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Biomedical subjects

J M Tusell

Publications and source records attributed to J M Tusell.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of hexachlorocyclohexane isomers on calmodulin mRNA expression in the central nervous system.

Three different calmodulin genes that encode the same protein have been found in the brain of all mammalian species so far examined. Little is known about the factors involved in regulating the expression of this gene family in the central nervous system. We have investigated the possibility of differential expression of two calmodulin genes, CaM I and CaM II, which are expressed strongly in neuronal cells in the adult rat brain, after treatment with the gamma (lindane) and the delta isomers of the hexachlorocyclohexane (HCH). In this study a decrease of CaM I mRNA (mainly in the 4.0 kb transcript) was found in the cortex of the rats after 24 h of isomer administration. CaM I expression seemed to be more sensitive to delta isomer action, whereas the gamma isomer acted mainly at CaM II level. The levels of mRNA of calmodulin CaM II gene were also found to decrease after lindane administration; delta-HCH produced an increase of this transcript. These results were obtained by Northern blot analysis and confirmed by means of in situ hybridization. Our results suggest that levels of neuronal calmodulin mRNA species are modified in response to changes in neuronal activity.

Animals↗
PubMed1995

Regulation of c-fos expression by convulsants and hexachlorocyclohexane isomers in primary cultures of cortical neurons.

Primary cortical cultures were used to study the effects of four convulsants on c-fos expression. Approximately 30% of the neurons in these cultures displayed c-fos nuclear immunostaining under basal conditions. The addition of tetrodotoxin, nifedipine, or delta-hexachlorocyclohexane produced a significant decrease in c-fos basal values. Lindane (gamma-hexachlorocyclohexane), Bay K 8644, pentylenetetrazole, and picrotoxinin produced a significant increase in c-fos immunoreactivity and in c-fos mRNA expression. Treatment of cells with tetrodotoxin before administration of the convulsant agents lowered c-fos staining below basal levels. In contrast, delta-hexachlorocyclohexane or nifedipine failed to block only the picrotoxin-induced increase. The differential pattern of expression shown by c-fos after these treatments suggests various mechanisms of action for the compounds studied. The results obtained with delta-hexachlorocyclohexane and nifedipine suggest that picrotoxinin activates c-fos expression by calcium-requiring intracellular signaling pathways that are different from those activated by Bay K 8644, pentylenetetrazole, or gamma-hexachlorocyclohexane, which, at least in part, act via L-type calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Convulsant agents activate c-fos induction in both a calmodulin-dependent and calmodulin-independent manner.

Calcium acts as a second messenger and can enter neurons through several types of calcium channel. We sought to determine whether the calcium-dependent mechanisms inducing c-fos expression are identical following activation, by appropriate drugs, of L-type voltage-sensitive calcium channels or NMDA and non-NMDA receptors or following inhibition of the GABAergic system. We used primary cortical neurons and OF1 mice, and the levels of c-fos protein and c-fos mRNA were detected after treatment with the drugs by means of immunocytochemistry and in situ hybridization. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) abolished gamma-hexachlorocyclohexane-, Bay K 8644-, pentylenetetrazole-, and kainic acid-induced increases in c-fos expression in cultured neurons. Conversely, W-7 did not affect either NMDA- or picrotoxinin-mediated increases in c-fos expression. In mice, the pattern of protooncogene expression displayed some differences compared with cultured neurons, depending on the treatment. W-7 administered before gamma-hexachlorocyclohexane, Bay K 8644, or pentylenetetrazole blocked the expression of c-fos elicited by these compounds. However, W-7 was not able to abolish c-fos expression induced by picrotoxinin. In the animals treated with W-7 before kainic acid or NMDA administration, c-fos expression was inhibited in cerebral cortex, but it was still present in hippocampus. These results agree with the existence of diverse mechanisms transducing the calcium signals to the nucleus. Calmodulin may mediate neuronal responses depending on the route by which calcium enters the neuron, resulting in activation of different enzymes.

Animals↗
PubMed1994

Anticonvulsant activity of calmodulin antagonist W-7 in convulsions induced by lindane and BayK-8644: effects in c-fos expression.

The anticonvulsant activity of calmodulin antagonist W-7, was investigated on convulsions induced in mice by the insecticide lindane and by the calcium channel agonist BayK-8644. We also studied the inhibitory effect of W-7 on on c-fos mRNA expression induced by both convulsants. We observed a good correlation between doses and the acute convulsive effects of lindane and BayK-8644. The incidence rate and time to onset were clearly dose-dependent. W-7 antagonized the convulsive effects of lindane and BayK-8644 in all the parameters studied. A significant decrease in the incidence rate and time to onset were observed when they are compared with the values obtained with the ED100 of lindane- and BayK-8644 induced seizures. Both were able to activate the mRNA expression of the proto-oncogene. The pattern of this expression displayed by in situ hybridization was very similar. A dramatic increase was found in dentate gyrus and high levels of mRNA expression also occurring in hippocampal fields and cortical regions. In accordance with the behavioural results, W-7 antagonized also the c-fos expression induced by lindane and BayK-8644. Our results suggest that lindane as BayK-8644 may activate voltage-dependent calcium channels leading to calmodulin activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Anticonvulsant activity of delta-HCH, calcium channel blockers and calmodulin antagonists in seizures induced by lindane and other convulsant drugs.

The anticonvulsant activity of delta-HCH and of a calmodulin antagonist, W-7 were investigated on convulsions induced in mice by lindane (ED100 100 mg/kg), by GABAergic antagonists PTZ (ED100 60 mg/kg) and PTX(ED100 4 mg/kg), by calcium channel agonist BAY-K-8644 (ED100 5 mg/kg), by two agonists of excitatory amino acid receptors, kainic acid (ED100 80 mg/kg) and NMDA (ED100 160 mg/kg and by the atypical benzodiazepine Ro 5-4864 (ED100 40 mg/kg). The anticonvulsant activity of a voltage-dependent calcium channel antagonist, nifedipine was also investigated on convulsions induced by Ro 5-4864, BAY-K-8644, kainic acid and NMDA. delta-HCH antagonized lindane- and BAY-K-8644-induced convulsions (ED50 231 (172-309) mg/kg and 148 (142-154) mg/kg, respectively) and at concentrations up to 300 mg/kg failed to antagonize Ro 5-4864, kainic acid and NMDA convulsions. In contrast delta-HCH potentiated PTX-induced seizures. Nifedipine antagonized BAY-K-8644- and kainic acid-induced convulsions (ED50 6.5 (4.3-9.7) mg/kg and 30 (13-70) mg/kg but at concentrations up to 20 mg/kg failed to antagonize Ro 5-4864 and 25% of protection was observed on NMDA-induced convulsions at the highest dose (20 mg/kg). The ED50 of W-7 to antagonize convulsions induced by lindane and BAY-K-8644 were 12 (8-19) mg/kg and 49 (29-85) mg/kg, respectively. Some anticonvulsant effect was observed against PTZ and NMDA but without any dose-dependent anticonvulsant activity. W-7 did not protect against PTX and kainic acid convulsions and 30% of protection was observed against convulsions at the highest dose of W-7 (75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Lindane-induced convulsions in NMRI and OF1 mice: antagonism with (+)MK-801 and voltage-dependent calcium channel blockers.

The convulsant profile of lindane was investigated in OF1 and NMRI mice lines in relation to other convulsants acting at the GABAA and NMDA receptor complexes. Thus, a specific GABA-gated chloride channel blocker, PTX, a GABAA receptor antagonist, PTZ, and an excitatory amino acid receptor agonist, NMDA, were used. Antagonism of the convulsant effects of each of these drugs was investigated with (+)MK-801, a blocker of the NMDA-operated cation channel, and with nifedipine, a voltage-dependent calcium channel antagonist. While no differences in potency for PTX or PTZ to induce seizures were observed between OF1 and NMRI mice, lindane was approximately 80 and 90% more potent in its ability to induce seizures and lethality, respectively, in OF1 than in NMRI mice. Brain lindane concentrations at the moment of convulsion, measured after ED100 doses of lindane (400 and 200 mg/kg for NMRI and OF1 mice, respectively), did not differ between OF1 and NMRI mice, suggesting that the different potency of lindane between these mouse lines is a consequence of pharmacokinetic factors. Furthermore, (+)MK-801 antagonized seizures induced by either lindane, PTX or PTZ with similar potencies in both mouse lines. These results, coupled with the different pharmacokinetics of lindane in OF1 and NMRI mice, suggest that the distinct effects of lindane in these mice are not mediated by different activities at either NMDA or GABAA receptor complexes. Nonetheless, nifedipine antagonized lindane-induced seizures with a three-fold higher potency in NMRI than in OF1 mice. In contrast, nifedipine failed to antagonize PTX and PTZ convulsions in both OF1 and NMRI mice. These results suggest that besides the GABAA receptor complex other mechanisms related to calcium mobilization may be involved in the convulsant action of lindane.

Animals↗
PubMed1992

Effect of different convulsants on calmodulin levels and proto-oncogene c-fos expression in the central nervous system.

In the present study, a relationship between convulsant activity and two cellular events, changes in calmodulin (CaM) concentration and proto-oncogene c-fos expression has been considered. c-fos has been found activated after the administration of the organochlorine insecticide lindane, the Ca2+ channel agonist Bay K, and N-methyl-D-aspartate (NMDA). The administration of the voltage-dependent Ca2+ channel antagonist nifedipine was able to block the expression elicited by lindane. The effect of lindane on c-fos expression could not be blocked by prior administration of MK-801, a non-competitive antagonist of the NMDA receptor. These results suggest a possible role for the voltage-dependent Ca2+ channels in the mechanism of action of lindane. By means of in situ hybridization, the different patterns of c-fos expression after the administration of the mentioned compounds have been described. A possible modification of the levels of CaM has also been investigated. Among all the subcellular fractions considered, only levels of nuclear CaM appeared to be affected after the different treatments. The changes observed seemed to follow a similar pattern to that described for c-fos induction. Calcium entry through these voltage-dependent calcium channels would be the link between membrane depolarizing events and expression of c-fos and/or increase in nuclear CaM.

Animals↗
PubMed1992

Repeated lindane exposure in the rat results in changes in spontaneous motor activity at 2 weeks post-exposure.

Male Wistar rats were given 25 doses of lindane, 10 mg/kg per day, 1 ml/kg p.o. in olive oil, or control vehicle. Two weeks after the last dose, the animals were assessed for modifications in spontaneous motor activity, plus-maze behavior, shuttle-box active avoidance acquisition, brain regional concentrations of biogenic amines and metabolites, and regional [35S]TBPS binding. Rats treated with lindane showed an increase in spontaneous motor activity. Although no additional behavioral or neurochemical modifications were found, the changes in activity observed at 2 weeks post-exposure further demonstrate the need to assess for long lasting neurobehavioral sequelae of repeated lindane exposure.

Administration, Oral↗
PubMed1992

c-fos expression as a model for studying the action of hexachlorocyclohexane isomers in the CNS.

The induction of protooncogene c-fos in the CNS after administration of several convulsants has been studied. The organochlorine insecticide gamma-hexachlorocyclohexane (gamma-HCH, lindane) has been shown to induce c-fos expression in different brain areas. Pentylenetetrazole and picrotoxin, a known gamma-aminobutyric acid-receptor antagonist, have also been considered. The administration of two nonconvulsant isomers of gamma-HCH, alpha-HCH, and delta-HCH, before the mentioned toxicants, affects the protooncogene expression in different ways. The differential pattern of expression displayed by c-fos after these treatments suggests the presence of diverse mechanisms of action for the compounds studied.

Animals↗
PubMed1992

Effect of gamma-hexachlorocyclohexane and its isomers on proto-oncogene c-fos expression in brain.

By means of in situ hybridization, the induction of proto-oncogene c-fos in rat brain after administration of several convulsants has been studied. The organochlorine insecticide gamma-hexachlorocyclohexane (lindane) has been shown to induce c-fos expression in a dose dependent manner. 30 mg/kg of lindane increased c-fos expression in cortical and hippocampal areas. The two non convulsant isomers of lindane, alpha- and delta-HCH, were not able to induce the expression of the proto-oncogene, but blocked that elicited by lindane. Pentylenetetrazole (PTZ) and picrotoxin (PTX), a known GABAA-receptor antagonist, have also been considered. Both of them were able to induce c-fos, although the pattern of expression was not the same in each case. alpha- and delta-HCH, were administered prior to the mentioned toxicants, affecting the proto-oncogene expression in different ways. We propose here that the distribution of c-fos mRNA after different treatments can be used as a marker of neurotoxic action.

Animals↗
PubMed1991

Evidence for acute tolerance to the behavioral effects of lindane: concomitant changes in regional monoamine status.

The effects of the organochlorine insecticide lindane on plus-maze ((+)-maze) behavior of rats and on regional monoamine status were studied at two time points, 30 min and 24 hr post-dosing. Animals were given lindane, 20 mg/kg, 30 min before (L1/2 group), or 40 mg/kg, 24 hr before (L24 group), experimental time; these schedules allowed the study of animals with equivalent brain concentration of lindane at two different time points after administration. The (+)-maze results indicated a reduction in the number of entries into the arms of the maze 30 min after administration of lindane that was not present 24 hr later, suggesting the development of an acute tolerance to the behavioral effects of the chemical. In a parallel group of animals, concentrations of noradrenaline (NA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were determined by HPLC in seven brain regions. Significant decreases in NA concentrations were found in L1/2 animals in hippocampus and cerebral cortex and also in the L24 group in the latter region. 5HT/5HIAA ratios increased in several brain regions in the L24 rats but not in the L1/2 rats, thus showing an inverse relationship with behavioral effects. DOPAC/DA and HVA/DA ratios in hypothalamus and cerebral cortex were, by contrast, increased in both groups of treated animals. In conclusion, it appears that an acute tolerance can develop to the behavioral effects of lindane, and that there are modifications produced in central monoaminergic systems by lindane that show brain region and and treatment schedule specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1990

Microcomputer adaptation of the wheel-shaped activity monitor: effects of lindane.

The development of microcomputers with increased power and memory capacity may allow for the spreading of the techniques of microanalysis of animal behavior in neurotoxicology. The present work describes the adaptation of the wheel-shaped activity monitor to a personal computer system (IBM-PC/XT/AT-compatible). The system has been used to study the effects elicited by a single 30 mg/kg dose of the organochlorine insecticide gamma-hexachlorocyclohexane (lindane) on the spontaneous behavior of rats. Lindane induced complex changes in behavior, the most prominent being a disruption of the temporal pattern of activity and changes in the local activity/locomotor activity ratios and in place preferences in the monitor. Effects on body weight and number of fecal boluses were also observed.

Animals↗
PubMed1989

GABAergic modulation of lindane (gamma-hexachlorocyclohexane)-induced seizures.

The main objective of this work was to study the role of the GABAergic system on the convulsions elicited by the organochlorine insecticide lindane. The concentration of lindane in rat brain at the onset of the first tonic convulsion was taken as the endpoint for the neurotoxic action of the insecticide administered by intravenous infusion. Pretreatment with the GABA agonists muscimol and progabide, the GABA uptake blocker SK&F 89976-A, the GABA transaminase inhibitor gamma-acetylenic GABA, and the GABA indirect agonist phenobarbital significantly increased the threshold concentration of lindane in brain required to induce convulsions. The GABA agonist THIP, the GABA competitive antagonist bicuculline, and the prodrug cetyl-GABA had no effect on the brain level of lindane required to induce seizures. The noncompetitive GABA antagonists, picrotoxinin and pentylenetetrazol, significantly decreased the brain concentration of lindane needed to elicit convulsions. The concentration of GABA in the brain of lindane-treated rats was only modified by the significant increase produced after gamma-acetylenic GABA pretreatment. These results show that the convulsions elicited by lindane can be facilitated by some GABA antagonists and antagonized by GABA mimetics, especially those that enhance GABA functionality. The present data are consistent with the proposed in vitro competition of lindane for the picrotoxinin binding site associated with the Cl- ionophore of the GABAA receptor, and suggest that lindane may also interact in vivo with this site.

Animals↗