tolerance was observed after 7 consecutive daily doses. Moreover, incarvillateine-induced antinociception was attenuated by theophylline, 1,3-dipropyl-8-cyclopentylxanthine, and 3,7-dimethyl-1-propargylxanthine, but not naloxone, indicating that the effects of incarvillateine on chronic pain were related to the adenosine system, but not opioid system. These results indicate that incarvillateine is a novel analgesic compound that is effective against inflammatory and neuropathic pain, and that its effects are associated with activation of the adenosine system.

Investigation of protective role of curcumin against paclitaxel-induced inner ear damage in rats.

OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the potential protective effect of curcumin on paclitaxel-induced ototoxicity in rats by means of immunohistochemical and histopathological analysis and distortion product otoacoustic emissions (DPOAEs). STUDY DESIGN: Animal study. METHODS: Forty Sprague-Dawley rats were randomized into five groups. Group 1 was administered no paclitaxel and curcumin during the study. Groups 2, 3, 4 and 5 were administered 5 mg/kg paclitaxel; 200 mg/kg curcumin; 5 mg/kg paclitaxel, followed by 200 mg/kg curcumin; 200 mg/kg curcumin and a day later 5 mg/kg paclitaxel followed intraperitoneally by 200 mg/kg curcumin once a week for 4 consecutive weeks, respectively. After the final DPOAEs test, the animals were sacrificed and their cochlea were prepared for hematoxylin and eosin and caspase-3 staining. RESULTS: The DPOAEs thresholds and histopathological and immunohistochemical findings were substantially correlated in all groups. The histopathologic findings in the cochlea of the paclitaxel-treated animals showed not only changes in the organ of Corti, but also damage to the stria vascularis and spiral limbus, including nuclear degeneration, cytoplasmic vacuolization, and atrophy of intermediate cells. Additionally, cochlear changes in group 2, such as intense apoptosis, were confirmed by caspase-3 immunohistochemical staining. In group 4, coreceiving curcumin could not sufficiently prevent paclitaxel-induced ototoxicity, and the results in group 5 were similar to the control group. CONCLUSIONS: In our study, we have concluded that pre- and coreceiving curcumin can significantly protect the cochlear morphology and functions on paclitaxel-induced ototoxicity in rats. Curcumin might be considered as a potential natural product that, used as a dietary supplement, could be easily given to patients undergoing paclitaxel chemotherapy. LEVEL OF EVIDENCE: NA

The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action.

BACKGROUND: This study aimed to evaluate the prophylactic effect of goshajinkigan (GJG) on paclitaxel (PTX)-induced neuropathy and to elucidate the mechanism of action. RESULTS: There was a time-dependent irreversible decrease in pain threshold in PTX group. In PTX/GJG group, pain threshold showed changes in the same level as control. Electron microscope showed that although the ganglion cells of control and PTX/GJG groups were normal, degeneration of the nucleus and swelling of the mitochondria were observed in PTX group. Expression of transient receptor potential vanilloid 4 (TRPV4) gene in PTX group significantly increased compared with that in control and PTX/GJG groups. In TRPV4 knock-out mice, no PTX-induced hyperalgesia was observed, and there was no significant difference in pain threshold between the 3 groups. CONCLUSIONS: These results showed that PTX induced hyperalgesia by enhancing TRPV4 expression, and suggested that GJG might alleviate hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression.

Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms.

The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL (CREL) have been well established in vitro; however, the in vivo mechanisms underlying this toxicity remain unclear. Thus, the aim of this study was to analyze the in vivo toxicity induced by infusion of PTX and CREL and to investigate the involvement of oxidative stress as a potential mechanism for this toxicity. We treated male Wistar rats with PTX and/or CREL for 1h using human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m(2) or CREL+ethanol+NaCl) and sacrificed immediately or 24h after these drug infusions to systemic biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a control in some groups. The oxidative profile was determined by measuring erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our findings showed that CREL infusion triggered immediate high plasma lipid peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and metahemoglobin formation. Pronounced oxidative effects were detected 24h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin levels. These data indicate the existence of a continuous oxidative stress generation during CREL-PTX treatment and highlight CREL as primarily responsible for the in vivo oxidative damage to RBCs.