Dietary phytate induces subclinical mechanical allodynia in mice

Neuropathic pain is a condition with varying origins, including reduced dietary micronutrient intake. Phytate is a polyphosphate found in seeds and grains that can act as an antinutrient due to the ability of sequester essential divalent metals. Here we tested whether moderate dietary phytate intake could alter nociceptive pain. We subjected weaning mice to a chow supplemented with 1% phytate for eight weeks. Body weight gain, glycemic responses, food ingestion, water ingestion, and liver and adipose tissue weights were not altered compared to controls. We observed a decreased mechanical allodynia threshold in the intervention group, although there were no changes in heat- or cold-induced pain. Animals consuming phytate showed reduced spinal cord tumor necrosis factor (TNF), indicating altered inflammatory process. These data provide evidence for a subclinical induction of mechanical allodynia that is independent of phytate consumption in animals with otherwise normal phenotypic pattern.

Anti-inflammatory and antinociceptive activities of an acid fraction of the seeds of Carpotroche brasiliensis (Raddi) (Flacourtiaceae)

Carpotroche brasiliensis is a native Brazilian tree belonging to the Oncobeae tribe of Flacourtiaceae. The oil extracted from its seeds contains as major constituents the same cyclopentenyl fatty acids hydnocarpic (40.5 percent), chaulmoogric (14.0 percent) and gorlic (16.1 percent) acids found in the better known chaulmoogra oil prepared from the seeds of various species of Hydnocarpus (Flacourtiaceae). These acids are known to be related to the pharmacological activities of these plants and to their use as anti-leprotic agents. Although C. brasiliensis oil has been used in the treatment of leprosy, a disease that elicits inflammatory responses, the anti-inflammatory and analgesic activities of the oil and its constituents have never been characterized. We describe the anti-inflammatory and antinociceptive activities of C. brasiliensis seed oil in acute and chronic models of inflammation and in peripheral and central nociception. The mixture of acids from C. brasiliensis administered orally by gavage showed dose-dependent (10-500 mg/kg) anti-inflammatory activity in carrageenan-induced rat paw edema, inhibiting both the edema by 30-40 percent and the associated hyperalgesia. The acid fraction (200 mg/kg) also showed significant antinociceptive activity in acetic acid-induced constrictions (57 percent inhibition) and formalin-induced pain (55 percent inhibition of the second phase) in Swiss mice. No effects were observed in the hot-plate (100 mg/kg; N = 10), rota-road (200 mg/kg; N = 9) or adjuvant-induced arthritis (50 mg/kg daily for 7 days; N = 5) tests, the latter a chronic model of inflammation. The acid fraction of the seeds of C. brasiliensis which contains cyclopentenyl fatty acids is now shown to have significant oral anti-inflammatory and peripheral antinociceptive effects.

2-pyridylarylhydrazone derivatives, a new class of platelet aggregation inhibitors

A series of 2-pyridylarylhydrazone derivatives was synthesized and compared with a previously reported pyrazole series, i.e., 4-acylpyrazolylarylhydrazone and 5-pyrazolylarylhydrazone, which present antiplatelet aggregation activity. The structures of these pyridylarylhydrazone derivatives were designed on the basis of the known bioisosteric relationship of the heteroaromatic ring. The antiplatelet aggregation activity was measured in vitro on citrated platelet-rich rabbit plasma in which aggregation was induced with 5 muM ADP, 5 mug/ml collagen and 200 muM arachidonic acid. Eighteen compounds belonging to the pyridine series were tested at 1 mM concentration and none inhibited ADP-induced rabbit platelet aggregation. 2-(2-Formylfurane)pyridylhydrazone exhibited a highly potent inhibitory activity on arachidonic acid-induced aggregation, with an IC50 of 0.35 muM. These results suggest that the hydrazone unit and the 2-furyl moiety of the arylhydrazone framework are important pharmacophores for antiplatelet activity.

Substituded pyrazolylhydrazones: a new class of platelet aggregation inhibitors

A series of 5-pyrazolylhydrazone derivates (I) were designed to be mixed hybrid isosteres of both BW-755C and CBS-1108 which belong to the class of dual cyclooxygenase and 5-lipoxygenase inhibitors. Pharmacological evaluation of some members of this series (Ia, 1-formy 1-3,4-methylenedioxy-6-nitrobenzene-5-(1-phenyl-3-methyl-4-nitropyrazolil)hydrazone; Ib, 2-formylfurane-5-(1-phenyl-3-methyll-4-nitropyrazolyl)hidrazone; Ic, (E)-2-(formylethenylfurane)-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydrazone showed that they inhibit the in vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5µM), collagen (5µg/ml) and arachidonic acid (100 µM). Compounds Ia and Ic at 100 µM concentration showed 49% and 58% inhibition, respectively, of ADP-induced aggregation. In the arachidonic acid-induced aggregation, compounds Ia and Ib at 100 µM concentration fully inhibited platelet aggregation. All compounds significantly inhibited the collagen-induced aggregation. In contrast, indomethacin (10 µM) showed 100% and 85% aggregation inhibition against arachidonic acid and collagen, respectivelym, and was inactive in the ADP- induced aggregation test. These results suggest that the structure-activity relationship in this series of compounds is dependent on the hydrazone moiety at position 5 of the pyrazole ring and on the distance between the aryl ring and the pyrazole ring and that the 2-furyl ring is at the optimal distance for the maximal activity