Research Title: Effects of Meloxicam on Implantation and Parturition of Rat.

Author: Sahar Majdi Jaffal, Published Year: 2006

Jordan Medical Journal , 40 (2): 88-95.

Faculty: Science

Abstract: Meloxicam, a selective cyclooxygenase-2 preferential inhibitor, was studied for its anti-implantation and parturition effects on pregnant rats. Regarding the effect of meloxicam on implantation, rats were dosed orally by 7.5 and 10 mg/kg/day from day 1 through 3 or from day 3 through 5 of gestation, respectively. While for the parturition effect, rats were dosed orally by the above doses from day 20 through 22 of gestation. The results of implantation experiments showed that the number of implantation sites was significantly decreased in all treated groups in a dose- and time-dependent manner. Whereas the number of resorption sites were significantly increased in all meloxicam treated groups. On the other hand, the results of parturition experiments indicated that meloxicam significantly prolonged the duration time of delivery in a dose-dependent manner. Further, significantly less viable fetuses and pups were delivered per female treated with meloxicam. In conclusion, the results indicate that meloxicam exhibited potential effect on implantation and parturition processes of pregnant rats.

Keywords: Meloxicam, Implantation, Parturition

Research Title: Nerve growth factor enhances cough and airway obstruction via TrkA and TRPV1 receptor-dependent mechanisms

Author: Sahar Majdi Jaffal, Published Year: 2009

Thorax, 64 (9): 791-797.

Faculty: Science

Abstract: Background: Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown. Objectives: In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed. Methods: Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index. Results: Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF-enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation. Conclusions: The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.

Keywords: Cough, airway obstruction, NGF, TRPV1

Research Title: Effect of inhibition of the ubiquitin-proteasome-system and IκB kinase on airway inflammation and hyperresponsiveness in a murine model of asthma.

Author: Sahar Majdi Jaffal, Published Year: 2011

International Journal of Immunopathology and Pharmacology , 24 (1): 33-42.

Faculty: Science

Abstract: The current treatment of asthma is far from optimal and there is a need for novel therapeutic approaches. NFkB has recently been highlighted as an important pro-inflammatory transcriptional factor and its blockade is believed to represent a new therapeutic approach for asthma. The purpose of this study is to investigate the effects of blocking the actions of NFkB, through inhibition of the ubiquitin-proteasome system (UPS) or IkB kinase (IKK), in a murine model of asthma. Treatment with the UPS inhibitor, MG-132 (0.03 and 0.1 mg/kg), did not significantly affect the ovalbumin-induced increase in total and differential cell numbers, histological changes such as perivascular and peribronchial inflammatory cell infiltration, perivascular and peribronchial fibrosis or the increased Penh to methacholine. In contrast, treatment of mice with the IKK inhibitor, BAY 11-7085, (3 and 10 mg/kg) dose-dependently inhibited the ovalbumin-induced increase in airway leukocyte influx and decreased the percentage of airway lymphocytes, neutrophils and eosinophils. Also, BAY 11-7085-treated (10 mg/kg) mice showed a significant decrease in the histologically assessed inflammatory indices as well as a significant reduction in the ovalbumin-induced increase in Penh to inhaled methacholine. Furthermore, BAY 11-7085 significantly inhibited the ovalbumin-induced increase in the level of phosphorylation of IkBalpha and extracellular regulated kinases (ERK) 1/2, whilst MG-132 significantly increased the phosphorylation of (ERK) 1/2. These findings confirm the critical role that NFkB plays in airway inflammation, highlight the importance of IKK in regulating the pro-inflammatory activity of NFkB and also suggest that UPS may not be a useful drug target for asthma treatment.

Keywords: ubiquitin-proteasome system (UPS), inflammation, hyperalgesia

Research Title: Anti-tussive and bronchodilator mechanisms of action for the enaminone E121.

Author: Sahar Majdi Jaffal, Published Year: 2011

Life Science , 89 (11-12): 378-387.

Faculty: Science

Abstract: Abstract Aims: In this study, we investigated whether the enaminone, E121, has anti-tussive effects in a guinea pig model of cough, and if so, whether this effect is mediated via a central or peripheral site of action. We also assessed whether E121 has bronchodilator effects and the molecular mechanisms underlying any anti-tussive and/or bronchodilator effects. Main methods: Whole body plethysmography was used to assess both cough and airway obstruction. A stereotaxic apparatus was used to administer drugs intracerebroventricularly (i.c.v.). Effects of E121 were examined in vitro on contractile effects in guinea pig bronchioles. Key findings: Pre-treatment of animals with E121 resulted in a significant inhibition in the citric acid-induced cough and airway obstruction compared to vehicle-pretreated animals. The K(ATP) antagonist, glibenclamide, significantly inhibited the anti-tussive and bronchoprotective effects of E121. Also, intra-tracheal administration of E121 resulted in a significant inhibition of both the citric acid-induced cough response and airway obstruction compared to vehicle-pretreated animals. By contrast, i.c.v. administration had no effect. Finally, E121 significantly inhibited carbachol-induced airway smooth muscle contractions, an effect that was reduced by both glibenclamide and propranolol. Interestingly, E121 enhanced histamine-induced cAMP release in human eosinophils although it did not directly elevate cAMP levels. Significance: The enaminone, E121, has anti-tussive and bronchodilatory effects and is topically, but not centrally, active. The anti-tussive mechanism of action of E121 seems to be K(ATP) channel dependent, whereas its bronchodilatory effects appear to be mediated via activation of both K(ATP) channels and β(2) receptors. Therefore, E121 may potentially represent a novel therapy for cough, particularly cough associated with airway obstruction.

Keywords: Cough, bronchodilation, enaminone

Research Title: Biasing the prostaglandin F2α receptor responses toward EGFR-dependent transactivation of MAPK.

Author: Sahar Majdi Jaffal, Published Year: 2012

Molecular Endocrinology, 26(7): 1189-1202.

Faculty: Science

Abstract: The G protein-coupled prostaglandin F2α (PGF2α) receptor [F prostanoid (FP) receptor] has been implicated in many physiological events including cardiovascular, respiratory, immune, reproductive, and endocrine responses. Binding of PGF2α to FP receptor elicits inositol production and protein kinase C-dependent MAPK activation through Gαq coupling. Here we report that AL-8810, previously characterized as an orthosteric antagonist of PGF2α-dependent, Gαq-mediated signaling, potently activates ERK1/2 in a protein kinase C-independent manner. Rather, AL-8810 promoted ERK1/2 activation via an epidermal growth factor receptor transactivation mechanism in both human embryonic kidney 293 cells and in the MG-63 osteoblast-like cells, which express endogenous FP receptors. Neither AL-8810- nor PGF2α-mediated stimulation of FP receptor promoted association with β-arrestins, suggesting that MAPK activation induced by these ligands is independent of β-arrestin's signaling scaffold functions. Interestingly, the spatiotemporal activation of ERK1/2 promoted by AL-8810 and PGF2α showed almost completely opposite responses in the nucleus and the cytosol. Finally, using [3H]thymidine incorporation, we noted differential regulation of PGF2α- and AL-8810-induced cell proliferation in MG-63 cells. This study reveals, for the first time, the signaling biased nature of FP receptor orthosteric ligands toward MAPK signaling. Our findings on the specific patterns of ERK1/2 activation promoted by FP receptor ligands may help dissect the distinct roles of MAPK in FP receptor-dependent physiological responses.

Keywords: PGF2α, FP, EGFR, MAPK

Research Title: (2013). Nerve growth factor enhances cough via a central mechanism of action.

Author: Sahar Majdi Jaffal, Published Year: 2013

Pharmacological Research , 74: 68-77.

Faculty: Science

Abstract: Abstract The mechanisms involved in enhanced cough induced by central and inhaled NGF in guinea pigs were investigated. Cough and airway function were assessed by plethysmography following inhaled or intracerebroventricular (i.c.v.) NGF treatment. Expression of TrkA and/or TRPV1 was determined in bronchi and/or brainstem by real-time PCR and immunoblotting. I.c.v. and inhaled NGF enhanced citric acid induced-cough and airway obstruction. Pretreatment (i.c.v.) with antagonists of TrkA (K252a) or TRPV1 (IRTX) significantly reduced both the NGF (i.c.v.) enhanced cough and airway obstruction whereas the NK1 antagonist (FK888) inhibited only cough. The H1 antagonist (cetirizine) did not affect either. Inhaled NGF increased phosphorylation of TrkA receptors in the bronchi but not the brainstem at 0.5h post-treatment. TrkA mRNA was elevated at 0.5h in the bronchi and at 24h in the brainstem while TRPV1 mRNA was elevated from 0.5h to 24h in brainstem and at 24h in the bronchi. Pretreatment (i.c.v.) with IRTX, but not K252a, significantly inhibited the inhaled NGF-enhanced cough. Central NGF administration enhances cough and airway obstruction by mechanisms dependent on central activation of TrkA, TRPV1 and NK1 receptors while inhaled NGF enhances cough via a mechanism dependent on central TRPV1 and not TrkA receptors. These data show that NGF, in addition to its effects on the airways, has an important central mechanism of action in the enhancement of cough. Therefore, therapeutic strategies targeting NGF signaling in both the airways and CNS may be more effective in the management of cough.

Keywords: ACSF; ASCIC-3; AUC; BSA; CNS; Cough; H(1); I.c.v.; Inhalation; NGF; NK(1); NTS; PBS; TRPV1; TrkA; acid sensing ion channel 3 protein;

Research Title: Cough reflex hypersensitivity: A role for neurotrophins.

Author: Sahar Majdi Jaffal, Published Year: 2017

Experimental Lung Research , 43(2): 93-108.

Faculty: Science

Abstract: Cough is one of the most common complaints for which sufferers seek medical assistance. However, currently available drugs are not very effective in treating cough, particularly that which follows an upper respiratory tract infection. Nonetheless, there has been a significant increase in our understanding of the mechanisms and pathways of the defensive cough as well as the hypersensitive/pathophysiological cough, both at airway and central nervous system (CNS) levels. Numerous molecules and signaling pathways have been identified as potential targets for antitussive drugs, including neurotrophins (NTs). NTs belong to a family of trophic factors and are critical for the development and maintenance of neurons in the central and peripheral nervous system including sympathetic efferents, sensory neuron afferents, and immune cells. Nerve growth factor (NGF) was the first member of the NT family to be discovered, with wide ranging actions associated with synapse formation, survival, proliferation, apoptosis, axonal and dendritic outgrowth, expression and activity of functionally important proteins such as ion channels, receptors, and neurotransmitters. In addition, NGF has been implicated in several disease states particularly neuropathic pain and most recently in the sensitization of the cough reflex. This review will briefly address the peripheral and central sensitization mechanisms of airway neurons and will then focus on NGF signaling and its role in cough hypersensitivity.

Keywords: CNS; airways; cough; hypersensitivity; mechanisms; nerve growth factor; nerves.

Research Title: Role of Cannabinoid Receptor 1 and the Peroxisome Proliferator-Activated Receptor α in Mediating Anti-nociceptive Effects of Synthetic Cannabinoids and a Cannabinoid-like Compound.

Author: Sahar Majdi Jaffal, Published Year: 2019

Inflammopharmacology, 2019: 1-2.

Faculty: Science

Abstract: Osteoarthritis (OA) is characterized by cartilage degeneration, subchondral sclerosis, and pain. Cannabinoids have well-established anti-nociceptive properties in animal models of chronic pain. The aim of this study is to evaluate the anti-nociceptive effects of synthetic cannabinoids (WIN-55,212 and HU210) and the cannabinoid-like compound palmitoylethanolamide (PEA) in rat models of OA and to assess the role of cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor α (PPARα) in mediating these effects. Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint was used as a model of osteoarthritis. The von Frey filament test and weight-bearing difference were used to assess the anti-nociceptive effects of WIN-55,212, HU210, and PEA on MIA-induced OA in rats. Open-field locomotor activity system was used confirm the analgesic effects of those compounds. HU210, WIN55, 212, and PEA in a dose-dependent manner restored the paw withdrawal threshold (PWT) and the weight-bearing difference induced by MIA injection. SR141716A (a CB1 antagonist) significantly reversed the anti-nociceptive effects of all the administered drugs in terms of PWT. However, in terms of weight-bearing difference, SR141716A significantly reduced the anti-nociceptive effect of HU210 but not PEA or WIN55, 212. GW6471 (a PPARα antagonist) significantly reversed the anti-nociceptive effects of PEA but not those of HU210 or WIN55, 212. HU210, WIN55, 212 and PEA significantly restored the MIA-induced reduction in locomotor activity. In conclusions, both CB1 and PPARα receptors are involved in mediating pain in osteoarthritis. Therefore, targeting these receptors may be of great clinical value.

Keywords: Osteoarthritis, Cannabinoids, Paw withdrawal, anti-nociceptive

Research Title: Analgesic and Anxiolytic Activities of Achillea biebersteinii: Evidence for the Involvement of GABAergic Systems.

Author: Sahar Majdi Jaffal, Published Year: 2019

Oriental Journal of Chemistry , 35(4): 1433-1442.

Faculty: Science

Abstract: Achillea biebersteinii (Asteraceae) is used in traditional medicine for treating abdominal pain, menstrual pain and headache. The analgesic, antidepressant and anxiolytic activities of this plant were studied. Moreover, molecular docking technique was used for plant constituents to determine their energy of binding against GABAA and GABAB receptors. A. biebersteinii decreased flinching in early and late phases of formalin test and increased the time in hot plate test. In forced swimming test, no difference in immobility time was found. In open field test, high doses decreased the crossed lines number and rearing behavior. A. biebersteinii increased the time that the animals spent in the open arm side of elevated plus maze apparatus. Both bicuculline and SCH 50911 reversed A. biebersteinii action. Lavndulyl-2-methylbutanoate and sesquisabinene hydrate, showed the lowest binding energies for both GABAA and GABAB receptors. In conclusion, A. biebersteinii exerted analgesic, anxiolytic but no antidepressant activity. Its effect involved interaction with GABAA and GABAB systems.

Keywords: Achillea Biebersteinii; Analgesic; Anxiolytic; Antidepressant; GABA Receptor; Molecular Docking

Research Title: Gastroprotective activity of Loranthus acaciae flower extract in a rodent model of ethanol-induced ulcer.

Author: Sahar Majdi Jaffal, Published Year: 2019

Applied Physiology Nutrition and Metabolism, 22: 1-6.

Faculty: Science

Abstract: Loranthus acaciae (Loranthaceae) is a perennial green semi-parasitic plant used in ethnopharmacological medicine for healing wounds. The protective effect of L. acaciae on gastric ulcer induced by ethanol was investigated in a rat model. Ulcer index and total glutathione level were measured and histological and immunohistochemical studies for the expression of cyclooxygenase-2 were performed. Furthermore, chemical constituents of the flower extract were analyzed. Ulcer index was significantly lowered in L. acaciae-treated groups. Protection ratios were 75.9%, 98.9%, and 70.7% for 250 mg/kg and 500 mg/kg of L. acaciae and 40 mg/kg of esomeprazole, respectively. Histological examination revealed fewer hemorrhage in mucosa and less edema in submucosa of L. acaciae-treated groups compared with control. In the esomeprazole-treated group, there was mild disruption in the surface epithelium and mild hemorrhage. However, edema and leucocytes infiltration in the submucosa layer were present. Immunohistochemical staining of stomach sections for cyclooxygenase-2 (COX-2) was negative in the control group as well as in the L. acaciae-treated groups. Total glutathione level in mucosa layer of the stomach was higher in L. acaciae-treated groups compared with control. Liquid chromatography-mass spectrometric analysis revealed the presence of loranthin and rutin as the major constituents. It can be concluded that L. acaciae imparted a gastroprotective action against ethanol-induced ulcer in rats. Novelty 500 mg/kg L. acaciae protected the stomach by 98.9% from ulcerogenic effect of ethanol. L. acaciae increased total glutathione level but not COX-2 expression in gastric mucosa. Loranthin and rutin were the major constituents in L. acaciae flower extract.

Keywords: Loranthus acaciae; Plicosepalus acacia; cyclooxygenase-2; cyclooxygénase-2; gastroprotecteur; gastroprotective; indice d’ulcère; ulcer index.