Phosphonate Derivatives of Paracetamol and Valproic Acid.

Paracetamol and valproic acid are standalone drugs with leading position in the world drug market. The phosphonate analogues of these drugs were synthesized and were tested in vivo. N-(4-hydroxyphenylcarbamoyl)phosphonic acid was four times more potent than paracetamol in preventing acetic acid-induced writhing. Phosphonate derivative of valproic acid, (2-propylpentanoyl)phosphonic acid, had similar in vivo activity to valproic acid in the pentylenetetrazole-induced kindling mouse model.

Measuring sociability of mice using a novel three-chamber apparatus and algorithm of the LABORAS™ system.

BACKGROUND: The social approach and social novelty tests utilizing the three-chamber apparatus are widely accepted to measure social behavior of rodents. The LABORAS™ system offers a possibility to assess sociability of mice in a reliable and objective manner. NEW METHOD: We assessed the capability of the LABORAS™ sociability cage and algorithm (2.6.6) to detect social behaviors in mice. Furthermore, we investigated whether the system is able to detect various levels of sociability due to genetic background or after pharmacological treatments. RESULTS: By comparing manual scoring with various detection zone settings of the automated registration, the most fitting algorithm with a detection zone radius of 90 mm was identified. When different strains were investigated, C57Bl/6 J and NMRI mice proved to be social, while CD1 mice were found asocial. The system was able to detect the sociability increasing effect of R-baclofen (0.5 mg/kg i.p.) and oxytocin (12 ng i.c.v.) in asocial CD1 mice. The negative control PCP impaired social behavior of C57Bl/6 J mice (1 mg/kg i.p.) and increased social avoidance in CD1 mice (0.3 mg/kg i.p.). COMPARISON WITH EXISTING METHOD(S): This setup, in contrast to video frame analysis softwares, determines signal changes caused by movements of rodents allowing accurate detection and analysis of trajectories. Parallel automated measurements also allow replacing time and labor intensive, highly subjective human observational work. CONCLUSIONS: The set-up provides a fast and reliable method to examine social behavior of mice in the three-chamber apparatus. The system is capable of detecting pro or antisocial activity of pharmacological agents.

Utility of different outcome measures for the nitroglycerin model of migraine in mice.

INTRODUCTION: Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet. METHODS: We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial pain hypersensitivity. RESULTS: We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan. DISCUSSION: Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the human NTG models of migraine, these tests might be valuable translational research tools for development of new anti-migraine drugs.

Effect of transient receptor potential vanilloid 1 (TRPV1) receptor antagonist compounds SB705498, BCTC and AMG9810 in rat models of thermal hyperalgesia measured with an increasing-temperature water bath.

The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. The effects of TRPV1 receptor antagonists were assessed in thermal hyperalgesia induced by the TRPV1 agonist resiniferatoxin (RTX), mild heat injury (51 degrees C, 20s) or plantar incision in rats. The control heat threshold was 43.2+/-0.4 degrees C. RTX induced an 8-10 degrees C decrease in heat threshold which was dose-dependently inhibited by oral pre-treatment with any of the TRPV1 receptor antagonists with a minimum effective dose of 1mg/kg. The mild heat injury-evoked 7-8 degrees C heat threshold drop was significantly reversed by all three antagonists injected i.p. as post-treatment. The minimum effective doses were as follows: SB705498 10, BCTC 3 and AMG9810 1mg/kg. Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.

New celecoxib derivatives as anti-inflammatory agents.

A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (+/-)-2-[4-(5- p-tolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.

Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain.

Chronic pain states and epilepsies are common therapeutic targets of voltage-gated sodium channel blockers. Inhibition of sodium channels results in central muscle relaxant activity as well. Selective serotonin reuptake inhibitors are also applied in the treatment of pain syndromes. Here, we investigate the pharmacodynamic interaction between these two types of drugs on spinal neurotransmission in vitro and in vivo. Furthermore, the ability of serotonin reuptake inhibitors to modulate the anticonvulsant and windup inhibitory actions and motor side effect of the sodium channel blocker lamotrigine was investigated. In the hemisected spinal cord model, we found that serotonin reuptake inhibitors increased the reflex inhibitory action of sodium channel blockers. The interaction was clearly more than additive. The potentiation was prevented by blocking 5-HT(2) receptors and PKC, and mimicked by activation of these targets by selective pharmacological tools, suggesting the involvement of 5-HT(2) receptors and PKC in the modulation of sodium channel function. The increase of sodium current blocking potency of lamotrigine by PKC activation was also demonstrated at cellular level, using the whole-cell patch clamp method. Similar synergism was found in vivo, in spinal reflex, windup, and maximal electroshock seizure models, but not in the rotarod test, which indicate enhanced muscle relaxant, anticonvulsant and analgesic activities with improved side effect profile. Our findings are in agreement with clinical observations suggesting that sodium channel blocking drugs, such as lamotrigine, can be advantageously combined with selective serotonin reuptake inhibitors in some therapeutic fields, and may help to understand the molecular mechanisms underlying the interaction.

Nitrone derivatives of trolox as neuroprotective agents.

Synthesis of nitrone derivatives of trolox is described. Their biological evaluation was performed in vitro for scavenging different free radicals, inhibiting Fe(2+)-induced lipid peroxidation, and in vivo in a permanent middle cerebral artery occlusion model in mice. New compounds exert pharmacological activities comparable to or better than those of trolox or nitrone-type reference compounds.