The novel analgesic compound OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia. (1/180)

We investigated the effects of OT-7100, a novel analgesic compound (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidi ne), on prostaglandin E2 biosynthesis in vitro, acute hyperalgesia induced by yeast and substance P in rats and hyperalgesia in rats with a chronic constriction injury to the sciatic nerve (Bennett model), which is a model for peripheral neuropathic pain. OT-7100 did not inhibit prostaglandin E2 biosynthesis at 10(-8)-10(-4) M. Single oral doses of 3 and 10 mg/kg OT-7100 were effective on the hyperalgesia induced by yeast. Single oral doses of 0.1, 0.3, 1 and 3 mg/kg OT-7100 were effective on the hyperalgesia induced by substance P in which indomethacin had no effect. Repeated oral administration of OT-7100 (10 and 30 mg/kg) was effective in normalizing the mechanical nociceptive threshold in the injured paw without affecting the nociceptive threshold in the uninjured paw in the Bennett model. Indomethacin had no effect in this model. While amitriptyline (10 and 30 mg/kg) and clonazepam (3 and 10 mg/kg) significantly normalized the nociceptive threshold in the injured paw, they also increased the nociceptive threshold in the uninjured paw. These results suggest that OT-7100 is a new type of analgesic with the effect of normalizing the nociceptive threshold in peripheral neuropathic hyperalgesia.  (+info)

The effects of clonazepam on quality of life and work productivity in panic disorder. (2/180)

Although panic disorder has been associated with impaired quality of life (QOL) and financial dependence, no prior study has examined whether a clinical intervention will improve these outcomes. This study examines the effects of clinically titrated doses of clonazepam versus placebo on QOL and work productivity (WP) in patients with panic disorder. QOL and WP were measured in conjunction with a randomized, double-blind, placebo-controlled trial. The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and Work Productivity and Impairment questionnaire were used to assess QOL and WP, respectively. Baseline assessments were obtained before randomizing patients to receive clinically titrated doses of clonazepam or placebo. Follow-up assessments were obtained after 6 weeks of therapy with the test drug or at premature termination from the study. Improvement on the SF-36 Mental Health Component Summary scale was more than twice as great with clonazepam than with placebo (P = 0.03). Clonazepam patients improved (P < 0.05) on all five measures of mental health-related QOL, and both measures of physical health-related QOL, and both measures of WP. Placebo patients improved on three of five measures of mental health-related QOL, but on no other measures. Patients with marked improvements on clinical measures of panic disorder severity, especially avoidance and fear of the main phobia, showed the greatest gains on the SF-36 Mental Health Component Summary scale. Clinically titrated doses of clonazepam significantly improved mental health-related QOL and WP in panic disorder patients. Lesser improvements were obtained with placebo.  (+info)

Reactive oxygen metabolites increase mitochondrial calcium in endothelial cells: implication of the Ca2+/Na+ exchanger. (3/180)

In endothelial cells, a bolus of hydrogen peroxide (H2O2) or oxygen metabolites generated by hypoxanthine-xanthine oxidase (HX-XO) increased the mitochondrial calcium concentration [Ca2+]m. Both agents caused a biphasic increase in [Ca2+]m which was preceded by a rise in cytosolic free calcium concentration [Ca2+]c (18 and 6 seconds for H2O2 and HX-XO, respectively). The peak and plateau elevations of [Ca2+] were consistently higher in the mitochondrial matrix than in the cytosol. In Ca2+-free/EGTA medium, the plateau phase of elevated [Ca2+] evoked by H2O2 due to capacitative Ca2+ influx was abolished in the cytosol, but was maintained in the mitochondria. In contrast to H2O2 and HX-XO, ATP which binds the P2Y purinoceptors induced an increase in [Ca2+]m that was similar to that of [Ca2+]c. When cells were first stimulated with inositol 1,4, 5-trisphosphate-generating agonists or the Ca2+-ATPase inhibitor cyclopiazonic acid (CPA), subsequent addition of H2O2 did not affect [Ca2+]c, but still caused an elevation of [Ca2+]m. Moreover, the specific inhibitor of the mitochondrial Ca2+/Na+ exchanger, 7-chloro-3,5-dihydro-5-phenyl-1H-4.1-benzothiazepine-2-on (CGP37157), did not potentiate the effects of H2O2 and HX-XO on [Ca2+]m, while causing a marked increase in the peak [Ca2+]m and a significant attenuation of the rate of [Ca2+]m efflux upon addition of histamine or CPA. In permeabilized cells, H2O2 mimicked the effects of CGP37157 causing an increase in the basal level of matrix free Ca2+ and decreased efflux. Dissipation of the electrochemical proton gradient by carbonylcyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), and blocade of the Ca2+ uptake by ruthenium red prevented [Ca2+]m increases evoked by H2O2. These results demonstrate that the H2O2-induced elevation in [Ca2+]m results from a transfer of Ca2+ secondary to increased [Ca2+]c, and an inhibition of the Ca2+/Na+ electroneutral exchanger of the mitochondria.  (+info)

Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential. (4/180)

Peripheral-type benzodiazepines have been shown to exert immunological effects. In this study, we examined the effects of the peripheral-type benzodiazepines on murine thymocytes. Murine thymocytes that were incubated with the peripheral-type benzodiazepines underwent apoptosis associated with the collapse of mitochondrial transmembrane potential (delta psi(m)). The drugs stimulated dexamethasone- and etoposide-induced apoptosis with the enhanced collapse of delta psi(m). The central-type benzodiazepines had no effect on either the delta psi(m) or apoptosis. The reduction of delta psi(m) depended on protein synthesis and protein phosphorylation. These results suggest that the immunomodulating effect of benzodiazepines is in part due to the modulation of thymocyte apoptosis associated with the collapse of delta psi(m).  (+info)

Central and peripheral benzodiazepine ligands prevent mitochondrial damage induced by noise exposure in the rat myocardium: an ultrastructural study. (5/180)

Noise represents an environmental stress factor affecting several organs and apparatuses, including the cardiovascular system. In experimental animals undergoing noise exposure, subcellular myocardial changes have been reported, especially at the mitochondrial level. In previous studies we found that diazepam, acting at both central and peripheral benzodiazepine receptors, prevented the onset of this myocardial damage. In the present study, we investigated the specific role played by central and/or peripheral benzodiazepine receptors in preventing noise-induced myocardial alterations. In particular, the effect of clonazepam as a selective ligand for central sites, in comparison with the efficacy of ligands selective for peripheral sites, such as Ro 5-4864 and PK-11195, was evaluated. Rats were pretreated with the test drugs 30 min before exposure to noise for 6 or 12 hr and then sacrificed. After fixing, samples of right atrium and ventricle were taken and processed for either transmission or scanning electron microscopy. After 6 hr of noise exposure, only the atrium exhibited significant mitochondrial alterations, whereas after 12 hr both atrium and ventricle were damaged. As expected, diazepam prevented noise-induced mitochondrial injury at both 6 and 12 hr. By contrast, clonazepam was effective only after 6 hr. The peripheral ligand PK-11195 attenuated mitochondrial damage at both 6 and 12 hr, whereas Ro 5-4864 was effective only after 12 hr. In the present study, we confirm that noise exposure induces mitochondrial damage in the rat myocardium. Drugs acting at both central and peripheral benzodiazepine receptors significantly prevent this damage. Differences in the amount and in the duration of the protective effect might depend on variability in the potency and in the pharmacokinetics of the specific drugs.  (+info)

Mitochondrial clearance of cytosolic Ca(2+) in stimulated lizard motor nerve terminals proceeds without progressive elevation of mitochondrial matrix [Ca(2+)]. (6/180)

This study used fluorescent indicator dyes to measure changes in cytosolic and mitochondrial [Ca(2+)] produced by physiological stimulation of lizard motor nerve terminals. During repetitive action potential discharge at 10-50 Hz, the increase in average cytosolic [Ca(2+)] reached plateau at levels that increased with increasing stimulus frequency. This stabilization of cytosolic [Ca(2+)] was caused mainly by mitochondrial Ca(2+) uptake, because drugs that depolarize mitochondria greatly increased the stimulation-induced elevation of cytosolic [Ca(2+)], whereas blockers of other Ca(2+) clearance routes had little effect. Surprisingly, during this sustained Ca(2+) uptake the free [Ca(2+)] in the mitochondrial matrix never exceeded a plateau level of approximately 1 microM, regardless of stimulation frequency or pattern. When stimulation ceased, matrix [Ca(2+)] decreased over a slow ( approximately 10 min) time course consisting of an initial plateau followed by a return to baseline. These measurements demonstrate that sustained mitochondrial Ca(2+) uptake is not invariably accompanied by progressive elevation of matrix free [Ca(2+)]. Both the plateau of matrix free [Ca(2+)] during stimulation and its complex decay after stimulation could be accounted for by a model incorporating reversible formation of an insoluble Ca salt. This mechanism allows mitochondria to sequester large amounts of Ca(2+) while maintaining matrix free [Ca(2+)] at levels sufficient to activate Ca(2+)-dependent mitochondrial dehydrogenases, but below levels that activate the permeability transition pore.  (+info)

Human neuronal gamma-aminobutyric acid(A) receptors: coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. (7/180)

gamma-Aminobutyric acid(A) receptors (GABARs) are heteromeric proteins composed of multiple subunits. Numerous subunit subtypes are expressed in individual neurons, which assemble in specific preferred GABAR configurations. Little is known, however, about the coordination of subunit expression within individual neurons or the impact this may have on GABAR function. To investigate this, it is necessary to profile quantitatively the expression of multiple subunit mRNAs within individual cells. In this study, single-cell antisense RNA amplification was used to examine the expression of 14 different GABAR subunit mRNAs simultaneously in individual human dentate granule cells (DGCs) harvested during hippocampectomy for intractable epilepsy. alpha4, beta2, and delta-mRNA levels were tightly correlated within individual DGCs, indicating that these subunits are expressed coordinately. Levels of alpha3- and beta2-mRNAs, as well as epsilon- and beta1-mRNAs, also were strongly correlated. No other subunit correlations were identified. Coordinated expression could not be explained by the chromosomal clustering of GABAR genes and was observed in control and epileptic rats as well as in humans, suggesting that it was not species-specific or secondary to epileptogenesis. Benzodiazepine augmentation of GABA-evoked currents also was examined to determine whether levels of subunit mRNA expression correlated with receptor pharmacology. This analysis delineated two distinct cell populations that differed in clonazepam modulation and patterns of alpha-subunit expression. Clonazepam augmentation correlated positively with the relative expression of alpha1- and gamma2-mRNAs and negatively with alpha4- and delta-mRNAs. These data demonstrate that specific GABAR subunit mRNAs exhibit coordinated control of expression in individual DGCs, which has significant impact on inhibitory function.  (+info)

A unique effect of clonazepam on frontal lobe seizure control. (8/180)

In a 16-year-old female, clonazepam (CZP) changed randomly occurring intractable tonic seizures of frontal lobe origin to a few sleep seizures when used as an adjunctive therapy. The significance of this change in the seizure pattern is discussed with an explanation of possible pathophysiologic mechanism.  (+info)