Central effects of the neurotropic mycotoxin fumitremorgin A in the rabbit (I). Effects on the spinal cord

Effects of a potent neurotropic mycotoxin, fumitremorgin A (FTA), on the spinal cord were studied, using rabbits lightly anesthetized with urethane and chloralose. Spontaneous discharges of L7 spinal ventral roots and common peroneal nerves were increased after intravenous injection of 100-200 micrograms/kg of FTA. Their abnormal discharge pattern represented the convulsive effect of FTA. Spinal monosynaptic reflexes became irregular in amplitude, with a slight predominance of smaller reflexes. Polysynaptic reflexes were inhibited in many cases. These FTA-induced changes in ventral root discharges and spinal reflexes were abolished by spinal transection at a segment of the upper level. These results suggest that FTA may have no direct facilitatory action on spinal motoneurons and that its remarkable motor effect has its origin in the supraspinal central nervous system.     

Central effects of the neurotropic mycotoxin fumitremorgin A in the rabbit. (II). Effects on the brain stem

In order to determine the main site of the convulsant action of the neurotropic mycotoxin fumitremorgin A, the role of the brain stem reticular formation was studied. In rabbits lightly anesthetized with urethane and chloralose, electrical stimulation of the reticular formation elicited burst discharges in the common peroneal nerve and in the tibial nerve. This facilitatory effect of electrical stimulation was markedly potentiated by intravenous administration of a small dose of FTA, before onset of actual convulsion. Under the influence of FTA, a remarkable increase in the spontaneous electrical activity of the midbrain reticular formation was observed. The firing pattern of some neurons in the reticular formation corresponded very well with abnormal burst discharges in the common peroneal nerve. These effects of FTA were inhibited by chlorpromazine (0.1-1.0 mg/kg, i.v.), diazepam (0.1-1.0 mg/kg, i.v.), mephenesin (5-10 mg/kg, i.v.) and pentobarbital (5-15 mg/kg, i.v.). It was concluded that FTA might activate some neurons in the midbrain reticular formation and that convulsive burst discharges in peripheral motor nerves resulted from abnormal activation of these neurons, although the role of the medullary reticular formation could not be excluded.     

Actions of a tremorgenic mycotoxin on amino acid transmitter release in vivo

The tremorgenic mycotoxin verruculogen was administered directly into the brain of freely moving rats by the use of cannula systems that superfused either the cortical surface or the lateral ventricular space. The tremor produced by these CNS routes was compared with that produced by i.p. administration of the toxin or the dried mycelium of the fungus that synthesizes the verruculogen. The nature and degree of tremor produced by the central vs peripheral routes suggest that the site of action of verruculogen is not immediately adjacent to the cannula sites in the brain. Measures of the amino acids in the superfusates collected during the verruculogen-induced tremor showed an increase in the excitatory neurotransmitters, glutamate and aspartate in superfusates from the lateral ventricle but not in superfusates from the cortical surface. The differential effect on transmitter release suggests that a subcortical action of verruculogen is responsible for its tremorgenic activity.     

Fate of TR-2, the hepatic metabolite of the tremorgenic mycotoxin verruculogen, in sheep

1. Verruculogen is eliminated in bile after transformation to TR-2, only a trace of which was excreted as such in faeces of sheep given verruculogen per os. Negligible TR-2 was present free in urine; no glucuronide was found. 2. An isomer of TR-2, a minor component of the bile of sheep given verruculogen, has been defined by 1H-n.m.r. spectroscopy and the isomerism involves the disposition of the two adjacent hydroxyl groups with a concomitant change in the conformation of the ring adjacent to the indole. 3. 14C-TR-2, added to the perfusate of isolated rat liver, was excreted unchanged in the bile, implying no significant loss of any biliary TR-2 subject to enterohepatic recycling in vivo. 4. 14C-TR-2 incubated anaerobically in sheep ileum contents was 95% transformed into more polar metabolites, the majority of the radiolabelled metabolites isolated being water soluble. 5. The principal fate of biliary TR-2 is as a metabolic substrate for the intestinal microflora.     

Fate of TR-2, the hepatic metabolite of the tremorgenic mycotoxin verruculogen,in sheep

Verruculogen is eliminated in bile after transformation to TR-2, only a trace of which was excreted as such in faeces of sheep given verruculogen per os. Negligible TR-2 was present free in urine; no glucuronide was found.

2. An isomer of TR-2, a minor component of the bile of sheep given verruculogen, has been defined by ¹H-n.m.r. spectroscopy and the isomerism involves the disposition of the two adjacent hydroxyl groups with a concomitant change in the conformation of the ring adjacent to the indole.

3. ¹⁴C-TR-2, added to the perfusate of isolated rat liver, was excreted unchanged in the bile, implying no significant loss of any biliary TR-2 subject to enterohepatic recycling in vivo.

4. ¹⁴C-TR-2 incubated anaerobically in sheep ileum contents was 95% transformed into more polar metabolites, the majority of the radiolabelled metabolites isolated being water soluble.

5. The principal fate of biliary TR-2 is as a metabolic substrate for the intestinal microflora.     

Neurobehavioral studies of tremorgenic mycotoxins verruculogen and penitrem A

Verruculogen (V) and penitrem A (PA) represent a group of toxic secondary metabolites of mold contaminants of foodstuffs known as 'tremorgenic mycotoxins', which produce a unique neurotoxic syndrome characterized by sustained tremors, limb weakness, ataxia and convulsions. In the present study the intraperitoneal median tremogenic dose in mice for V was found to be 0.92 mg/kg and that for PA, 0.19 mg/kg. Behavioral and neurochemical parameters were assessed following acute exposure to varying neurotoxic and subneurotoxic doses of these mycotoxins. Measures of spontaneous motor activity (photoactometer) and exploratory reflex behaviors (open field) were markedly depressed by both V and PA. Notably, at dose levels of V or PA that were not accompanied by any overt signs of neurotoxicity, significant neuromotor depression was still observed. Acquisition of a conditioned avoidance shuttle response was disrupted, but only at a high neurotoxic dose level of V. Neurochemical analyses revealed no clear catecholaminergic or cholinergic involvement in the neurotoxic syndrome of eigher V or PA.     

酪蛋白磷酸肽的药理作用

酪蛋白磷酸肽具有促进钙、铁、锌的吸收、利用,增强精卵的结合等作用。近年来对其进行了深入研究发现它在增强机体免疫力,促肿瘤细胞凋亡方面有潜在的药理作用,通过对其作用机制的研究,将为其用于临床提供理论依据。     

Cytotoxic effects of mycotoxin combinations in mammalian kidney cells

The cytotoxicity of three Fusarium mycotoxins (beauvericin, deoxynivalenol and T-2 toxin) has been investigated using the NR assay, after 24, 48 and 72 h of incubation. The IC₅₀ values ranged from 6.77 to 11.08, 3.30 to 10.00 and 0.004 to 0.005 for beauvericin, deoxynivalenol and T-2 toxin, respectively. Once the potential interaction has been detected, a quantitative assessment is necessary to ensure and characterize these interactions, that is, each mycotoxin contributes to the toxic effect in accord with its own potency. Combination of mycotoxins was determined in Vero cells after 24, 48 and 72 h of exposure. Isobolograms and median effect method of Chou and Talalay were used to assess the nature and quantitative aspects of interaction observed between studied mycotoxins. Median effect analysis was used to calculate the combination index (CI) with values >1 indicating synergism, 1 additive effect, and <1 antagonism. CI values of BEA + DON (1.22-2.74), BEA + T-2 toxin (1.43-5.89), DON + T-2 toxin (3.13-7.62) and BEA + DON + T-2 toxin (1.32-2.68) for 24, 48 and 72 h produced antagonistic effects in Vero cells. The highest antagonistic effect in Vero cells was observed with binary DON and T-2 toxin mixture.     

Mutagenicity and genotoxicity of the mycotoxin ochratoxin A

Natural occurrence of the mycotoxin ochratoxin A in food commodities has been linked to endemic diseases in certain human populations, where a high incidence of nephropathy is observed (Balkan endemic nephropathy). The increase of renal disease is accompanied with a high risk for urinary tract tumours. Despite epidemiological and experimental evidence for the carcinogenicity of ochratoxin A the underlying mechanism needs to be established. The pivotal role of cytochrome P450 in the mutagenicity of ochratoxin A could be demonstrated in experiments with cell lines stably expressing the human cytochrome P450 enzymes. CYP1A1, 1A2, 2C10 and 3A4, which were able to activate the non-mutagenic ochratoxin A into mutagenic metabolites. In the cell lines the bacterial lacZ' gene was used as reporter gene for mutagenicity. Sequencing of the lacZ' gene resulted in the detection of large deletions. In addition, in metabolically competent rat hepatocytes an increase of single strand breaks could be observed by means of the DNA alkaline elution assay. These DNA alterations could be related to biotransformation processes, indicating extensive metabolism of ochratoxin A. The discrepancies found between microsomal and cellular metabolism leads to the conclusion that ochratoxin A mediated mutagenicity requires additional processing of cytochrome P450 derived metabolism.     

芦荟的药理作用

芦荟具有抗肿瘤、抗炎抑菌、增加免疫力及抗胃粘膜损伤等作用，我国植物资源非常丰富，大量培植和开发芦荟将具有广阔的应用前景。     

Pharmacological effects of Hoe 249: A new potential antidepressant

The 1-(2-hydroxy-1-phenylethyl)-imidazole derivative Hoe 249 has a profile which suggests the compound is a promising candidate for clinical evaluation as an antidepressant drug. In pharmacological tests commonly considered predictive of antidepressant activity, e.g., reserpine- and tetrabenazine-antagonism, reversal of oxotremorine- and apomorphine-induced hypothermia, and potentiation of yohimbine toxicity, Hoe 249 is equipotent to nomifensine, but does not meet excitation and stereotypic behavior in a comparable dose range. Hoe 249 shows weak anticonvulsant activity against pentylenetetrazole-induced seizures and it causes a slight dose-dependent prolongation of hexobarbital narcosis. Biochemical studies characterize Hoe 249 as an inhibitor of synaptosomal dopamine and norepinephrine uptake, whereas serotonin uptake is not influenced. © 1992 Wiley-Liss, Inc.     

Pharmacological and therapeutic effects of A3 adenosine receptor agonists

The A(3) adenosine receptor (A(3)AR) coupled to G(i) (inhibitory regulative guanine nucleotide-binding protein) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A(3)AR as a potential therapeutic target. Highly selective A(3)AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A(3)AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. At present, A(3)AR agonists are being developed for the treatment of inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.     

Pharmacological correction of the cytogenetic effects of cisplatin

Beginning with the first hours of experiments, cisplatin evoked an increase of chromosomal aberrations in CBA/CaLac bone marrow cells. Significant increase of structural infringements of chromosomes due to chromatid breaks was revealed in metaphase plates of murine bone marrow preparations through 24 h after cisplatin intraperitoneal introduction. In late terms of research (90th day), the high level of aberrations of chromosomes was retained. The most pronounced correction of cisplatin mutagenicity was achieved using a preliminary course of thiophan introduction.     

Combined effects of mycotoxin mixtures on human T cell function

Combined effects of mycotoxin mixtures are of major concern due to the widespread occurrence of human exposure to mixtures. Owing to the lack of sufficient mixture data regarding the human immune function, the aim of this study was to specify, evaluate and predict the combined effects of mycotoxin mixtures upon the functional activity of immune cells. Therefore, a well established model for immunotoxic studies using stimulated human peripheral blood mononuclear cells (PBMC) was applied. To predict the combined effect of the mixture the concepts of concentration addition and response addition were used. Comparable to the individual mycotoxins the mixture suppressed the cytokine production in a concentration-dependent manner. The mixture effect was stronger than the effects caused by the toxins applied singly. The response addition concept described the mixture data within their experimental uncertainty. The in vitro test model presented here was practical to detect and quantify combined effects. Low and weak effect concentrations of mycotoxins may cause strong inhibitory effects on immune functions when occurring together. The experimental design using the concepts of concentration addition and response addition was suitable for predicting the combined effects of mycotoxin mixtures in functional in vitro assays.     

Pharmacological studies on the hypotensive effects of clonidine

The arterial pressure and heart rate of cats anaesthetized with urethane and chloralose were measured following treatment with clonidine (5 μg/kg). Blood pressure and heart rate were consistently decreased, effects which were blocked by haloperidol and phenoxybenzamine in doses which block central noradrenaline (NA) receptor sites; antagonism did not seem to be related to their peripheral adrenolytic properties. Pimozide and spiroperidol, in doses which block central dopamine but not NA receptor sites, did not block the hypotensive effects of clonidine. Pimocide and spiroperidol alone caused slight hypotension and bradycardia which, at least with regard to pimozide were not related to peripheral α-adrenergic receptor blocking activity. Clonidine potentiated these effects of pimocide and spiroperidol. The present findings indicate that the hypotensive effect of clonidine is due to stimulation of central NA receptor sites. Furthermore, dopaminergic mechanism may also be involved in vasomotor regulation.     

Applications of flow cytometry to toxicological mycotoxin effects in cultured mammalian cells: A review

This review gives an overview of flow cytometry applications to toxicological studies of several physiological target sites of mycotoxins on different mammalian cell lines. Mycotoxins are secondary metabolites of fungi that may be present in food, feed, air and water. The increasing presence of mycotoxins in crops, their wide distribution in the food chain, and their potential for toxicity demonstrate the need for further knowledge. Flow cytometry has become a valuable tool in mycotoxin studies in recent years for the rapid analysis of single cells in a mixture. In toxicology, the power of these methods lies in the possibility of determining a wide range of cell parameters, providing valuable information to elucidate cell growth and viability, metabolic activity, mitochondrial membrane potential and membrane integrity mechanisms. There are studies using flow cytometry technique on Alternaria, Aspergillus, Fusarium and Penicillium mycotoxins including information about cell type, assay conditions and functional parameters. Most of the studies collected in the literature are on deoxynivalenol and zearalenone mycotoxins. Cell cycle analysis and apoptosis are the processes more widely investigated.     

Pharmacological and clinical effects of buspirone

Clinical trials have demonstrated that buspirone (BuSpar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or chlorazepate. Buspirone has a unique structure and a pharmacologic profile which distinguishes it from the benzodiazepines. Because it lacks the anticonvulsant, sedative, and muscle-relaxant properties associated with other anxiolytics, buspirone has been termed "anxioselective." Animal studies suggest that it lacks potential for abuse, and this finding is supported by clinical investigations. Further preclinical work supports the contention that buspirone lacks liability to produce physical dependence or to significantly interact with central nervous system depressants such as ethanol. Moreover, biochemical investigations have not identified any direct interaction of buspirone with the benzodiazepine-gamma-aminobutyric acid-chloride ionophore complex. Pharmacologic studies on the molecular level indicate that buspirone interacts with dopamine and serotonin receptors. Recent behavioral, electrophysiological, and biochemical studies have clearly demonstrated that early hypotheses that buspirone might be considered a neuroleptic are no longer tenable. Recent evidence indicates that other neurotransmitter systems (serotonin, norepinephrine, acetylcholine) mediate buspirone's effects. It is hoped that future studies can define the mechanism by which buspirone alleviates the clinical manifestations of anxiety.