Reproduction of "passive" avoidance in rats by administering pharmacologic agents

In experiments on rats learned to passive avoidance reaction in one trial with subsequent administration of electroconvulsive shock (two hours after learning), the influence of different factors on the retrieval of the lost reaction was tested after three days. The greatest restoring capacity was exhibited by a non-specific reminding agent, the bell, gamma-amino-butyric acid (200 mg/kg) and etimizol (1.5 mg/kg). In animals with a preserved reaction, a number of pharmacological agents impaired retrieval of the habit (caffeine 5 mg/kg, carbocholine 0.01 mg/kg and metamizil 0.5 mg/kg). Optimal conditions for the restoration of the lost reaction were formed by etimizol and gamma-aminobutyric acid. Cholinergic mechanisms play a certain role in the functioning of the retrieval apparatus.     

Effect of etimizol on instrumental learning in rats

The action of etimizol on the acquisition of the conditioned reflexes with different complexity and biological significance of reinforcement was studied. The acquisition was performed in a shuttle box and U-shaped maze using food and footshock stimuli. The time interval between administration of etimizol (3 mg/kg) and the onset of learning varied between 0.5 and 3 h in the several series. Etimizol did not facilitate the learning in rats whatever the time of administration and biological modality of reinforcement. It is suggested that the positive effect of etimizol on the memory is related to its influence on the consolidation stage.     

Effects of sc administration of recombinant human insulin-like growth factor I (IGF-I) on normal human subjects

Recombinant human insulin-like growth factor I (IGF-I) was administered subcutaneously to each of 5 normal human subjects at doses of 0 mg/kg (control), 0.06 mg/kg, or 0.12 mg/kg successively at one week intervals. After 0.06 mg/kg or 0.12 mg/kg IGF-I injections, plasma IGF-I levels increased from 185 +/- 17 ng/ml (mean +/- SEM) to maximal levels of 396 +/- 21 ng/ml at 3 hours and from 169 +/- 14 ng/ml to 480 +/- 27 ng/ml at 4 hours, respectively. These two peak values were statistically different (p less than 0.05). After 0.06 mg/kg and 0.12 mg/kg IGF-I administration, blood glucose levels decreased from 85 +/- 2 mg/dl to minimal levels of 73 +/- 3 mg/dl at 3 hours and from 83 +/- 1 mg/dl to 50 +/- 4 mg/dl at 2 hours, respectively. These two minimal values were statistically different (p less than 0.001). Serum insulin and C-peptide levels were decreased in a dose dependent manner after IGF-I administration. There were no changes between blood urea nitrogen levels before and 4 hours after IGF-I administration. The urinary GH concentration decreased after 0.06 mg/kg IGF-I administration, but increased and maintained normal values after 0.12 mg/kg IGF-I administration.     

Antagonism between long acting Monoamine Oxidase Inhibitors (MAOI) and MD780515, a new specific and reversible MAOI

The inhibition of type A and B monoamine oxidase (MAO A and B) in rat brain, liver and heart by MD780515, 3-[4-(3 cyanophenylmethoxy) phenyl]-5-(methoxymethyl)-2-oxazolidinone, has been investigated ex vivo with 5-hydroxytryptamine (5-HT) and β-phenylethylamine (PEA) as substrates. MAO A was strongly inhibited for four hours after oral administration of 10 mg/kg MD780515 (maximum inhibition : 72%, 86% and 83% in brain, liver and heart respectively. In contrast, in heart where PEA is deaminated by type A MAO, the predominant form of MAO in that tissue, the inhibition was 68% 30 minutes after administration of the compound. In all cases, MAO activities reached control values 24 hours after drug administration (10 mg/kg), whereas some inhibitory activity was still present 24 hours after oral administration of higher doses. The strong MAO A inhibition (68 to 83%) remaining in the three tissues 24 hours after oral administration of clorgyline (5 mg/kg) was completely removed by pretreatment with MD780515 (10 mg/kg). In the same conditions, MD780515 protected against the inhibition (53%) by clorgyline of PEA deamination in heart. Oral pretreatment with increasing doses of MD780515 (2.6 to 84 mg/kg) gradually removed brain MAO A inhibition caused by clorgyline (92%, 28.2 mg/kg) or tranylcypromine (88%, 4.8 mg/kg), the complete removal being observed at the dose of 21 mg/kg of MD780515 for clorgyline, and at 42 mg/kg for tranylcypromine. Inhibition of brain MAO B by tranylcypromine (96%) was not modified by pretreatment with the same range of oral doses of MD780515. The results are consistent with a specific and reversible inhibition of MAO A activity by MD780515 which can protect against long acting MAO A inhibitory effects of clorgyline and tranylcypromine. MD780515 enhances the selectivity of tranylcypromine.     

DA-8159 has erectile potentials much longer than the plasma half-life in a conscious rabbit model

DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.     

Chemotherapeutic effect of 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole in experimental staphylococcal infection]

Chemotherapeutic activity of 3-(5-nitrofuryl)-7-(5-nitrofurfuryliden)-3, 3a, 4, 5, 6, 7-hexahydro-2H-indazol (compound 26) was studied on albino mice with experimental staphylococcal infection. The animals were contaminated intraperitoneally. The results of culture of the specimens of the organs of the mice killed within various terms and the values of the spleen bacterial index served as the criteria of the effectiveness. Compound 26 was administered in doses of 20, 10 and 5 mg/kg once a day for 3 days. The treatment was started simultaneously with or 24 hours after the contamination. The results showed that compound 26 in a dose 20 mg/kg (0.4 mg/mouse) possessed high chemotherapeutic activity in experimental staphylococcal infection of albino mice and could be recommended for a thorough study as a potential agent for chemotherapy of staphylococcal infection.     

Cross-protection of newly emerging HPAI H5 viruses by neutralizing human monoclonal antibodies: A viable alternative to oseltamivir

Newly emerging highly pathogenic avian influenza (HPAI) H5N2, H5N3, H5N5, H5N6, H5N8 and H5N9 viruses have been spreading in poultry and wild birds. The H5N6 viruses have also caused 10 human infections with 4 fatal cases in China. Here, we assessed the cross-neutralization and cross-protection of human and mouse monoclonal antibodies against 2 viruses: a HPAI H5N8 virus, A/chicken/Netherlands/14015526/2014 (NE14) and a HPAI H5N6 virus, A/Sichuan/26221/2014 (SC14). The former was isolated from an infected chicken in Netherlands in 2014 and the latter was isolated from an infected human patient in Sichuan, China. We show that antibodies FLA5.10, FLD21.140, 100F4 and 65C6, but not AVFluIgG01, AVFluIgG03, S139/1 and the VRC01 control, potently cross-neutralize the H5N8 NE14 and H5N6 SC14 viruses. Furthermore, we show that a single injection of >1 mg/kg of antibody 100F4 at 4 hours before, or 20 mg/kg antibody 100F4 at 72 hours after, a lethal dose of H5N8 NE14 enables mice to withstand the infection. Finally, we show that a single injection of 0.5 or 1 mg/kg antibody 100F4 prophylactically or 10 mg/kg 100F4 therapeutically outperforms a 5-day course of 10 mg/kg/day oseltamivir treatment against lethal H5N8 NE14 or H5N6 SC14 infection in mice. Our results suggest that further preclinical evaluation of human monoclonal antibodies against newly emerging H5 viruses is warranted.     

Hypotensive response of ethanol in rats pretreated with disulfiram or nitrefazole

The effect of disulfiram or nitrefazole pretreatment on ethanol induced hypotension was examined in urethane anesthetized rats. A relatively low dose of ethanol (150 mg/kg; i.p.) produced a characteristic hypotensive response in rats pretreated for various periods with disulfiram or nitrefazole. This hypotensive episode started 5-10 minutes following ethanol administration and lasted 40-60 minutes. The hypotensive response was not seen unless disulfiram or nitrefazole treatment preceded ethanol administration by a least 6-8 hours. The low dose of ethanol produced a plasma ethanol concentration of 10mg/100ml or less. One treatment with nitrefazole (200 mg/kg) rendered rats vulnerable to ethanol-induced hypotension for 6 but not 8 days. One treatment with disulfiram (200 mg/kg) lasted 4 but not 6 days. In addition, the hypotensive response was greater in rats treated with nitrefazole than in rats treated with an equal dose (200 mg/kg) of disulfiram.     

Reduced incidence of retained placenta with induction of parturition in the cow

Two experiments were designed to determine whether pretreatment with Opticortenol (OPT), a long-acting corticosteroid, prior to induction of parturition with 25 mg of dexamethasone (DEX) alone or in combination with 500 mug cloprostenol (CLO) would result in a reduced incidence of retained placenta. In Experiment 1, 70% of the cows pretreated with 25 mg OPT on Day 270 of gestation calved before or within 24 hours of the scheduled induction treatment on Day 277. Cows induced to calve with DEX plus CLO without OPT pretreatment had an increased rate of placental retention (P<0.05), whereas, cows that received OPT were not different from the controls. In Experiment 2, cows received either 1 mg/25 kg OPT (high dosage) or 1 mg/50 kg OPT (low dosage) on Day 270 of gestation and were induced with DEX plus CLO on either Day 274 (4 days) or Day 276 (6 days). Cows claved 29.0 to 31.8 hours after induction treatment with 95% beginning to calve between 0700 and 1900 hours. The interval from calving to placental release and the incidence of retained placenta was not different between the high dosage 6-day group (29.4+/-8.2 hours, 29%) and the non-induced control cows (16.1+/-10.7 hours, 5%). When three cows in the high dosage 6-day group that retained their placentas for 30 to 36 hours were considered as not retained, the incidence of placental retention for that group was reduced still further to 17%. First service conception rates and pregnancy rates were lower in cows with retained placentas. Differences were significant (P<0.01) in Experiment 1 but not in Experiment 2. It was concluded that pretreatment with 1 mg/25 kg OPT 6 days prior to induction of parturition with DEX plus CLO in combination results in a predictable calving time, high calf viability, and a low incidence of placental retention.     

Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria.

Adults with malaria in Sri Lanka were treated with parenteral chloroquine diphosphate, either 2.5 mg base/kg intramuscularly at 0, 1, 12, 13, 24, and 25 hours or 5 mg base/kg subcutaneously at 0, 12, and 24 hours. Both regimens were completed with oral chloroquine phosphate, 5 mg base/kg, at 36 and 48 hours. Mean peak chloroquine concentrations in the first 12 hours, which were 0.5 (range 0.3-0.6) mg/l (1.4 (0.9-1.7) mu mol/l) [corrected] with the intramuscular regimen and 0.3 (0.2-0.4) mg/l (1.0 (0.7-1.3) mu mol/l) [corrected] with the subcutaneous regimen (p less than 0.05), were reached in median times of 90 (65-90) minutes and 30 (30-60) minutes respectively (p less than 0.05) after the start of treatment. The mean area under the plasma concentration curve for the first 12 hours was 1.4 (0.9-2.1) mg/l.h (4.5 (2.8-6.4) mu mol/l.h) [corrected] after intramuscular administration and 1.8 (0.8-2.3) mg/l.h (5.7 (2.7-7.2) mu mol/l.h) [corrected] after subcutaneous administration (p greater than 0.1). Mean maximum plasma concentrations were higher after intramuscular administration (0.6 (0.4-0.8) mg/l (1.7 (1.3-2.5) mu mol/l)) [corrected] than after subcutaneous administration (0.4 (0.4-0.5) mg/l (1.3 (1.3-1.5) mu mol/l)) [corrected] (p less than 0.05), but both regimens produced satisfactory plasma profiles. Chloroquine resistance was found in the only case of Plasmodium falciparum malaria. Chloroquine is absorbed rapidly after divided dose intramuscular injection and single dose subcutaneous injection and does not cause hypotension or neurotoxicity in adults. Similar regimens should be evaluated in children before the parenteral use of this drug is abandoned.     

Cardioprotective effect of prostacyclin and 7-oxo-PGI2 in rats against chronic isoproterenol damage

Isoproterenol (ISO) was injected in 5 mg/kg i.p. doses to rats, daily for two weeks. We evaluated the developed myocardial hypoxia and necrosis quantitatively by histological methods. To follow the time course of cardioprotection prostacyclin or 7-oxo-PGI2 were injected daily, i.p. 5, 30 min and 1, 2, 3, 4 hours before or after the ISO to groups of ten rats, respectively. Cardioprotection was defined as the reduction of necrotized areas and was expressed as percentage change compared to the control (saline treated) group. 1 microgram/kg PGI2 and 50 micrograms/kg 7-oxo-PGI2+ showed nearly equipotent cardioprotection (37.3-7.9% and 38.3-6.8%, respectively). The peak effect of both compounds appeared when injected prior to ISO in the 120. min but the action of 7-oxo-PGI2 was more prolonged. The different doses of prostacyclin analogs given after the ISO injection were ineffective with the exception of 50 micrograms/kg 7-oxo-PGI2 (29.75 +/- 5.2%).     

Long-term enhancement of morphine hypalgesia as a result of periodic blockade of opiate receptors using naloxone

A significant enhancement of the analgetic effect of morphine (6 mg/kg, subcutaneously; tail withdrawal reflex at 60 degrees C) was observed in rats 3-4 hours after single naloxone (1 mg/kg) administration. Periodical naloxone injection (0.5 mg/kg, subcutaneously, 3 times per day at 3.5-hour intervals for 3 days) led to a prominent and long-term (testing on the 20th and 105th hour after the last naloxone administration) enhancement of morphine analgesia (2.6 mg/kg subcutaneously) and insignificant inhibition of stress analgesia during two-hour immobilization of animals. These modifications of morphine and stress analgetic effects are considered a result of adaptive changes of opiate receptors after their blockade.     

Synchronization of estrus and fertility in goats with norgestomet ear implants

Estrus was synchronized in 64 dairy goats in July with norgestomet ear implants. Half the does received ear implants that contained 6 mg norgestomet and the remaining does received implants that contained 3 mg. Implants were left in place for 11 days. Each doe received i.m. injections of 400 IU PMSG and 50 mug cloprostenol 24 hours prior to implant removal. Twenty-eight of 32 does (87.5%) that received 6 mg or 3 mg norgestomet exhibited onset of estrus within 24 hours of implant removal. All does had exhibited onset of standing estrus by 43 hours after implant removal. Does were hand-mated to fertile bucks twice daily while in standing estrus. There were no differences between does implanted with 6 mg or 3 mg in fertility to the induced estrus (74.2% vs 75% kidding), mean length of gestation (151.0 +/- 3.2 vs 151.6 +/- 2.0 days), mean number of kids per doe (2.1 +/- 0.8 vs 2.3 +/- 0.7) or in mean kid weights (3.10 +/- 0.80 vs 3.06 +/- 0.86 kg) (6 mg vs 3 mg, respectively). It was concluded that ear implants that contained 3 mg of norgestomet were equally as effective as implants that contained 6 mg for synchronization of estrus in dairy goats.     

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.     

Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats

Background

Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens.

Methods

Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats.

Results

Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose.

Conclusions

The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4–5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.

     

Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test

Morphine-6-glucuronide (M6G), a major metabolite of morphine with agonist opioid-receptor activity, was reported to be a substrate of P-glycoprotein (P-gp). Inhibition of P-gp may thus result in higher brain uptake of M6G. The goal of this observer-blinded, placebo controlled study, was to compare the antinociceptive effects of M6G in homozygous P-gp knockout (mdr1a(-/-)) and wildtype (mdr1a(+/+)) mice. M6G was injected intraperitoneally as a single dose of 0, 0.5, 1, 2.5, 5, and 10 mg/kg. Eight P-gp knockout and eight wildtype mice were studied per dose. A hot plate test was performed before and 5, 15, 30, 60, 90, 120, and 150 min after M6G administration. Plasma-concentrations of M6G, morphine, and morphine-3-glucuronide (M3G) were measured after intraperitoneal injection of 5 mg/kg M6G in another 14 P-gp knockout and 14 wildtype mice. No difference neither in the dose response relationship, nor in the time course of response latency times were observed between P-gp knockout and wildtype mice. However, latency times increased with higher doses of M6G, with antinociception significantly different from placebo at a M6G dose of 5 and 10 mg/kg. P-gp knockout mice tended to have higher plasma concentrations than the wildtype. However, plasma concentrations widely overlapped between groups and therefore no statistical significant group difference could be detected. We conclude that despite reported doubling of M6G brain uptake, absence of mdr1a coded P-gp does not enhance antinociceptive effects of M6G in the hotplate test after acute single-dose administration in mdr1a(-/-) knockout mice.     

Acute reversible cataract due to nitrocompounds in Japanese quail (Coturnix coturnix japonica)

The present study was designed to examine the usefulness of the Japanese quail as an experimental model of cataractogenic activity. Chemicals, 2, 6-dibromo-4-nitro-phenol (2, 6-D), 2, 4-dinitroanisole (2, 4-DA), and 2, 4-dinitrophenol (2, 4-D; for the positive control), were administered singly through an oral route to 2-week old male Japanese quails to investigate the reversibility of cataracts. A single administration of 2, 4-D (36 and 43 mg/kg) produced reversible cataract in 14 of 16 animals (87.5%). This cataract was seen 1 or 2 hours after treatment and continued for 1 to 12 hours. Treatment with 2, 6-D (20 and 25 mg/kg) and 2, 4-DA (120 and 150 mg/kg) caused cataracts in 7 of 11 (63.6%) and 8 of 8 surviving animals (100%), respectively. Cataracts produced by 2, 6-D and 2, 4-DA, which were observed from 1 and 2 to 4 hours after the treatment, continued for 6 to 15 and 1 to 13 hours, respectively. Mortalities in the 25 mg/kg group of 2, 6-D, 120 mg/kg and 150 mg/kg group of 2, 4-DA were found in 2 of 5 animals, 1 of 5 animals and 5 of 9 animals, respectively. These results indicate that the Japanese quail is useful as an animal model to evaluate toxicity to the eye and cataractogenesis.     

Novel 8 alpha-ergolines with inhibitory and stimulatory effects on prolactin secretion in rats

Four derivatives of the ergot dopamine (DA) agonist lisuride (LIS), namely 6-n-propyl-lisuride (6-n-propyl-LIS), transdihydrolisuride (TDHL), 6-n-propyl-transdi-hydrolisuride (6-n-propyl-TDHL) and 2-bromolisuride (2-Br-LIS) were investigated in female rats with regard to their influence on hyperprolactinaemia induced by pretreatment with reserpine (2 mg/kg i.p., 24 h) at various intervals following their subcutaneous or oral administration (0.05 mg/kg). Two hours after administration, LIS, 6-n-propyl-LIS, and 6-n-propyl-TDHL caused a statistically significant inhibition of reserpine-induced hyperprolactinaemia of about the same extent. Eight hours after administration 6-n-propyl-LIS and 6-n-propyl-TDHL were as active as after 2 h in inhibiting prolactin (PRL) secretion whereas LIS was almost ineffective in this respect. TDHL caused a statistically significant inhibition of PRL secretion at 2 and 8 h after oral administration; this effect was less pronounced after s.c. administration. In contrast to the aforementioned derivatives 2-Br-LIS further increased the reserpine-induced hyperprolactinaemia. In normal male rats pretreatment with 2-Br-LIS (0.025-6.25 mg/kg s.c., 2 h) dose-dependently stimulated PRL secretion. The present data support the assumption of the longlasting DA agonistic action of 6-n-propyl-LIS and 6-n-propyl-TDHL and of the antidopaminergic properties of 2-Br-LIS recently derived from behavioural studies.     

Rat-1 Fibroblasts Engineered with GAD65 and GAD67 cDNAs in Retroviral Vectors Produce and Release GABA

Abstract: The effects of the adenosine A₁ agonist N ₆-cyclohexyladenosine (CHA) on MPTP-induced dopamine (DA) depletion in the striatum of C57BL/6 mice were studied. Twenty hours after a single injection of MPTP (30 mg/kg, s.c.), the toxin caused 62% depletion of striatal DA. CHA (0.2–3 mg/kg, s.c.), when given together with MPTP, prevented the toxin-induced DA depletion in a dose-dependent manner. This protective action was apparently mediated by the A¹ receptors, because this effect was selectively antagonized by pretreating the animals with the A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg, i.p.) but not with the A₂ antagonist 1,3-dipropyl-7-methylxanthine (25 mg/kg, i.p.). When CHA (3 mg/kg) was injected 5 h after MPTP administration, at which point striatal DA levels were already reduced significantly, a rapid and complete recovery of the striatal DA levels occurred. These neurochemical data suggest that the A₁ agonist CHA is potentially useful as a neuroprotective agent against MPTP-induced toxicity.     

Single-photon emission computed tomographic imaging of the early time course of therapy-induced cell death using technetium 99m tricarbonyl His-annexin A5 in a colorectal cancer xenograft model

As apoptosis occurs over an interval of time after administration of apoptosis-inducing therapy in tumors, the changes in technetium 99m ((99m)Tc)-tricarbonyl (CO)? His-annexin A5 (His-ann A5) accumulation over time were examined. Colo205-bearing mice were divided into six treatment groups: (1) control, (2) 5-fluorouracil (5-FU; 250 mg/kg), (3) irinotecan (100 mg/kg), (4) oxaliplatin (30 mg/kg), (5) bevacizumab (5 mg/kg), and (6) panitumumab (6 mg/kg). (99m)Tc-(CO)? His-ann A5 was injected 4, 8, 12, 24, and 48 hours posttreatment, and micro-single-photon emission computed tomography was performed. Immunostaining of caspase-3 (apoptosis), survivin (antiapoptosis), and LC3-II (autophagy marker) was also performed. Different dynamics of (99m)Tc-(CO)? His-ann A5 uptake were observed in this colorectal cancer xenograft model, in response to a single dose of three different chemotherapeutics (5-FU, irinotecan, and oxaliplatin). Bevacizumab-treated mice showed no increased uptake of the radiotracer, and a peak of (99m)Tc-(CO)? His-ann A5 uptake in panitumumab-treated mice was observed 24 hours posttreatment, as confirmed by caspase-3 immunostaining. For irinotecan-, oxaliplatin-, and bevacizumab-treated tumors, a significant correlation was established between the radiotracer uptake and caspase-3 immunostaining (r = .8, p < .05; r = .9, p < .001; r = .9, p < .001, respectively). For 5-FU- and panitumumab-treated mice, the correlation coefficients were r = .7 (p = .18) and r = .7 (p = .19), respectively. Optimal timing of annexin A5 imaging after the start of different treatments in the Colo205 model was determined.