Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling

Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injury and programmed cell death through the regulation of a number of Ca2+-dependent enzymes such as phospholipases, proteases, and nucleases. Mitochondria along with the endoplasmic reticulum play pivotal roles in regulating intracellular Ca2+ content. Mitochondria are endowed with multiple Ca2+ transport mechanisms by which they take up and release Ca2+ across their inner membrane. During cellular Ca2+ overload, mitochondria take up cytosolic Ca2+, which in turn induces opening of permeability transition pores and disrupts the mitochondrial membrane potential (Dym). The collapse of Dym along with the release of cytochrome c from mitochondria is followed by the activation of caspases, nuclear fragmentation and cell death. Members of the Bcl-2 family are a group of proteins that play important roles in apoptosis regulation. Members of this family appear to differentially regulate intracellular Ca2+ level. Translocation of Bax, an apoptotic signaling protein, from the cytosol to the mitochondrial membrane is another step in this apoptosis signaling pathway

Effect of withdrawal from long-term nifedipine administration on open-field habituation in the rat

The effects of withdrawal from long-term administration of nifedipine (2.5 mg/kg, ip, twice daily for 30 days) on open-field habituation were evaluated in 3-month old male Wistar rats (13-14 animals per group). Habituation was evaluated by the ratio between locomotion or rearing frequencies obtained in the second and the first open-field session for each animal. Nifedipine treatment did not modify the locomotion ratio (with a mean +/- SEM ratio of 0.66 +/- 0.12 for control and 0.45 +/- 0.08 for nifedipine-treated group) nor the rearing ratio (with a mean +/- SEM ratio of 0.51 +/- 0.12 for control and 0.62 +/- 0.18 for nifedipine-treated group). The possible factors underlying the discrepancy between the present results and the commonly reported positive effects of calcium channel blockers on memory are discussed.

Effects of single and long-term administration of nifedipine on nociception and stereotyped behavior of rats

In the present investigation, nociception and stereotyped behavior were evaluated in 3-month old male Wistar rats after a single nifedipine dose (2.5 and 5.0 mg/kg, ip, 1 h before testing, 6-7 rats per group for stereotypy studies and 15 animals per group for nociception experiments) or after long-term nifedipine treatment (2.5 mg/kg, ip, twice daily for 30 days, with testing performed 72 or 96 h after the last injection, 7 rats per group for stereotypy studies and 14-16 animals per group for nociception experiments). Stereotypy was induced with 2.5 mg/kg amphetamine, ip, and nociception was measured by the tail-immersion test. Administration of a single nifedipine dose did not modify nociception or amphetamine-induced stereotypy (with a mean +/- SEM tail-withdrawal latency of 4.5 +/- 0.5 s for control, 4.4 +/- 0.3 s for 2.5 mg/kg nifedipine and 4.7 +/- 0.7 s for 5.0 mg/kg nifedipine and with mean +/- SEM sum of stereotypy scores of 32.5 +/- 1.6 for control, 29.1 +/- 1.0 for 2.5 mg/kg nifedipine and 29.1 +/- 1.6 for 5.0 mg/kg nifedipine). Withdrawal from long-term nifedipine treatment did not affect stereotyped behavior (with mean +/- SEM sum of stereotypy scores of 28.7 +/- 1.6 for control and 30.7 +/- 1.3 for nifedipine-treated rats) but significantly increased tail-withdrawal latencies (with a mean +/- SEM tail-withdrawal latency of 4.1 +/- 0.3 s for control and 6.4 +/- 0.6 s for nifedipine-treated rats). Therefore, long-term nifedipine treatment induced plastic modifications in nociception but not in stereotyped behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of single and long-term administration of nifedipine on dopamine-related behaviors

The effects of single (2.5 and 5.0 mg/kg) and long-term (2.5 mg/kg, twice daily, for 30 days) ip administration of nifedipine on open-field and apomorphine-induced stereotyped behavior were evaluated in young male Wistar rats (12-16 animals per group for the open-field studies and 7 animals per group for the stereotypy experiments). Administration of a single dose of nifedipine produced no changes in ambulation or rearing frequencies or in immobility duration in the open-field compared to controls. Similarly, treatment with a single dose of nifedipine did not modify apomorphine-induced stereotypy. Withdrawal from long-term nifedipine administration caused a significant increase only in rearing frequency 24 h after the last drug injection (with a mean +/- SEM frequency of 23.2 +/- 2.8 for the nifedipine group and of 14.7 +/- 2.0 for control rats, after 6-min observation). This enhancement of rearing frequency was no longer observed 48 h after abrupt nifedipine withdrawal (means +/- SEM: 15.0 +/- 2.2 and 19.6 +/- 2.7 for nifedipine-treated and control rats, respectively). The other open-field behavioral parameters and apomorphine-induced stereotypy (which was observed 96 h after nifedipine withdrawal) were not affected by long-term nifedipine treatment; for example, the sum of stereotypy scores (mean +/- SEM) was 26.9 +/- 3.0 for nifedipine-treated rats and 25.5 +/- 2.2 for vehicle-treated animals. The possible mechanisms underlying these results are discussed in light of the changes in dopaminergic neurotransmission induced by dihydropyridine calcium channel blockers

Anxiety-induced antinociception in the mouse

It has been suggested that exposure to the elevated plus-maze (EPM) apparatus induces antinociceptive effects in mice as measured by the tail-flick assay,, which are not blocked by the opiate antagonist naltrexone. The a) if exposure limited to the open or the enclosed arm of the EPM would alter this effect; b) whether or not pharmacologically induced anxiety (1.0 mg/kg pentylenetetrazole, PTZ) would also reduce nociceptions: c) if exposure to the EPM would alter visceral pain, as measured by the abdominal contortion test. The simultaneous exposure to both the open and enclosed arms of the EPM, but not the exposure limited to each type of arm, led to statistically significant increases in tail withdrawal latencies (TWL). Indeed, 10 min after exposure to both arms, TWL values (means ñ SEM) were 10.31 ñ 0.87 s as compared to a baseline value of 5.46 ñ 0.53 s. The acute administration of PTZ significantly increased TWL. Conversely, EPM-induced antinociception was not detected by the abdominal contortion test. These results confirm the existence of EPM-induced antinociceptive effects demonstrated by others and show that they may be multiple determinants

Comparison of the effect of calcium withdrawal from the medium and of blockade of extracellular calcium entry by isradipine on the contractile responses of the isolated rat stomach

The role of calcium in drug-induced contractions of rat gastric fundus strips was evaluated by determining the effect of two procedures on the dose-respponse curves of agonists: a) removal of calcium from the nutrient solution and b) blockade of calcium channels with the dihydrophydine isradipine. Gastric strips were obtanied from adult Wistar rats and suspended in Tyrode solution at 37-C for contraction studies. Dose-response curves for carbachol (CCh), serotonin (5-HT), KCl and BaCl2 were constructed under the two conditions descrived above. A complete blockade of contractile effects was observed for 5-HT and KCl 60 min after calcium withdrawal of after using 3 mM (45 min) of the calcium antagonist. A lower dose of antagonist or a shorter incubation in calcium-free solution caused a partial decrease of dose-response curves, added to a 30-fold shift to the right after the calcium antagonist (1mM), or a larger than 100-fold shift 3 min after calcium removal. In contrast, dose-response curves for CCh and BaCl2 were not significantly affected by either type of treatment. It is concluded that 5-HT and KCl utilize extracellular sources of calcium, whereas CCh or BaCl2 depends on a tightly-bound calcium pool in this preparation