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.

Research Title: Evidence for the involvement of opioid receptor in Ajuga chamaepitys action in chemical and thermal models of pain in BALB/c mice.

Author: Sahar Majdi Jaffal, Published Year: 2019

Medicinal Chemistry Research , 28: 992-999.

Faculty: Science

Abstract: Ajuga chamaepitys is a small herbaceous annual or biannual plant that belongs to Lamiaceae family. It grows in Europe and Eastern parts of the Mediterranean. One of the ethno-pharmacological uses of this plant is its use as a painkiller. In the present experimental work, the antinociceptive effect of the methanolic extract of A. chamaepitys collected from Jordan was investigated using chemical and thermal models of pain in mice. A. chamaepitys extract decreased significantly the number of writhes that were induced in mice by the injection of 1?etic acid compared to negative control group. The inhibitory effect produced by 300 mg/kg of the extract given i.p was comparable to that of 300 mg/kg aspirin. The i.p administration of 450 mg/kg A. chamaepitys caused a remarkable decrease in paw licking time during the early and late phases of formalin test. Furthermore, the latency time increased in hot plate test but not in tail flick test in animals that were treated i.p with 300 mg/kg A. chamaepitys extract compared to control animals. The involvement of opioid receptor was proven in formalin and hot-plate tests by abolishing the effect of A. chamaepitys extract by pretreatment with naloxone, an opioid antagonist. LC-MS analysis resulted in the identification of 19 compounds. Isovitexin, orientin, flavonol, and cyanidin were the major compounds. Our results suggest that the methanolic extract of A. chamaepitys has pronounced antinociceptive effects, which provide the scientific basis of the traditional therapeutic use of A. chamaepitys in folk medicine.

Keywords: Ajuga chamaepitys, antinociceptive, medicinal plant, hyperalgesia

Research Title: Antinociceptive action of Ononis spinosa leaf extract in mouse pain models.

Author: Sahar Majdi Jaffal, Published Year: 2019

Acta Poloniae Pharmaceutica - Drug Research , 76(2): 299-304.

Faculty: Science

Abstract: Abstract: Ononis spinosa (spiny restharrow) is a perennial herb that belongs to the Fabaceae family. Among several uses, the aerial parts of O. spinosa are used in traditional medicine for toothache. In this study, analgesic activity of the methanolic extract of leaves was studied. In writhing test, the 300 mg/kg and 600 mg/kg doses of O. spinosa extract produced 90.1% and 94.5% inhibition of abdominal cramps, respectively compared to 23.6% inhibition produced by 30 mg/kg diclofenac sodium. O. spinosa methanolic extract reduced the time of licking in early and late phases of the formalin test. The inhibitory effect of O. spinosa extract was more pronounced in late phase. The lowest dose tested (300 mg/kg) of O. spinosa extract produced 81.0% inhibition compared to 50.5% inhibition in 30 mg/kg diclofenac sodium in the late phase of the formalin test. This effect was not abrogated by glibenclamide, naloxone or atropine indicating that the action of O. spinosa in formalin test is not mediated by ATP-sensitive K+ channel, opioid or muscarinic receptors. In tail-flick and hot-plate tests, O. spinosa increased the latency time at 30 min and 150 min. Naloxone antagonized the action of O. spinosa in both tests suggesting an interaction with the opioid receptor as a possible mechanism of O. spinosa in thermal pain models at the spinal and supraspinal levels. Phytochemical screening indicated the presence of phenolics, saponins, flavonoids, and terpenoids. Alkaloids, sterols, and anthraquinone glycosides were absent. HPLC analysis confirmed the presence of kaempferol, apigenin and myricetin in the extract.

Keywords: Ononis spinosa, analgesic activity, opioid receptor

Research Title: Antinociceptive action of Achillea biebersteinii methanolic flower extract is mediated by interaction with cholinergic receptor in mouse pain models.

Author: Sahar Majdi Jaffal, Published Year: 2019

Inflammopharmacology , 7(5): 961-968.

Faculty: Science

Abstract: Achillea biebersteinii is a perennial aromatic herb that grows in the Mediterranean area. The leaves of this plant are used in foods as bittering and appetizing agents. In folk medicine, it is used for the treatment of stomachache and abdominal pain. In this study, the analgesic effect of A. biebersteinii methanolic flower extract was tested in three pain models, namely: writhing, tail-flick and paw-licking (formalin) tests. A. biebersteinii extract inhibited abdominal cramps produced by acetic acid. The effect of A. biebersteinii was better than that of 70 mg/kg indomethacin. In tail flick, A. biebersteinii extract increased latency at 30 min and was as effective as 100 mg/kg diclofenac sodium. In formalin test, A. biebersteinii extracts decreased paw-licking and flinching response in early and late phases. Atropine blocked the action of A. biebersteinii extract (300 mg/kg) in the late phase of formalin test as well as in writhing and tail-flick tests. GC-MS analysis revealed that ascaridole and iso-ascaridole were the main constituents of A. biebersteinii flower extract. In conclusion, this study shows for the first time that the antinociceptive effect of A. biebersteinii is mediated by the cholinergic receptor.

Keywords: Achillea biebersteinii; Antinociceptive effect; Cholinergic receptor; GC–MS; Paw-licking test; Tail-flick test; Writhing test.

Research Title: Antinociceptive Action of Moringa peregrina is Mediated by Interaction with α2-Adrenergic Receptor.

Author: Sahar Majdi Jaffal, Published Year: 2020

Balkan Medical Journal , 37: 189-195.

Faculty: Science

Abstract: Background: Moringa peregrina (M. peregrina) is an edible, drought-resistant tree that is native to semi-arid countries. It is used as a painkiller in folk medicine. Aims: To study the antinociceptive effects of the leaf extract of M. peregrina in mice. Study Design: Animal experimentation. Methods: We employed thermal (hot plate and tail-immersion tests) and chemical (writhing and formalin tests) pain models in male BALB/c mice (eight animals per group) to investigate the mechanisms involved in the antinociceptive actions of M. peregrina. Additionally, we identified the chemical constituents present in the extract of M. peregrina by using liquid chromatography-mass spectrometry analysis, and predicted the possible active constituents that interact with the receptor based on molecular docking simulations. Results: In the writhing test, 200 mg/kg of M. peregrina extract restricted abdominal cramps by up to 55.97% (p<0.001). Further, it reduced the time of paw-licking in the early and late phases of formalin test by up to 56.8% and 65.5%, respectively, as compared to the percentage inhibitions of 50.5% and 48.4% produced by 30 mg/kg diclofenac sodium in the early and late phases, respectively (p<0.05). This effect was abrogated by yohimbine (1 mg/kg, intraperitoneally), but not by methysergide (5 mg/kg, intraperitoneally), in the late phase only, which indicates that the action of M. peregrina in formalin test is not mediated by 5-HT2 serotonin receptors, but rather via α2-adrenergic receptors. In the hot plate test, but not on tail-immersion test, the high dose (400 mg/kg) of the extract increased the latency time after 30 minutes of its administration. Yohimbine antagonized the action of M. peregrina in the hot plate test. Based on LC-MS analysis, the major constituents found in M. peregrina methanolic extract were chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, and rutin. Depending on the molecular docking results, the activity of M. peregrina extract could be due to the binding of chrysoeriol 7-O-diglucoside, quercetin, and rutin to the α2-adrenergic receptor. Conclusion: Interaction with the α2-adrenergic receptor serves as a possible mechanism of the M. peregrina analgesic effect.

Keywords: Adrenergic alpha-2 receptor antagonists, analgesics, molecular docking, Moringa peregrina

Research Title: Anti-nociceptive effect of Arbutus andrachne L. methanolic leaf extract mediated by CB1, TRPV1 and PPARs in mouse pain models.

Author: Sahar Majdi Jaffal, Published Year: 2020

Inflammopharmacology 37:189-195.,

Faculty: Science

Abstract: Arbutus andrachne L. is a medicinal plant that grows in Jordan and has many valuable effects. In the present study, the anti-nociceptive effect of A. andrachne methanolic leaf extract was determined in mice using thermal and chemical tests. Our findings show that different doses of A. andrachne extract reduced the number of writhings significantly compared to control group. The leaf extract also reduced the time of paw licking in the early and late phases of formalin test. In all the conducted tests, 300 mg/kg body wt. was the best effective dose. A peroxisome proliferator-activated receptor alpha (PPARα) antagonist reversed the action of the plant extract in the early phase of formalin test while antagonists of the PPARα, PPAR gamma (PPARγ) and cannabinoid 1 (CB1) receptors were responsible for abolishing its effect in the late phase of this test. Also, the extract administration increased the latency time in hot plate and tail flick, an effect that was reversed by the antagonists of PPARγ, CB1 and transient receptor potential vanilloid 1 (TRPV1). No effect was noticed for α2-adrenergic receptor antagonist in the action of A. andrachne in any of the conducted tests in this study. Furthermore, analysis of the constituents in the methanolic leaf extract using liquid chromatography mass spectrometry (LCMS) showed that the extract is rich in compounds that have anti-nociceptive and/or anti-inflammatory effects such as arbutin, rutin, linalool, linoleic acid, gallic acid, lauric acid, myristic acid, hydroquinone, β-sitosterol, ursolic acid, isoquercetin, quercetin, (+)-gallocatechin, kaempferol, α-tocopherol, myricetin 3-O-rhamnoside and catechin gallate. In conclusion, A. andrachne showed promising anti-nociceptive effects in thermal and chemical models of pain. These findings can open an avenue for natural pain relief.

Keywords: Analgesia; Arbutus andrachne; CB1; PPAR; TRPV1; α2 adrenergic.

Research Title: The desensitization of the transient receptor potential vanilloid 1 by nonpungent agonists and its resensitization by bradykinin.

Author: Sahar Majdi Jaffal, Published Year: 2020

Neuroreport , 31(11):781-786.

Faculty: Science

Abstract: Transient receptor potential vanilloid type-1 (TRPV1) channels have crucial roles in inflammatory hyperalgesia. Different inflammatory mediators can modulate TRPV1 sensitization. Bradykinin is an algogenic substance released at the site of inflammation. The aim of the present study is to investigate the desensitization of TRPV1 receptor by nonpungent agonists and to determine how bradykinin and prostaglandin E2 receptors (EP3 and EP4) modulate the resensitization of TRPV1 receptor after being desensitized by nonpungent agonists. Tail flick test was used to investigate capsaicin-induced thermal hyperalgesia and the desensitization of TRPV1 by the nonpungent agonists (olvanil and arvanil) in male BALB/c mice weighed (22-25 g). Resensitization of TRPV1 by bradykinin and the role of prostaglandin receptors in mediating sensitization of TRPV1 were also investigated. Intraplantar injection of capsaicin (0.3 µg) produced a robust thermal hyperalgesia in mice, while olvanil (0.3 µg) or arvanil (0.3 µg) produced no hyperalgesia, emphasizing their lack of pungency. Olvanil and arvanil significantly attenuated capsaicin-induced thermal hyperalgesia in mice. Bradykinin significantly reversed the desensitizing effects of arvanil, but not olvanil. EP4 but not EP3 receptors mediate the sensitization of TRPV1 By bradykinin in vivo. The present study provides evidence for a novel signaling pathway through which bradykinin can regulate the TRPV1 ion channel function via EP4 receptor.

Keywords: TRPV1, pain, EP3, EP4, hyperalgesia