noscapine and Disease-Models--Animal

Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored. Randomly divided groups of rats (n = 6) were Sham-operated, I-R, PG (8 mg/kg), NOS (10 mg/kg), and PG + NOS (8 mg/kg + 10 mg/kg). The rats were exposed to bilateral common carotid artery occlusion, except Sham-operated, to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC

Topics: Animals; Area Under Curve; Blood-Brain Barrier; Brain Ischemia; Disease Models, Animal; Drug Therapy, Combination; Half-Life; Ischemic Stroke; Male; Neuroprotective Agents; Noscapine; Oxidative Stress; Progesterone; Rats; Rats, Wistar; Reperfusion Injury

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability.. Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg.. The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 μm with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96±4.66 and 32.05±3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94±0.18 × 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin.. Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Cisplatin; Disease Models, Animal; Drug Carriers; Drug Liberation; Drug Resistance, Neoplasm; Drug Stability; Drug Synergism; Emulsions; Humans; Mannose; Mice; Models, Animal; Nanoparticles; Noscapine; Rats; Time Factors; Transcytosis; Xenograft Model Antitumor Assays

Noscapine has demonstrated potent antitumour activity and minimum toxicity in cancer models. Recently, noscapine has been shown to limit tumour growth and lymphatic metastasis of PC3 human prostate cancer mice. The prophylactic effects of noscapine are not known.. Nude mice received oral noscapine (300 mg/kg per day; 'treatment'; n=10) or diluent ('control'; n=10) for 56 days, beginning 7 days after inoculation with PC3 human prostate cancer cells; or noscapine for 70 days, beginning 7 days before inoculation ('pretreatment'; n=10).. Mean total tumour volumes were 1731.6+/-602.0 mm(3) in the control group, 644.3+/-545.1 mm(3) in the noscapine pretreatment group and 910.9+/-501.1 mm(3) in the noscapine treatment group (p<0.001 pretreatment vs. control, p<0.05 pretreatment vs. control, p<0.001 pretreatment vs. treatment group), with no evidence of toxicity. Noscapine pretreatment and treatment also reduced tumour weight, the incidence of metastasis and primary tumour inhibition rate.. Pretreatment with oral noscapine limited tumour growth and lymphatic metastasis of PC3 human prostate cancer in this mouse model and conferred a significant additional benefit over noscapine treatment in final tumour volume.

Topics: Animals; Antitussive Agents; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Humans; Lymphatic Metastasis; Male; Mice; Mice, Nude; Noscapine; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Owing to grave socio-medical consequences, polycystic ovary syndrome (PCOS) is a highly alarming endocrinopathy. For searching better therapeutics for PCOS, we present a rat model for PCOS using antiprogestin RU486 and evaluate the efficacy of noscapine for its treatment.. Female Wistar rats weighing 200+/-10 g bwt, exhibiting regular estrous cycle were administered an oral dose of RU486 [20 mg/kg body weight (bwt)/day] in olive oil for 13 consecutive days and compared with controls receiving 0.1 ml olive oil/100 g bwt/day. PCOS induced rats were administered varying dosing regimens of noscapine and were further compared with flutamide, the conventional drug for PCOS. Consecutively, vaginal smears and ovulation was noted and rats from all the groups were sacrificed and serum hormone levels for LH, FSH, PRL, estradiol, and testosterone were measured by enzyme-linked immunosorbent assay. Uteri and ovaries were excised free of adjacent tissue, weighed and further recruited for ascertaining ovary histologic parameters.. Our data go in accordance with previous studies where RU486 administered rats mimicked classical PCOS parameters seen in women. PCOS induced rats with ovulation blockade, persistent estrus and polycystic ovary resumed estrous cycle in 3-4 days post noscapine administration (120 mg/kg bwt/day). Folliculogenesis was followed by ovulation with reduced cystic manifestation and restored ovary and uterus weight. Biochemically, serum LH, PRL, estradiol, and testosterone concentration showed reduction while FSH and progesterone concentration increased significantly when compared with the conventional drug flutamide.. The amelioration of PCOS by noscapine is a novel observation that makes it a potential candidate for being a better therapeutic modality.

Topics: Analgesics, Opioid; Androgen Antagonists; Animals; Cysts; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrous Cycle; Female; Flutamide; Follicle Stimulating Hormone; Hormone Antagonists; Luteinizing Hormone; Mifepristone; Noscapine; Organ Size; Ovary; Ovulation; Polycystic Ovary Syndrome; Prolactin; Rats; Rats, Wistar; Testosterone; Uterus

Cytotoxic free radicals and release of several neurotransmitters such as bradykinin contribute to the pathogenesis of hypoxic-ischemic brain damage. We have studied the efficacy of noscapine, an opium alkaloid and a bradykinin antagonist, in reducing post-hypoxic-ischemic damage in developing brain of 7-d-old rat pups. Hypoxic-ischemic injury to the right cerebral hemisphere was produced by legation of the right common carotid artery followed by 3 h of hypoxia with 8% oxygen. Thirty to 45 min before hypoxia the rat pups received noscapine (dose = 0.5-2 mg/kg) or saline. Pups were scarified at 24 h post recovery for the assessment of cerebral damage by histological methods. Our results showed that noscapine was an effective agent in reducing the extent of brain injury after hypoxic-ischemic insult to neonatal rats. Therefore, it is concluded that noscapine may be a useful drug in the managements of patients after stroke.

Topics: Animals; Antitussive Agents; Basal Ganglia; Brain Edema; Cerebral Cortex; Disease Models, Animal; Female; Fetus; Hypoxia-Ischemia, Brain; Male; Noscapine; Pregnancy; Rats