Biomedical subjects

C Post

Publications and source records attributed to C Post.

At least 37 records · Page 2Linked to original sources

PubMed1997

Effectiveness of anthracycline against experimental prion disease in Syrian hamsters.

Prion diseases are transmissible neurodegenerative conditions characterized by the accumulation of protease-resistant forms of the prion protein (PrP), termed PrPres, in the brain. Insoluble PrPres tends to aggregate into amyloid fibrils. The anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDX) binds to amyloid fibrils and induces amyloid resorption in patients with systemic amyloidosis. To test IDX in an experimental model of prion disease, Syrian hamsters were inoculated intracerebrally either with scrapie-infected brain homogenate or with infected homogenate coincubated with IDX. In IDX-treated hamsters, clinical signs of disease were delayed and survival time was prolonged. Neuropathological examination showed a parallel delay in the appearance of brain changes and in the accumulation of PrPres and PrP amyloid.

Amyloid↗

PubMed1997

Modulation of the hepatic expression of the estrogen-regulated mRNA stabilizing factor by estrogenic and antiestrogenic nonsteroidal xenobiotics.

Estrogen-mediated accumulation of apolipoprotein II (apoII) mRNA in the avian liver is due, in part, to its stabilization. This stabilization appears to be due to the estrogen-regulated mRNA stabilizing factor (E-RmRNASF) that is expressed in response to estrogen. The E-RmRNASF protects the mRNA from targeted endonucleolytic degradation (Ratnasabapathy, Cell Mol Biol Res 41: 583-594, 1995). To determine whether certain environmental xenobiotics altered the expression of the gene encoding E-RmRNASF by mimicking estrogen, roosters were given estrogen, tamoxifen, clomiphene, hexachlorophene, lindane, rotenone, chlordecone, dichlorodiphenyltrichloroethane (DDT); Araclor, methoxychlor, dieldrin, toxaphene, or bisphenol-A parenterally. Uniformly radiolabeled, capped, and polyadenylated apoII mRNA, incubated in vitro in the presence of liver cytosolic extracts from birds that received estrogen, tamoxifen, hexachlorophene, chlordecone, or Araclor, remained stable, indicating that these agents were estrogenic and stimulated the expression of E-RmRNASF. However, the same mRNA was degraded in similar extracts from control roosters and those treated with clomiphene, DDT, methoxychlor, dieldrin, rotenone, toxaphene, lindane, or bisphenol-A. To determine whether the latter agents were antiestrogenic, roosters were given a 1:5 molar combination of estrogen and each of the xenobiotics. ApoII mRNA showed degradation in liver extracts from roosters that received clomiphene, toxaphene, or bisphenol-A, indicating that these agents prevented estrogenic stimulation of expression of the E-RmRNASF and were antiestrogenic. However, the rest of the xenobiotics failed to antagonize estrogenic stimulation of E-RmRNASF gene expression. These results set a precedent in showing the estrogenic and antiestrogenic effects in vivo of environmental xenobiotics on the expression of a regulatory protein involved in estrogen-mediated mRNA stabilization.

Animals↗

PubMed1997

Effects of nicergoline on age-related decrements in radial maze performance and acetylcholine levels.

The effects of chronic oral administration of nicergoline (5.0 mg/kg; bid) on locomotor activity, eight-arm radial maze performance plus striatal, cortical, and hippocampal acetylcholine (ACh) levels were examined in young and aged Wistar rats. Chronic nicergoline administration did not modify either the locomotor activity or radial maze learning in young rats. Young rats learned the radial maze procedure rapidly and improved their performance throughout the successive training sessions. Radial maze performance in young rats was characterised by very few arm reentries. Aged rats were hypoactive and did not explore or enter the radial maze arms, and consequently performed poorly in the radial maze throughout the training sessions. Nicergoline treatment did not significantly modify locomotor activity in aged rats. Aged rats treated with nicergoline also performed poorly initially but improved with repeated training in the radial maze. This improvement was associated with an increasing number of arms being entered and very few arm reentries. Reduced acetylcholine (ACh) levels were also associated with age. Aged rats had significantly reduced levels of ACh in the straitum and cortex, but not the hippocampus as compared to young rats. Nicergoline treatment did not change ACh levels in young rats, but substantially restored the reduced ACh levels in aged rats. These results indicate that nicergoline is an effective cognitive enhancer in a learning model of age-related deficits and that these results may be related to changes in the cholinergic system.

Acetylcholine↗

PubMed1997

Selective inhibition of alcohol intake in diverse alcohol-preferring rat strains by the 5-HT2A antagonists amperozide and FG 5974.

The present studies sought to elucidate the role of 5-HT2A receptor antagonists in suppressing alcohol intake by comparing the effects of amperozide and FG 5974 on alcohol, food, and water intake in strains of alcohol-preferring rats: P, Alko Alcohol (AA), and Fawn-Hooded (FH). Both amperozide and FG 5974 have 5-HT2A receptor antagonist properties, but FG 5974 also shows presynaptic 5-HT1A receptor agonist activity. After establishment of stable baselines for intake measures in a two-bottle continuous access paradigm, rats (n = 10) were injected with 1 of 5 doses (0, 2.5, 5.0, and 10.0 mg/kg, sc) of amperozide or FG 5974 at weekly intervals. Amperozide dose-dependently reduced alcohol intake, total fluid intake, and alcohol preference in all three strains under continuous access conditions, whereas FG 5974 was less effective. Food intake was also suppressed by amperozide at higher doses, whereas it was increased by FG 5974. Amperozide also dose-dependently reduced alcohol intake when it was available for only 1 hr/day, but FG 5974 tended to increase it. After oral administration, amperozide was also more effective than FG 5974 in reducing alcohol intake. Despite these differences in efficacy in suppressing alcohol intake, both compounds produced taste aversion to a novel saccharin solution. These complex findings suggest that biochemical properties other than 5-HT2A receptor antagonism (e.g., 5-HT1A receptor agonism) may be involved in the effects of amperozide and FG 5974 on alcohol intake and other consummatory behaviors.

Alcohol Drinking↗

PubMed1996

Modulation of phosphoinositide turnover by chronic nicergoline in rat brain.

Basal and agonist-stimulated phosphoinositide (PI) turnover and inositol 1,4,5 -trisphospate (InsP3) content in rat brain were investigated after chronic nicergoline (SERMION) treatment. Oral administration of nicergoline (5 mg/kg b.i.d. for 7 weeks) enhanced the basal turnover of PI in the cerebral cortex compared to controls. This effect was paralleled by a significant rise of cortical InsP3 levels. No significant changes of noradrenaline- or carbachol-induced accumulation of [3H]-inositol-I-phophate ([3H]-InsP1) were found in cortices from nicergoline-treated rats. On the contrary, in the striatum nicergoline significantly potentiated the responsiveness of noradrenaline- and carbachol-stimulated PI turnover, leaving unchanged the basal production of [3H]-InsP1 and InsP3 levels. The results suggest that the interaction of nicergoline with PI transducing pathway might have relevance to the mechanisms of action of nicergoline.

Animals↗

PubMed1996

Neuropeptide-converting enzymes in cerebrospinal fluid: activities increased in pain from herniated lumbar dis, but not from coxarthrosis.

We measured activities of dynorphin-converting enzyme (DCE), substance P endopeptidase (SPE) and angiotensin-converting enzyme (ACE) in cerebrospinal fluid (CSF) in 13 patients with rhizopathic pain from an herniated lumbar disc, in 9 patients with pain from coxarthrosis and in 11 control patients without pain. In the patients with disc hernia and coxarthrosis, another sample of CSF was analyzed 3-12 months after treatment, when pain had subsided. The DCE activity in the patients was higher than that in both the control patients and the patients with pain from coxarthrosis (nociceptive pain). Similarly, the activity of SPE was lower in the patients with herniated lumbar disc than in controls and in the patients with coxarthrosis. After treatment, the difference in activity compared to controls was lower, but still significant in patients with herniated discs. The ACE activity did not differ from controls in patients with ischialgia, while it was increased in patients with coxarthrosis. This increase also remained after arthroplasty with pain relief. In conclusion, measurements of neuropeptides may be useful for evaluating neuropathic pain.

Adult↗

PubMed1995

Modulation of hippocampal ACh release by chronic nicergoline treatment in freely moving young and aged rats.

The effects of nicergoline on basal and K(+)-stimulated release of ACh in the hippocampus of 3- and 19-month old rats has been studied by microdialysis. A significant decrease of basal ACh release (59%) was found in aged vehicle treated rats in comparison to young rats. High-K+ (100 mM) in the perfusate strongly increased the release of ACh by up to 6-fold over the baseline of both young and aged rats. Chronic oral administration of nicergoline to aged rats (5 mg/kg b.i.d. for 6 weeks) significantly reversed (93%) the age-related decrease of basal release of ACh, leaving the increase due to K+ depolarization unchanged. In young animals, nicergoline did not affect the basal output of ACh, but enhanced the K(+)-evoked release of ACh by 39%. Results from this study demonstrate that nicergoline treatment increases the ability of hippocampal cholinergic terminals to release ACh, and suggest that this drug can reset the cholinergic impairement associated with aging.

Acetylcholine↗

PubMed1995

Calcitonin gene related peptide gene expression in collagen-induced arthritis.

Changes in calcitonin gene related peptide (CGRP) gene expression in spinal motoneurons and dorsal root ganglia (DRG) of rats subjected to collagen II induced arthritis (CIA) were evaluated by semiquantitative in situ hybridization. The effects of systemic treatment with the corticosteroid budesonide on basal CGRP expression and on changes under inflammatory conditions were examined. CIA caused a significant increase in CGRP mRNA levels in DRG. Budesonide reduced the constitutive CGRP mRNA levels in DRG, compared with untreated control rats, and reversed the CIA-induced increase. In contrast, CIA caused a marked decrease of CGRP mRNA levels in motoneurons. Budesonide had no effect on constitutive CGRP mRNA levels in motoneurons and attenuated the decrease in CGRP mRNA levels in motoneurons of rats subjected to CIA. Thus, peripheral inflammation and systemic corticosteroids have differential effects on CGRP expression in sensory and motor neurons. This may be relevant for the pathophysiology and pharmacotherapy of chronic inflammatory pain and motor dysfunction in chronic arthritis.

Animals↗

PubMed1994

Spinal prodynorphin gene expression in collagen-induced arthritis: influence of the glucocorticosteroid budesonide.

Changes in the spinal expression of the opioid precursor and prodynorphin, which has been implicated in the response to peripheral inflammation, were examined with semi-quantitative in situ hybridization histochemistry in rats subjected to collagen II-induced arthritis. The effects of glucocorticosteroid treatment on the basal and inflammation-induced prodynorphin expression were evaluated. Collagen II-induced arthritis caused a 16-fold increase in prodynorphin mRNA levels which comprised all neurons expressing low levels under normal conditions. In the superficial dorsal horn, one group of neurons of a large size reacted with a dramatic increase of prodynorphin mRNA, while another group of small neurons exhibited a moderate elevation of prodynorphin mRNA levels. In the deep dorsal horn of arthritic rats, most prodynorphin neurons were large and showed high prodynorphin mRNA levels. Systemic treatment with the glucocorticosteroid budesonide attenuated the arthritis-induced increase of prodynorphin mRNA expression in a topospecific manner. The budesonide-induced reduction of prodynorphin mRNA levels was more pronounced in the deep dorsal horn than in the superficial dorsal horn. Budesonide treatment of control animals caused a small, but significant increase in prodynorphin mRNA levels in the superficial laminae I/II without affecting prodynorphin mRNA levels in the deep dorsal horn. The degree of arthritis correlated closely with spinal prodynorphin mRNA levels. The tight correlation between severity of arthritis and prodynorphin mRNA levels in non-treated and corticosteroid-treated arthritic rats suggests that spinal prodynorphin expression is a good parameter for the evaluation of the influence of peripheral inflammation and of the efficacy of analgesic/anti-inflammatory drugs in its treatment. Opposite effects of budesonide on basal and inflammation-induced prodynorphin expression may involve a spinal site of action in addition to peripheral anti-inflammatory mechanisms. We suggest that the collagen II-induced arthritis in the rat is an excellent model for human rheumatoid arthritis allowing for the study of molecular plasticity of anti-inflammatory and anti-nociceptive drug action at different levels of the neuroaxis.

Administration, Topical↗

PubMed1993

A rat model for investigation of spinal mechanisms in detrusor instability associated with infravesical outflow obstruction.

A rat model of infravesical outflow obstruction was modified to allow cystometric investigation in conscious, free-moving animals after intrathecal drug administration. The catheter position and extent of drug distribution were controlled by injection of dye and dissection of the spinal canal. Continuous cystometries were performed in awake normal rats as well as rats with bladder hypertrophy and hyperactivity following infravesical outflow obstruction. In some animals of each group, cystometry was performed with simultaneous recording of intra-abdominal pressure. The possible effects of the presence of the intrathecal catheter were studied, as well as the effects of saline, local anesthetics, morphine and naloxone administered through the catheter. Neither the presence of the intrathecal catheter nor injection of saline affected the cystometric pattern. Bupivacaine (50 micrograms) produced paralysis of both lower extremities and a complete, though reversible, suppression of micturition in normal rats. In rats with hypertrophy, intrathecal bupivacaine in doses of 50 micrograms and 100 micrograms produced decreases in micturition pressure, increases in bladder capacity and dribbling incontinence. However, the amplitude of spontaneous contractile activity increased after the administration. The inhibitory effects of morphine (0.5-10 micrograms) on micturition in normal rats, which were rapidly reversed by naloxone, were in accordance with results obtained in previous studies in anesthetized animals. Rats with bladder hypertrophy showed a similar response to morphine and naloxone. However, the bladder hyperactivity was not inhibited by morphine. We conclude that the present model seems reliable for the study of spinal mechanisms in the development of detrusor instability associated with infravesical outflow obstruction.

Animals↗

PubMed1993

Cerebrospinal fluid dynorphin-converting enzyme activity is increased by voluntary exercise in the spontaneously hypertensive rat.

The activity in cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) has been studied after voluntary exercise in the spontaneously hypertensive (SH) rat. The exercise consisted of spontaneous running in wheels for 4-5 weeks and the average running distance during the last two weeks was 4.0 km/24h. CSF samples were obtained under anaesthesia from the cisterna magna after penetration of the atlanto-occipital membrane. DCE transforms the members of the dynorphin family of opioid peptides into Leu-enkephalin-Arg6. In the present investigation a radioimmunoassay was used for quantitation of Leu-enkephalin-Arg6 release from dynorphin A1-17 and dynorphin B1-13. The rats that were running had a DCE activity (vs. both substrates) in CSF that was approximately 6-12 times higher than in animals not given the running opportunity. A statistically significant correlation between the two prodynorphin-derived substrate peptides was found in terms of DCE activity. We therefore propose that a single enzyme activity may be responsible for the hydrolysis of dynorphin B1-13 and dynorphin A1-17. Furthermore, a significant correlation was also found between running activity and DCE activity 12-14 h before the CSF was withdrawn. Besides measurement of DCE activity by radioimmunoassay, the formation of Leu-enkephalin-Arg6 was identified by reversed-phase micro-column liquid chromatography and plasma desorption mass spectrometry. The experiment shows that voluntary exercise affects opioid peptidergic mechanisms.

Amino Acid Sequence↗

PubMed1993

Chronic administration of morphine decreases level of dynorphin A in the rat nucleus accumbens.

The effect of chronically administered morphine on the levels of dynorphin A in distinct regions of the brain (including medial frontal cortex, olfactory tubercule, nucleus accumbens, dorsal and medial striatum), was determined in male Sprague-Dawley rats. The drug was delivered through a subcutaneously implanted Azlet miniosmotic pump over a period of 5 days. The concentration of peptide was probed by radioimmunoassay, following pre-separation of tissue extracts by reversed phase separation on a SepPak C-18 cartridge. The result showed that the level of dynorphin A remained unaltered in all regions studied immediately before (tolerance) and 20 hr after (withdrawal) the pump was removed. A significant decrease in the level of dynorphin was found in the n. accumbens 48 hr (abstinence) after removal of the pump. It is suggested that previously observed changes in the reward system during abstinence may be connected with dynorphinergic neurones in the limbic system.

Animals↗

PubMed1992

Decreased cerebrospinal fluid neuropeptide-converting enzyme activity in monoarthritic rats.

The activity in rat cerebrospinal fluid (CSF) of dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE) was determined in control animals and in rats with monoarthritis. Enzymatic activities were measured with specific radioimmunoassays toward the N-terminal products Leu-enkephalin-Arg6 and substance P1-7, respectively. A monoarthritis stable during weeks 2-6 post-injection was induced by injection (0.05 ml) into one joint with Freund's adjuvant. Both SPE and DCE were significantly decreased 15 days after the intraarticular injection. Despite the degree of arthritis that was sustained equally at four weeks after inoculation, both DCE and SPE were back to control levels at that time. It can therefore be concluded that arthritis from a single joint is sufficient to elicit changes in CSF convertase activities, and that these effects disappear between 2 and 4 weeks after injection, although the arthritis persists.

Animals↗

PubMed1992

Decreased neuropeptide-converting enzyme activities in cerebrospinal fluid during acute but not chronic phases of collagen induced arthritis in rats.

We investigated the effects of collagen II-induced arthritis on two cerebrospinal fluid (CSF) enzymes converting dynorphin A and substance P (SP), namely dynorphin-converting enzyme (DCE) and substance P endopeptidase (SPE). The products generated by these enzymes are the bioactive fragments Leu-enkephalin-Arg6 and substance P, respectively. The strain used (DA rats) is very sensitive towards induction of arthritis. The collagen arthritis is a chronic autoimmune arthritis induced by native rat collagen type II (CII). Following intradermal injection of CII into the tailbase. CSF was sampled on day 21 (acute arthritis) and day 38 (chronic arthritis). Control rats were untreated because the strain used developed an acute and self-limited arthritis (adjuvant arthritis) when administered vehicle (i.e. incomplete Freund's adjuvant). The DCE activity was significantly lowered in the acute phase of arthritis (P less than 0.05) when analysed with two-factor analysis of variance (ANOVA). The enzyme converting SP (SPE) also showed a significant decrease in the acute phase of arthritis (P less than 0.05). These results demonstrate that both DCE and SPE are affected in the acute phase of arthritis. A functional role of these enzymes in processing pain-related neuropeptides is therefore implicated.

Acute Disease↗

PubMed1992

Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice.

Intrathecal (i.t.) injection of the competitive and selective N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-5-phosphonopentanoic acid (AP5), D-2-amino-7-phosphonoheptanoic acid (AP7), beta-D-aspartylaminomethyl phosphonic acid (Asp-AMP), 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and gamma-D-glutamylaminomethyl phosphonic acid (Glu-AMP) produced dose-dependent and reversible analgesic effects in the mouse hot-plate and formalin tests of nociception. They were slightly more potent in the formalin test but had no or negligible effects in the tail-flick test. The non-selective or non-NMDA receptor antagonists 6-cyano-7-nitro-quinoxalinedione (CNQX), 6,7-dinitro-quinoxalinedione (DNQX), gamma-D-glutamylglycine (gamma DGG), gamma-glutamylaminomethyl sulphonic acid (GAMS), kynurenic acid, cis-2,3-piperidine dicarboxylic acid (cis-PDA; partial agonist) and p-bromobenzoyl piperazine dicarboxylic acid (pBB-PzDA) had the same efficacy in the mouse hot-plate, tail-flick and formalin tests (gamma DGG and pBB-PzDA were not tested in the formalin test). This heterogeneous group of antagonists was somewhat more potent in the tail-flick test and slightly less potent in the formalin test than in the hot-plate test. Of the two glycine site antagonists tested, 7-chlorokynurenic acid (7-Cl-Kyn) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), the effect of the latter was compatible with selective action at the NMDA receptor complex while the action of the former was comparable to those of non-selective excitatory amino acid (EAA) receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1992

Histopathology and evaluation of potentiation of morphine-induced antinociception by intrathecal droperidol in the rat.

Clinical studies have indicated that a low dose of the dopamine D2-receptor antagonist droperidol given epidurally potentiate the antinociceptive effect of epidural morphine. The present study was conducted in order to evaluate this drug interaction in a rat model. Rats were given morphine and droperidol intrathecally in several combinations of doses. It was found that droperidol had no antinociceptive effect by itself, nor in combination with morphine. It was also shown that droperidol and morphine exert no histopathological effects on the rat spinal cord. This discrepancy between clinical findings and experimental pain studies suggests different modes of action of droperidol in the two situations.

Animals↗

PubMed1992

Local antinociceptive and hyperalgesic effects in the formalin test after peripheral administration of adenosine analogues in mice.

Adenosine administered to humans has been reported to induce pain after intravenous administration. On the other hand adenosine analogues have been shown to possess antinociceptive effects after peripheral and intrathecal administration in animals. The aim of the present study was to investigate the effect of peripheral administration of adenosine agonists with different affinities for the A1 and A2 adenosine receptors on a persistent pain stimulus using the formalin test. The drugs chosen were, R-phenylisopropyl-adenosine (R-PIA) with high affinity for the A1 receptor, N-ethylcarboxamide-adenosine (NECA) with almost equal affinity for the A1 and A2 receptor and 2-(2-aminoethylamino)-carbonylethylphenylethylamino-adenosin e (APEC) with high affinity for the A2 receptor. The drugs were mixed with formalin and administered subcutaneously into the dorsal hind paw in mice to study the local effects. They were also injected separately from the formalin solution in different paws to evaluate the systemic effect. The total time of licking the injected paw during the first 5 min. was recorded. In high doses all compounds reduced the licking activity, but a low dose of APEC (1 microM) injected together with the formalin solution had an algesic effect. All effects were antagonized by theophylline. These results suggests that A1 adenosine receptors mediate a local peripheral antinociceptive effect and the involvement of local peripheral A2 receptors in the enhancement of the algesic response.

Absorption↗

PubMed1992

Repeated intrathecal injections of dezocine produce antinociception without evidence for neurotoxicity in the rat: a study of morphometric evaluation of spinal cord histology.

This study was designed to determine the antinociceptive and spinal cord histologic effects of a new agonist/antagonist opioid drug dezocine. This drug was injected intrathecally in rats at a dose of 50 or 125 micrograms twice daily for 14 days. The tail-flick test showed that the antinociceptive effect declined gradually, with no detectable effects by day 14. Quantitative histologic techniques and light and electron microscopy showed that neither dose, compared with vehicle, created any morphologic changes in the spinal cord that could be attributed to a neurotoxic or otherwise degenerative effect of the drug. In conclusion, dezocine is a drug that gives rise to sustained antinociceptive effects when administered intrathecally and causes no morphologic changes in the rat spinal cord that could be indicative of neurotoxic potential.

Analgesics↗