2-Hydroxybenzohydrazide as a novel potential candidate against nociception, inflammation, and pyrexia: in vitro, in vivo, and computational approaches.

The current study was designed to evaluate the 2-hydroxybenzohydrazide (HBH) as a drug having efficacy against pyrexia, inflammation, and nociception. Besides, the therapeutic effects of HBH on oxidative stress and C-reactive proteins were also evaluated. The pharmacological studies on HBH (20-60 mg/kg) were conducted using nociception, inflammation, and pyrexia standard models. Naloxone antagonism was performed to assess the possible involvement of opioidergic mechanisms. The antioxidant study was conducted on ABTS and DPPH assays using gallic acid as a standard. Moreover, the binding capability of HBH with enzymes cyclooxygenase-I/II (COX-I/II) was determined using molecular modeling analysis. The findings indicated that the HBH dose-dependently inhibited pain, inflammation, and pyrexia. The HBH has significant anti-nociceptive and anti-inflammatory activities at 60 mg/kg (***p < 0.001), similar to the lower doses of diclofenac sodium (50 mg/kg) and tramadol (30 mg/kg). The HBH at 60 mg/kg reduced pyrexia as paracetamol (150 mg/kg). The HBH at 20-60 mg/kg doses declined the plasma C-reactive protein concentration. The mechanistic studies showed that the anti-nociceptive effect of HBH was antagonized by naloxone, indicating that the opioidergic mechanisms are involved. Furthermore, computational studies showed that the HBH exhibited an affinity for COX-I/II target receptors. The HBH significantly inhibited ABTS and DPPH radicals (IC50 = 33.81 and 26.74 µg/ml). These results proposed that the HBH has significant antipyretic, anti-inflammatory, and anti-nociceptive activities involving opioidergic mechanism.

Role of plant phytochemicals and microbial enzymes in biosynthesis of metallic nanoparticles.

Metal-based nanoparticles have gained tremendous popularity because of their interesting physical, biological, optical, and magnetic properties. These nanoparticles can be synthesized using a variety of different physical, chemical, and biological techniques. The biological means are largely preferred as it provides an environmentally benign, green, and cost-effective route for the biosynthesis of nanoparticles. These bioresources can act as a scaffold, thereby playing the role of reducing as well as capping agents in the biosynthesis of nanoparticles. Medicinal plants tend to have a complex phytochemical constituent such as alcohols, phenols, terpenes, alkaloids, saponins, and proteins, while microbes have key enzymes which can act as reducing as well as stabilizing agent for NP synthesis. However, the mechanism of biosynthesis is still highly debatable. Herein, the present review is directed to give an updated comprehensive overview towards the mechanistic aspects in the biosynthesis of nanoparticles via plants and microbes. Various biosynthetic pathways of secondary metabolites in plants and key enzyme production in microbes have been discussed in detail, along with the underlying mechanisms for biogenic NP synthesis.

Multifunctional theranostic applications of biocompatible green-synthesized colloidal nanoparticles.

Phytochemicals offer immense promise for sustainable development and production of nanotechnology-enabled products. In the present study, Olax nana Wall. ex Benth. (family: Olacaceae) aqueous extract was used as an effective stabilizing agent to produce biogenic silver (ON-AgNPs) and gold nanoparticles (ON-AuNPs), which were investigated for biocompatibility and prospective biomedical applications (antibacterial, anticancer, antileishmanial, enzyme inhibition, antinociceptive, and anti-inflammatory activities). Various characterization techniques (XRD, FTIR, SEM, TEM, DLS, EDX, and SAED) revealed efficient biosynthesis of ON-AgNPs (26 nm) and ON-AuNPs (47 nm). In the toxicological assessment, ON-AgNPs and ON-AuNPs were found biocompatible towards human RBCs and macrophages (IC50 > 200 µg/mL). In a concentration range of 62.5-2000 µg/mL, a strong antibacterial effect was produced by ON-AgNPs against Staphylococcus epidermidis (MIC = 7.14 µg/mL) and Escherichia coli (8.25 µg/mL), while ON-AuNPs was only active against Staphylococcus aureus (9.14 µg/mL). At a concentration of 3.9-500 µg/mL, a dose-dependant inhibition of HepG2 cancer cells was produced by ON-AgNPs (IC50 = 14.93 µg/mL) and ON-AuNPs (2.97 µg/mL). Both ON-AgNPs and ON-AuNPs were found active against Leishmania tropica (KMH23) promastigotes (IC50 = 12.56 and 21.52 µg/mL) and amastigotes (17.44 and 42.20 µg/mL), respectively, after exposure to a concentration range of 1-200 µg/mL for 72 h. Preferential enzyme inhibition against urease and carbonic anhydrase II were noted for ON-AgNPs (39.23 and 8.89%) and ON-AuNPs (31.34 and 6.34%), respectively; however, these were found inactive against xanthine oxidase at 0.2 mg/mL. In the in vivo antinociceptive (acetic acid-induced abdominal constrictions) and anti-inflammatory (carrageenan-induced paw edema) activities, ON-AgNPs and ON-AuNPs at doses of 40 and 80 mg/kg, significantly attenuated the tonic nociception (P < 0.001) and ameliorated the carrageenan-induced inflammation (P < 0.01, P < 0.001). The results of in vitro and in vivo activities indicated that the biogenic nanoparticles can be used as valuable theranostic agents for further exploration of diverse biomedical applications.

Current state and prospects of the phytosynthesized colloidal gold nanoparticles and their applications in cancer theranostics.

The design, development, and biomedical applications of phytochemical-based green synthesis of biocompatible colloidal gold nanoparticles (AuNPs) are becoming an emerging field due to several advantages (safer, eco-friendly, simple, fast, energy efficient, low-cost, and less toxic) over conventional chemical synthetic procedures. Biosynthesized colloidal gold nanoparticles are remarkably attractive in several biomedical applications including cancer theranostics due to small size, unusual physico-chemical properties, facile surface modification, high biocompatibility, and numerous other advantages. Of late, several researchers have investigated the biosynthesis and prospective applications (diagnostics, imaging, drug delivery, and cancer therapeutics) of AuNPs in health care and medicine. However, not a single review article is available in the literature that demonstrates the anti-cancer potential of biosynthesized colloidal AuNPs with detailed mechanistic study. In the present review article, we for the first time discuss the biointerface of colloidal AuNPs, plants, and cancer mainly (i) comprehensive mechanistic aspects of phytochemical-based synthesis of AuNPs; (ii) proposed anti-cancer mechanisms along with biomedical applications in diagnostics, imaging, and drug delivery; and (iii) key challenges for biogenic AuNPs as future cancer nanomedicine.

A multi-target therapeutic potential of Prunus domestica gum stabilized nanoparticles exhibited prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory and analgesic properties.

BACKGROUND: Phytotherapeutics exhibit diverse pharmacological effects that are based on the combined action of a mixture of phytoconstituents. In this study, Prunus domestica gum-loaded, stabilized gold and silver nanoparticles (Au/Ag-NPs) were evaluated for their prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory, and analgesic properties. METHODS: Au/Ag-NPs were biosynthesized and characterized with UV-Vis, FTIR, SEM, EDX, and XRD techniques. The effect of gum and metal ion concentration, reaction temperature, and time on the synthetic stability of nanoparticles was studied along with their post-synthetic stability against varying pH and salt concentrations, long-term storage and extremes of temperature. Nanoparticles were tested for anticancer (HeLa cervical cancer cells), antibacterial (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), urease inhibition (jack-bean urease), anti-inflammatory (carrageenan-induced paw edema), and antinociceptive (abdominal constriction response) activities. RESULTS: The nanoparticles were mostly spherical with an average particle size between 7 and 30 nm (Au-NPs) and 5-30 nm (Ag-NPs). Au/Ag-NPs maintained their colloidal stability and nanoscale characteristics against variations in physicochemical factors. Au/Ag-NPs have potent anticancer potential (IC50 = 2.14 ± 0.15 µg/mL and 3.45 ± 0.23 µg/mL). Au/Ag-NPs selectively suppressed the growth of S. aureus (10.5 ± 0.6 mm, 19.7 ± 0.4 mm), E. coli (10 ± 0.4 mm, 14.4 ± 0.7 mm), and P. aeruginosa (8.2 ± 0.3 mm, 13.1 ± 0.2 mm), as well as showed preferential inhibition against jack-bean urease (19.2 ± 0.86%, 21.5 ± 1.17%). At doses of 40 and 80 mg/kg, Au-NPs significantly ameliorated the increase in paw edema during the 1st h (P < 0.05, P < 0.01) and 2-5 h (P < 0.001) of carrageenan-induced inflammation compared to the 200 and 400 mg/kg doses of P. domestica gum (P < 0.05, P < 0.001). At similar doses, Au-NPs also significantly abolished (P < 0.01) the tonic visceral, chemically-induced nociception, which was comparable to that of P. domestica gum (200 mg/kg; P < 0.05, 400 mg/kg; P < 0.01).

A Novel Pregabalin Functionalized Salicylaldehyde Derivative Afforded Prospective Pain, Inflammation, and Pyrexia Alleviating Propensities.

A novel pregabalin derivative named as pregsal ((S,E)-3-(((2-hydroxybenzylidene)amino)methyl)-5-methylhexanoic acid) was synthesized by a simple imination reaction between pregabalin and salicylaldehyde and was evaluated in the in vivo testing paradigms. The compound was characterized by UV, IR, 1 H, 13 C NMR, HR ESI-MS, and elemental analysis. It was screened (30, 50, 75, and 100 mg/kg) for antinociceptive, anti-inflammatory, and antipyretic activities in relation to pregabalin. The synthesized compound significantly attenuated the tonic acetic acid-induced nociceptive pain (30 mg/kg (P < 0.05), 50 mg/kg (P < 0.01), 75 and 100 mg/kg (P < 0.001)), and thermal-induced hyperalgesia (P < 0.001). These activities were succinctly antagonized (P < 0.05, P < 0.01, P < 0.001) by naloxone and pentylenetetrazole, implicating the involvement of opioidergic and GABAergic mechanisms. The compound also inhibited the temporal inflammatory response and alleviated the yeast-induced pyrexia (P < 0.05, P < 0.01, and P < 0.001). These findings suggest that the synthesized compound possessed prospective pain, inflammation, and pyrexia relieving propensities and therefore may serve as a potential drug candidate for the therapeutic management of chronic pain conditions.

NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect - why do we keep using it?

The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.

Antinociceptive, muscle relaxant and sedative activities of gold nanoparticles generated by methanolic extract of Euphorbia milii.

BACKGROUND: Nanotechnology has potential future for enhancing therapeutic efficacy and reducing the unwanted effects of herbal drugs. The biological research on Euphorbia species has been supported by the use of some plants in traditional medicines. Many species of Euphorbia have been reported as having strong sedative and analgesic effects. In the present research work gold nanoparticles of Euphorbia milii methanolic extract (Au-EM) were synthesized, characterized and tested for antinociceptive, muscle relaxant and sedative activities. METHODS: Au-EM was prepared by stirring 1 mM warm trihydrated tetrachloroaurate solution with E. milii methanolic extract without using any external reducing agents. The gold nanoparticles were characterized by UV-Visible spectroscopy, infrared spectrophotometery, atomic force microscopy and scanning electron microscopy while their stability was evaluated against varying pH and different volumes of sodium chloride (NaCl). The metal sensing capacity of Au-EM was tested towards cobalt, copper, lead, mercury and nickel. Au-EM was evaluated in BALB/c mice at a dose of 10 and 20 mg/kg for antinociceptive, muscle relaxant and sedative activities in comparison with the crude E. milii methanolic extract. RESULTS: Au-EM showed remarkable stability in different NaCl and pH solutions. Au-EM produced significant (P < 0.01) antinociceptive effect at doses of 10 and 20 mg/kg as compared to the crude E. milii methanolic extract. In the rotarod test, Au-EM showed significant muscle relaxant effect at 10 mg/kg (P < 0.05) and 20 mg/kg (P < 0.01) after 30, 60 and 90 min. In an open field test significant sedative effect (P < 0.05) of Au-EM was observed at 10 and 20 mg/kg. Moreover significant detection sensitivity was demonstrated towards all the tested heavy metals. CONCLUSIONS: These results concluded that the gold nanoparticles improved the potency of E. milii methanolic extract and exhibited significant analgesic, muscle relaxant and sedative properties. The significant metals sensing ability and enhanced stability in different NaCl and pH solutions may enable us to explore different formulations of E. milii gold nanoparticles for potentially effective and safe nano-herbal therapy.

Synthesis and bioactivities of silver nanoparticles capped with 5-amino-ß-resorcylic acid hydrochloride dihydrate.

BACKGROUND: Conjugated and drug loaded silver nanoparticles are getting an increased attention for various biomedical applications. Nanoconjugates showed significant enhancement in biological activity in comparison to free drug molecules. In this perspective, we report the synthesis of bioactive silver capped with 5-Amino-ß-resorcylic acid hydrochloride dihydrate (AR). The in vitro antimicrobial (antibacterial, antifungal), enzyme inhibition (xanthine oxidase, urease, carbonic anhydrase, α-chymotrypsin, cholinesterase) and antioxidant activities of the developed nanostructures was investigated before and after conjugation to silver metal. RESULTS: The conjugation of AR to silver was confirmed through FTIR, UV-vis and TEM techniques. The amount of AR conjugated with silver was characterized through UV-vis spectroscopy and found to be 9% by weight. The stability of synthesized nanoconjugates against temperature, high salt concentration and pH was found to be good. Nanoconjugates, showed significant synergic enzyme inhibition effect against xanthine and urease enzymes in comparison to standard drugs, pure ligand and silver. CONCLUSIONS: Our synthesized nanoconjugate was found be to efficient selective xanthine and urease inhibitors in comparison to Ag and AR. On a per weight basis, our nanoconjugates required less amount of AR (about 11 times) for inhibition of these enzymes.

Efficient microwave synthesis of flurbiprofen derivatives and their enhancement of efficacy in chronic inflammatory pain models and gastro-protective potential in post-operative model.

Present research was designed to synthesize and characterize the flurbiprofen derivatives and to evaluate their analgesic, anti-inflammatory and gastro-protective activities in post-operative and chronic inflammatory pain models. Flurbiprofen derivatives were produced by using three-step processes involving esterification, hydrazide production, and schiff base, each of which modified a different carboxyl group. All the newly synthesized flurbiprofen derivatives (NS5-NS8) were characterized by 1H NMR,13C NMR,19F NMR and HR-ESI-MS, and the post-operative, inflammatory pain and ulcerogenic activities were determined in well-established in-vivo animal models. To evaluate post-operative and inflammatory pain, various doses of compounds [1, 3, 10, and 30 mg/kg (bwt)] were used, while their ulcerogenic potential was assessed at doses of 100 and 150 mg/kg (bwt). The incisional damage linked pain was significantly (p < 0.001) reduced by derivatives at different doses in both the acute and repeated tests with decreased response of phologistic agent-induced inflammation. The stomach histology and biochemical features demonstrate that the synthesized derivatives have no potential to cause ulcerogenicity as compared to aspirin and flurbiprofen. Furthermore, docking shows that the hydrazide moiety of these compounds is crucial in interacting within COX-2 binding site. Therefore, the synthesized compounds exhibit strong analgesic and anti-inflammatory effects and a low risk of causing ulcers. These attributes render them potentially valuable therapeutic agents for the treatment of pathological disorders associated with inflammation and pain.Communicated by Ramaswamy H. Sarma.

Enhanced biocidal activity of Au nanoparticles synthesized in one pot using 2, 4-dihydroxybenzene carbodithioic acid as a reducing and stabilizing agent.

BACKGROUND: The conjugation of gold nanoparticles with biocides such as natural products, oligosaccharides, DNA, proteins has attracted great attention of scientists recently. Gold NPs covered with biologically important molecules showed significant enhancement in biological activity in comparison with the activity of the free biocides. However, these reports are not very systematic and do not allow to draw definitive conclusions. We therefore embarked in a systematic study related to the synthesis and characterization of biocidal activities of Au nanoparticles conjugated to a wide variety of synthetic and natural biomolecules. In this specific report, we investigated the activity of a synthetic biocide, 2-4, Dihydroxybenzene carbodithioic acid (DHT). RESULTS: Au nanoparticles (NP) with a mean size of about 20 nm were synthesized and functionalized in one pot with the help of biocide 2,4-Dihydroxybenzene carbodithioic acid (DHT) to reduce HAuCl4 in aqueous solution. Conjugation of DHT with gold was confirmed by FT-IR and the amount of DHT conjugated to the Au nanoparticles was found to be 7% by weight by measuring the concentration of DHT in the supernatant after centrifugation of the Au NPs. To ascertain the potential for in vivo applications, the stability of the suspensions was investigated as a function of pH, temperature and salt concentration. Antibacterial, antifungal, insecticidal and cytotoxic activities of the Au-DHT conjugates were compared with those of pure DHT and of commercially available biocides. In all cases, the biocidal activity of the Au-DHT conjugates was comparable to that of commercial products and of DHT. CONCLUSIONS: Since the DHT concentration in the Au-DHT conjugates was only about 7%, our results indicate that conjugation to the Au NPs boosts the biocidal activity of DHT by about 14 times. The suspensions were found to be stable for several days at temperatures of up to 100°C, salt concentrations up to 4 mol/L and a pH range of 2-13.

Methyl 2,4-dihy-droxy-5-(4-nitro-benzamido)-benzoate.

In the title compound, C(15)H(12)N(2)O(7), the dihedral angle between the aromatic rings is 4.58 (13)° and the nitro group is rotated from its attached ring by 18.07 (17)°. Intra-molecular N-H⋯O and O-H⋯O hydrogen bonds generate S(5) and S(6) rings, respectively. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, generating [001] C(7) chains. The chains are linked by C-H⋯O inter-actions, forming a three-dimensional network, which incorporates R(2) (2)(7) and R(2) (2)(10) loops.

Methyl 2,4-dihy-droxy-5-(2-methyl-propanamido)-benzoate.

In the title compound, C(12)H(15)NO(5), the dihedral angle between the benzene ring and the C atoms of the terminal isopropyl group is 83.48 (16)°. Intra-molecular N-H⋯O and O-H⋯O hydrogen bonds generate S(5) and S(6) rings, respectively. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, generating C(7) chains propagating in [001]. Weak aromatic π-π stacking [centroid-centroid separation = 3.604 (3) Å] is also observed.

Bio-oriented synthesis of ibuprofen derivatives for enhancement efficacy in post-operative and chronic inflammatory pain models.

The discovery of post-operative, chronic inflammatory pain and any gastroulcerogenic potential using well-established animal models in vivo with new structures, high efficiency, broad-spectrum, and low toxicity has been the focus of medicinal chemists. In the present article, we are reporting the design and synthesis of various derivatives of ibuprofen by modifying the carboxyl group of ibuprofen using three steps reactions; esterification under microwave-irradiation in 10 minutes, hydrazide formation, and finally schiff's base reaction. Microwave-assisted esterification reaction can be employed to quickly explore and increase molecular diversity in synthetic chemistry. All of the newly synthesized compounds (NS1-NS4) were characterized by 1H-, 13C-NMR, and HR-ESI-MS spectroscopy and evaluated for post-operative, chronic inflammatory pain and any gastroulcerogenic potential using well-established animal models in vivo. The synthesized compounds at the tested doses of 100 and 150 mg kg-1 significantly attenuated the incisional-injury induced post-operative pain like condition and, also inhibited the phologistic agent induced inflammatory responses in both the acute and chronic testing paradigms. The gastric histological and biochemical parameters exhibited that the synthesized compounds were devoid of any ulcerogenic potential in comparison to aspirin and ibuprofen. These findings concluded that the synthesized ibuprofen derivatives exhibited profound analgesic, anti-inflammatory properties with reduced ulcerogenic potential and might be considered as effective therapeutic agents to treat pathological conditions associated with pain and inflammation.

3-mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-ß-lactamase inhibitors.

The production of ß-lactamases is an effective strategy by which pathogenic bacteria can develop resistance against ß-lactam antibiotics. While inhibitors of serine-ß-lactamases are widely used in combination therapy with ß-lactam antibiotics, there are no clinically available inhibitors of metallo-ß-lactamases (MBLs), and so there is a need for the development of such inhibitors. This work describes the optimisation of a lead inhibitor previously identified by fragment screening of a compound library. We also report that thiosemicarbazide intermediates in the syntheses of these compounds are also moderately potent inhibitors of the IMP-1 MBL from Pseudomonas aeruginosa. The interactions of these inhibitors with the active site of IMP-1 were examined using in silico methods.

2-(6-Meth-oxy-naphthalen-2-yl)-1-(morpholin-4-yl)propan-1-one.

In the title compound, C(18)H(21)NO(3), the naphthalene group and the basal plane of the morpholine ring (r.m.s. deviations = 0.0177 and 0.0069 Å, respectively) are oriented at a dihedral angle of 44.0 (2)°. In the crystal, mol-ecules are linked by C-H⋯π inter-actions.

2-(4-Isobutyl-phen-yl)-1-(morpholin-4-yl)propan-1-one.

In the title compound, C(17)H(25)NO(2), the morpholine ring adopts a chair conformation. The benzene ring makes a dihedral angle of 39.81 (13)° with the basal plane of the morpholine group.

5-Carb-oxy-2,4-dihy-droxy-anilinium chloride dihydrate.

In the title compound, C(7)H(8)NO(4) (+)·Cl(-)·2H(2)O, the organic mol-ecule is almost planar with an r.m.s. deviation of 0.0164 Šfor all non-H atoms. An S(6) ring motif is formed due to an intra-molecular O-H⋯O hydrogen bond. In the crystal, the mol-ecules are linked into a three-dimensional network by N-H⋯Cl, N-H⋯O, O-H⋯Cl and O-H⋯O hydrogen bonds.

The antioxidant N-(2-mercaptopropionyl)-glycine (tiopronin) attenuates expression of neuropathic allodynia and hyperalgesia.

The current pharmacotherapy of neuropathic pain is inadequate as neuropathic pain involves varied clinical manifestations with multifactorial etiology, modulated by a cascade of physical and molecular events leading to different clinical presentations of pain. There is an accumulating evidence of the involvement of oxidative stress in neuropathy, and antioxidants have shown promise in mitigating neuropathic pain syndromes. To explore the evidence supporting this beneficial proclivity of antioxidants, this study investigated the antinociceptive effectiveness of N-(2-mercaptopropionyl)glycine or tiopronin, a well-recognized aminothiol antioxidant, in a refined chronic constriction injury (CCI) rat model of neuropathic pain. Tiopronin (10, 30, and 90 mg/kg, i.p.) and pregabalin (30 mg/kg, i.p.) were administered daily after CCI surgery. The neuropathic paradigms of mechanical/cold allodynia and mechanical/heat hyperalgesia were assessed on days 3, 7, 14, and 21 post-nerve ligation. At the end of study, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were estimated in the sciatic nerve, dorsal root ganglion, and spinal cord for assessing the extent of oxidative stress. The expression of neuropathic nociception was attenuated by tiopronin which was observed as a significant attenuation of CCI-induced allodynia and hyperalgesia. Tiopronin reversed the neuronal oxidative stress by significantly reducing MDA, and increasing SOD, CAT, and GSH levels. Pregabalin also showed similar beneficial propensity on CCI-induced neuropathic aberrations. These findings suggest prospective neuropathic pain attenuating efficacy of tiopronin and further corroborated the notion that antioxidants are effective in mitigating the development and expression of neuropathic pain and underlying neuronal oxidative stress.

Pharmacological evaluation of the gabapentin salicylaldehyde derivative, gabapentsal, against tonic and phasic pain models, inflammation, and pyrexia.

Gabapentinoids are effective drugs in most animal models of pain and inflammation with variable effects in humans. The current study evaluated the pharmacological activity of gabapentin (GBP) and its salicylaldehyde derivative (gabapentsal; [2-(1-(((2-hydroxybenzylidene) amino) methyl) cyclohexyl) acetic acid]; GPS) in well-established mouse models of nociceptive pain, inflammatory edema, and pyrexia at doses of 25-100 mg/kg. GPS allayed tonic visceral pain as reflected by acetic acid-induced nociception and it also diminished thermally induced nociception as a mimic of phasic thermal pain. Antagonism of GPS-induced antinociceptive activities by naloxone (NLX, 1.0 mg/kg, subcutaneously, s.c), beta-funaltrexamine (ß-FNT, 5.0 mg/kg, s.c), naltrindole (NT, 1.0 mg/kg, s.c), and nor-binaltorphimine (NOR-BNI, 5.0 mg/kg, s.c), and pentylenetetrazole (PTZ-15 mg/kg, intraperitoneally, i.p) implicated an involvement of both opioidergic and GABAergic mechanisms. Tail immersion test was conducted in order to delineate the mechanistic insights of antinociceptive response. Inflammatory edema induced by carrageenan, histamine, or serotonin was also effectively reversed by GPS in a fashion analogous to aspirin (150 mg/kg, i.p), chlorpheniramine (1.0 mg/kg, i.p), and mianserin (1.0 mg/kg, i.p), respectively. Additionally, yeast-induced pyrexia was decreased by GPS in a comparable manner to acetaminophen (50 mg/kg, i.p). These observations suggest that GPS possesses ameliorative properties in tonic, phasic, and tail immersion tests of nociception via opioidergic and GABAergic mechanisms, curbs inflammatory edema, and is antipyretic in nature.