Pharmacological Analysis of the Anti-inflammatory and Antiallodynic Effects of Zinagrandinolide E from Zinnia grandiflora in Mice.

Zinagrandinolide E (1, ZGE) is an elemanolide with antinociceptive action isolated from Zinnia grandiflora (Asteraceae), valued in North México and southwestern United States for pain relief. Herein, we report the anti-inflammatory and antiallodynic action of ZGE (1) in carrageenan-induced inflammation and tactile allodynia in mice and in a neuropathic pain model in hyperglycemic mice. Local peripheral administration of ZGE (1-30 µg/paw) induced dose-dependent acute anti-inflammatory and antiallodynic effects. The anti-inflammatory effect was comparable to diclofenac (30 µg/paw). Intrathecal (i.t.) administration of ZGE (30 µg) in acute experiments did not affect carrageenan-induced inflammation but significantly reduced tactile allodynia in a dose-dependent fashion. In long-term experiments (15 or 6 days), using two different scheme treatments (pretreatment or post-treatment), ZGE (3-30 µg/paw) showed antiallodynic but not anti-inflammatory action. Local peripheral (3-30 µg/paw) or intrathecal (3-30 µg) administration of ZGE partially reversed tactile allodynia in hyperglycemic mice, better or comparable, respectively, with those of pregabalin (30 µg/paw or 30 µg i.t.). The effects were dose-dependent. According to the pharmacological tools employed, the anti-inflammatory and antiallodynic activities of ZGE are multitarget; these involve the opioidergic, serotoninergic, and GABAergic systems, as well as the NO-cGMP-ATP-sensitive K+ channel signaling pathway.

Antinociceptive effects of ceftriaxone in formalin-induced nociception.

Ceftriaxone (CFX) is a ß-lactam antibiotic with analgesic properties. However, its role in the formalin-induced nociception remains unknown. The purpose of this study was to investigate the antinociceptive effect of CFX in the 1% formalin test in rats. Formalin induced a typical nociceptive response (flinching behavior) of two phases. Local peripheral pretreatment (20 min) with CFX (400-800 µg/paw) slightly attenuated the flinching behavior in phase 2, but not phase 1. Acute intraperitoneal pretreatment (20 min) also reduced phase 2 of the formalin test. In both cases, CFX induced a dose-dependent antinociception. We also tested the effect of CFX 1 day after its administration and in two schedules of repeated administration. One-day pretreatment with CFX (50-400 mg/kg, ip) induced a dose-dependent antinociceptive effect in formalin-treated rats. Repeated administration (daily during 3 or 7 days) with CFX (50-400 mg/kg, ip) diminished formalin-induced nociception. Results suggest that local or systemic as well as single or repeated administration of CFX reduces formalin-induced nociception.

Antinociceptive Potential of Zinnia grandiflora.

An aqueous extract prepared from the aerial parts of Zinnia grandiflora was found not to induce acute toxicity (LD50> 5g/kg, p.o.) in mice when tested by the Lorke method. This extract showed notable antinociceptive and anti-inflammatory actions when evaluated by the formalin- (ED50 = 224.62 ± 38.17 mg/kg, p.o.) and the carrageenan-induced paw edema models in mice, respectively. The organic-soluble fractions obtained by partitioning the infusion with CH2Cl2 and EtOAc were also active in the formalin test. The most important antinociceptive effect was observed with the CH2Cl2 fraction; extensive fractionation of the latter yielded three new elemanolides, namely, zinagranolides D-F (1-3), which were characterized structurally by spectroscopic means. The structure of compound 2 was established unequivocally by an X-ray crystallographic analysis. This compound exerted a significant antinociceptive effect in the formalin assay, better than that of diclofenac used as a positive control.

Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1-400 Inhibitors.

Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B1-400), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B1-400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a-15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b-37b). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.

Anxiolytic- and antidepressant-like effects of an aqueous extract of Tanacetum parthenium L. Schultz-Bip (Asteraceae) in mice.

AIM: Tanacetum parthenium L. Schultz-Bip (Asteraceae) is widely used worldwide in traditional medicine for the treatment of convulsions and culture-bound syndromes such as susto (fear). The aim of this work was to evaluate the anxiolytic- and antidepressant-like effects of an aqueous extract of T. parthenium in behavioral paradigms in mice. The effects of T. parthenium were compared with those produced by anxiolytic and antidepressant drugs. We carried out the chemical characterization of the main constituents of T. parthenium. The involvement with the GABAergic and serotoninergic neurotransmitter systems were explored be means of synergic and antagonist experiments. MATERIALS AND METHODS: The anxiolytic-like effect was evaluated using the Burying Behavior Test (BBT) and the Elevated Plus-Maze Test (PMT). The antidepressant-like effect was evaluated in the Forced Swimming Test (FST), and ambulatory activity was assessed in the Open Field Test (OFT). Employing the behavioral tests, synergism and antagonism experiments with Alprazolam, Muscimol, and Picrotoxin were carried out in the PMT. In a series of independent experiments, concomitant administration of T. parthenium and Alprazolam, Fluoxetine, or p-chlorophenylalanine were conducted in the FST. For chemical characterization, High-Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry (HPLC-ESI-MS) analysis was performed. RESULTS: T. parthenium exerts clear anxiolytic- and antidepressant-like effects in mice, without affecting the ambulatory activity of the experimental subjects. CONCLUSIONS: Anxiolytic- and antidepressant-like T. parthenium effects result, at least part from the involvement of the GABAergic system. Our results support the use of Tanacetum parthenium in traditional medicine and suggest its therapeutic potential in the comorbid anxiety and depression.