Toxicity of aromatic hydrocarbons. VII. Hepatotoxicity of 9-nitrophenanthrene, and protection against it by beta-naphthoflavone

Male Sprague-Dawley rats were treated with a single i.p. injection of DMSO (3.0 ml/kg) or 9-nitrophenanthrene (9-NP, mg/kg) in DMSO. 9-NP produced a significant elevation of serum aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and gamma-glutamyl transpeptidase (GGTP) levels relative to DMSO-injected rats 24 hr after injection. With the exception of GGTP, the increase in enzyme activities induced by 9-NP was significantly reduced by a 3-day pretreatment with beta-naphthoflavone (BNF; 40 mg/kg/day) in DMSO. The effect of 9-NP on GGTP levels was enhanced by BNF pretreatment.     

Toxicity of polycyclic aromatic hydrocarbons. V. Protective effect of beta-naphthoflavone against hepatotoxicity induced by diphenaldehyde in rats

Male Sprague-Dawley rats were treated ip with beta-naphthoflavone (40 mg/kg/day) in corn oil or in DMSO for three days. Diphenaldehyde (90 mg/kg in DMSO) was injected ip 24 hr after pretreatment. The increase in the levels of aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, gamma glutamyl transpeptidase, and lactate dehydrogenase was significantly lower in rats pretreated with BNF. This suggests that the BNF-induced P-450 isozyme systems have a protective effect against the acute hepatotoxicity of diphenaldehyde.     

The effect of monooxygenase inducing agents on the incorporation of [35S]methionine into hepatic microsomal protein of rainbow trout (Salmo gairdneri)

Treatment of rainbow trout (Salmo gairdneri) with 150 mg/kg BNF resulted in an increase in hepatic microsomal monooxygenase activity as assessed by ECOD and EROD when compared to those activities in corn oil-pretreated animals. Administration of 100 mg/kg 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) to trout had no significant effect on these catalytic activities or on BeND. The amount of radioactivity in hepatic microsomes at 24, 48 or 72 hr following the administration of 75 muCi of [35S]methionine was consistently higher in animals pretreated with BNF than in those treated with corn oil or 6-CB. Autoradiography/fluorography of electrophoretograms demonstrated the appearance of at least three radiolabeled bands in the 50,000-60,000 mol. wt range in solubilized microsomes from BNF-treated fish which were not present in microsomes from control animals or fish treated with 6-CB. These data indicate that the stimulation of hepatic microsomal catalytic activities observed following the administration of 3-MC-type agents to rainbow trout is due, at least in part, to induction of enzyme(s) rather than activation of existing enzyme(s). These results further support the observation that fish appear to be non-responsive to phenobarbital-type inducing agents.     

Amiodarone reduces the effect of T3 on beta adrenergic receptor density in rat heart

The effect of injection of 1 mg/kg triiodothyronine on cardiac beta-adrenoceptor state was investigated in hypothyroid rats and compared to the effect in hypothyroid rats pretreated with amiodarone (200 mg/kg/day for 8 days). The Kd values of iodocyanopindolol binding to the beta-receptors were not influenced by either T3 injection or by amiodarone treatment. In the absence of amiodarone, injection of triiodothyronine resulted in a small decrease in receptor density at 6 hr, followed by an increase at 24 hr. Rats treated with amiodarone showed a similar response pattern to hormone injection (i. e. a small decrease in receptor density at 6 hr, followed by an increase at 24 hr), but the amplitude of the response was significantly reduced. Moreover, in vehicle injected rats amiodarone treatment resulted in a decrease in receptor density when rats were mildly hypothyroid, but not when rats were severely hypothyroid. It is concluded that amiodarone interferes (directly or indirectly) with thyroid hormone action in the heart.     

Effect of adrenalectomy and 5-hydroxytryptophan on phasic release of luteinizing hormone

The effect of 5-hydroxytryptophan (5-HTP) on serum progesterone and the possible role of adrenal progesterone in mediating stimulation by 5-HTP of phasic release of luteinizing. hormone (LH) were investigated in estradiol benzoate (EB)-treated ovariectomized rats. LH surges were induced in long-term (at least two weeks) ovariectomized rats by two injections of EB (20 micrograms/rat, s.c.) with an interval of 72 hrs. Administration of 5-HTP (50 mg/kg, i.p.) at 1000 hr in EB-treated ovariectomized rats resulted in a four-fold increase in serum progesterone within 30 mins, and significantly stimulated the LH surge at 1600 hr. This facilitative effect of 5-HTP on serum LH, but not progesterone, was further potentiated in rats pretreated with P-chlorophenylalanine (PCPA) 72 hrs earlier. Adrenalectomy shortly before 5-HTP administration attenuated the LH surge in saline treated controls, and completely blocked the facilitative effect of 5-HTP on the afternoon surge of LH in rats pretreated with PCPA 72 hrs earlier. On the other hand, chronic adrenalectomy (for 6 days) followed by hydrocortisone (0.2 mg/rat/day) replacement not only had no effect on the LH surge in saline treated controls, but also failed to prevent 5-HTP from facilitating the LH surge in PCPA pretreated rats. On the first day of bleeding, the basal LH value at 1000 hr in sham operated controls was significantly suppressed by PCPA pretreatment 48 hrs earlier. The second dose of 5-HTP administered on the next day failed to potentiate LH surges in either sham operated or adrenalectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

3-Alkynyl selenophene protects against carbon-tetrachloride-induced and 2-nitropropane-induced hepatic damage in rats

The aim of this study was to investigate the protective effect of 3-alkynyl selenophene (3-ASP) on acute liver injury induced by carbon tetrachloride (CCl₄) and 2-nitropropane (2-NP) in rats. On the first day of treatment, the animals received 3-ASP (25 mg/kg, p.o.). On the second day, the rats received CCl₄ (1 mg/kg, i.p.) or 2-NP (100 mg/kg, p.o.). Twenty-four hours after CCl₄ or 2-NP administration, the animals were euthanized, and their plasma and liver were removed for biochemical and histological analyses. The histological analysis revealed extensive injury in the liver of CCl₄-exposed and 2-NP-exposed rats, which was attenuated by 3-ASP. 3-ASP significantly attenuated (1) the increase in plasmatic aspartate and alanine aminotransferase activities and lipid peroxidation levels induced by CCl₄ and 2-NP; (2) the inhibition of δ-aminolevulinic dehydratase activity caused by 2-NP; and (3) the decrease in ascorbic acid (AA) levels and catalase (CAT) activity caused by CCl₄. AA levels and CAT activity remained unaltered in the liver of rats exposed to 2-NP. The protective effect of 3-ASP on acute liver injury induced by CCl₄ and 2-NP in rats was demonstrated.     

Effects of short- and long-acting dopamine agonists on sensitized dopaminergic neurotransmission in rats with unilateral 6-OHDA lesions

The effects of short and long-acting dopamine agonists on sensitized dopaminergic transmission in an animal model of Parkinson's disease were investigated. Rats with 6-hydroxydopamine (6-OHDA) lesions of the left nigrostriatal dopaminergic pathway were pre-exposed i.p. to 50 mg/kg methyl levodopa for 10 days. After a 7-day withdrawal period, these animals were treated with saline i.p., 0.05 mg/kg apomorphine s.c., or 0.5 mg/kg cabergoline i.p., once daily for 7 days. On the 8th day, rats in each treatment group received a challenge dose of 0.05 mg/kg apomorphine or saline s.c. The temporal changes in the number of rotations away from the 6-OHDA lesion side were evaluated after the challenge. The apomorphine challenge increased the number of rotations more markedly in the apomorphine pretreated rats than in the other pretreatment groups. In cabergoline pretreated rats, the number of rotations was significantly lower than that of saline-pretreated animals. Pretreatment with saline did not alter the apomorphine sensitivity of rotational behavior. These findings suggest that the repeated administration of long-acting dopamine agonists may reduce sensitized dopaminergic transmission in dopamine-depleted rats, whereas short-acting ones may further enhance sensitization of the transmission process.     

Effect of tryptophan administration on serotonin and 5-hydroxyindoleacetic acid content in the brainstem of Lilly 110140-pretreated rats.

Adult male Sprague-Dawley rats were divided into 3 groups. One group was pretreated with Lilly 110140 (10 mg/kg) 27 hours and again 3 hours before sacrifice while a second group received Lilly 110140 only 3 hours before sacrifice. The third or control group received only equivalent volumes of saline. Animals from each group were administered 25 mg/kg L tryptophan intraperitoneally (i.p.) 0, 30, 60 or 90 minutes before sacrifice. Equivalent elevations in serum and also brainstem tryptophan content were observed in all three groups with the peak observed at 30 minutes. Brainstem serotonin content was significantly elevated in both groups of Lilly 110140-pretreated rats but not in the control group. Brainstem 5-hydroxyindoleacetic acid was significantly elevated after tryptophan administration in the control and the 3 hour and 27 hour, Lilly 110140-pretreated groups but not in the 3 hour Lilly 110140 pretreated group. The results indicate that neither 3 or 3 hours and 27 hours of Lilly 110140 pretreatment appreciably affects the increase in brainstem serotonin synthesis induced by the i.p. administration of 25 mg/kg of L tryptophan.     

Relationships between alterations in glutathione metabolism and the disposition of inorganic mercury in rats: effects of biliary ligation and chemically induced modulation of glutathione status

Influences of biliary ligation and systemic depletion of glutathione (GSH) or modulation of GSH status on the disposition of a low, non-nephrotoxic i.v. dose of inorganic mercury were evaluated in rats in the present study. Renal and hepatic disposition, and the urinary and fecal excretion, of inorganic mercury were assessed 24 h after the injection of a 0.5-micromol/kg dose of mercuric chloride in control rats and rats pretreated with acivicin (two 10-mg/kg i.p. doses in 2 ml/kg normal saline, 90 min apart, 60 min before mercuric chloride), buthionine sulfoximine (BSO; 2 mmol/kg i.v. in 4 ml/kg normal saline, 2 h before mercuric chloride) or diethylmaleate (DEM; 3.37 mmol/kg i.p. in 2 ml/kg corn oil, 2 h before mercuric chloride) that either underwent or did not undergo acute biliary ligation prior to the injection of mercury. Among the groups that did not undergo biliary ligation, the pretreatments used to alter GSH status systemically had varying effects on the disposition of inorganic mercury in the kidneys, liver, and blood. Biliary ligation caused the net renal accumulation of mercury to decrease under all pretreatment conditions. By contrast, biliary ligation caused significant increases in the hepatic burden of mercury in all pretreatment groups except in theacivicin-pretreated group. Blood levels of mercury also increased as a result of biliary ligation, regardless of the type of pretreatment used. The present findings indicate that biliary ligation combined with methods used to modulate GSH status systemically have additive effects with respect to causing reductions in the net renal accumulation of mercury. Additionally, the findings indicate that at least some fraction of the renal accumulation of inorganic mercury is linked mechanistically to the hepato-biliary system.     

Modification of the hepatotoxicity of D-galactosamine in the rat by cycloheximide.

The effect of cycloheximide (1.5 mg/kg), a potent inhibitor of protein biosynthesis, on D-galastosamine (375 mg/kg)-induced hepatic necrosis and hepatic triglyceride accumulation was studied in rats. Serum transaminase levels, 24 hr after D-galactosamine administration, were significantly reduced in animals treated simultaneously or 4 hr before D-galactosamine with cycloheximide, when compared to animals given D-galactosamine alone. Transaminase levels in rats given cycloheximide 4 hr after D-galactosamine were not reduced. Histological grading of hepatocyte necrosis showed a similar pattern of protection in the pretreated and simultaneously treated groups. Hepatic triglycerides were significantly reduced only in the latter group. Fatality 48 hr after D-galactosamine administration was significantly less common in rats pretreated with cycloheximide when compared to rats given D-galactosamine without cycloheximide, and surviving animals in the cycloheximide pretreated group had a lower serum transaminase level, a lower necrosis score, and a reduced hepatic triglyceride level. These data are consistent with the concept that protein synthesis is important in the pathogenesis of D-galactosamine-induced hepatotoxicity.     

Influence of acetone on the severity of the liver injury induced by haloalkane mixtures.

Acetone potentiation of haloalkane-induced liver injury is a well-known phenomenon. Acetone-treated rats challenged with a trichloroethylene-CCl4 mixture exhibit a more sever liver injury than that predicted by the addition of the single potentiating effects of each. The purpose of the present study was to determine if acetone exerted similar interactions with other haloalkane mixtures. The testing protocol used was designed and performed to allow categorization of interactions occurring among two or three agents. Rats were treated (p.o.) with corn oil or acetone (10.2 mmol/kg) and were administered (i.p.) 18 h later 1,1-dichloroethylene (0.6 mmol/kg), trichloroethylene (5.6 mmol/kg), tetrachloroethylene (19.6 mmol/kg), 1,1,1-trichloroethane (10.0 mmol/kg), 1,1,2-trichloroethane (1.1 mmol/kg), 1,1,2,2-tetrachloroethane (1.0 mmol/kg), CHCl3 (6.2 mmol/kg), CCl4 (1.0 mmol/kg), or a mixture of two haloalkanes (all 28 combinations were tested). Liver injury was assessed 24 h later using plasma alanine aminotransferase activity and a quantitative histological evaluation. In corn oil pretreated rats, the hepatotoxic responses observed for the 28 mixtures were additive for 26 of 28 mixtures and supra-additive for 2 of 28, whereas in acetone-pretreated rats the responses observed were additive for 17 of 28, infra-additive for 10 of 28, and supra-additive for 1 of 28. Mixtures containing 1,1,1-trichloroethane or tetrachloroethylene resulted only in no change in toxicity or infra-additivity. Increased toxic responses (additivity and supra-additivity) were observed with certain binary mixtures containing CCl4, CHCl3, 1,1,2-trichloroethane, or 1,1-dichloroethylene.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenergic stimulation of adrenocortical secretion in immature fowl

In 5-6-week-old cockerels the circulating corticosterone concentration was significantly increased in birds i.m. injected 30 and 60 min previously with adrenaline (0.33 mg/kg), noradrenaline (0.33 mg/kg) or a beta-adrenergic agonist (isoprotorenol, 1 mg/kg), but was reduced in birds pretreated with an alpha-adrenergic agonist (phenylephrine, 1 mg/kg). The stimulation of corticosterone secretion induced by a 30 min period of forced exercise (0.04 km/hr; 0 degree incline) was potentiated by noradrenaline, isoprotorenol and phentolamine pretreatment. In response to exogenous adrenocorticotrophin (ACTH, 8 i.u./kg), administered i.v., the increase in the plasma corticosterone concentration was elevated above that in the controls in birds pretreated with adrenaline, noradrenaline, isoprotorenol or phentolamine (an alpha antagonist administered at 1 mg/kg). The corticosterone response to ACTH was suppressed by phenylephrine pretreatment. These results demonstrate that both basal and stimulated levels of adrenocortical activity may be subtly regulated by adrenergic mechanisms acting at a site(s) within the hypothalamo-pituitary-adrenal axis.     

Worsening of long-term myocardial function after successful pharmacological pretreatment with cyclosporine.

Pretreatment with cyclosporine (CsA) decreases infarct size 24h after myocardial ischemia/reperfusion (I/R). The goal of this study was to determine effects of CsA pretreatment on long-term cardiac function after I/R-injury. Rats were randomly assigned to group-1: vehicle-only, group-2: CsA-5mg/kg/day, and group-3: CsA-12.5mg/kg/day given orally for three days prior to I/R-injury (30 min of left anterior descending coronary artery occlusion). Post-I/R survival and cardiac function were evaluated 14 days after I/R-injury by echocardiography and invasive hemodynamic measurements. Rats with I/R-injury showed increased left ventricular pressure (LVEDP) compared to rats without I/R-injury (p<0.005). Although CsA initially decreased infarct size, no differences of LVEDP were seen 14 days after I/R-injury (vehicle: 21.2+/-8.9 mmHg, CsA-5mg/kg/day: 21.5+/-0.7 mmHg, CsA-12.5mg/kg/day: 20.5+/-9.4 mmHg). Ejection fraction and fractional shortening were decreased compared to baseline, but showed no differences between groups. On day 14, a dose-dependent increase in left ventricular end diastolic diameter was seen (p<0.001). CsA pretreatment was associated with a dose-dependent decrease in post-I/R-survival (vehicle: 56%, CsA-5mg/kg/day: 32%, CsA-12.5mg/kg/day: 16%; p=0.017). CsA pretreatment did not improve long-term cardiac function despite decreased infarct size 24h after I/R-injury, but increased post-I/R mortality significantly. Poor cardiac function after CsA pretreatment might be caused by left ventricular dilation.     

Toxicity of polycyclic aromatic hydrocarbons. IV. Effects of diphenaldehyde, a major product of ozonized phenanthrene, in rats

Diphenaldehyde is the major product of phenanthrene ozonized on silica gel. Male Sprague-Dawley rats were treated with a single ip injection of DMSO (3.0 ml/kg) or diphenaldehyde (90 mg/kg) in DMSO. Diphenaldehyde produced significant alterations in levels of serum aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, gamma-glutamyl transpeptidase, and lactate dehydrogenase relative to DMSO-injected rats 24 hr after injection. These results, as well as gross observations on necropsy, suggest that diphenaldehyde exhibits significant hepatotoxicity.     

Mechanism of dimethylsulfoxide protection against the teratogenicity of secalonic acid D in mice

Dimethylsulfoxide (DMSO) is known to antagonize the teratogenic effects of secalonic acid D (SAD) in mice. To establish the optimum protective dose of DMSO, pregnant CD-1 mice were treated, i.p., with 30 mg/kg of SAD in 5% (w/v) NaHCO3, containing 0, 10, 20, or 30% (v/v) DMSO on day 11 of gestation. Data indicate that at 10% and 20% levels, DMSO affords an apparent dose-related protection against SAD-induced cleft palate, whereas 30% DMSO enhanced fetal resorption with no reduction in the incidence of cleft palate. Ultraviolet spectra and TLC mobility indicated that DMSO at 20% did not directly interact with SAD. Distribution and elimination of 14C-SAD was studied in fetal and maternal tissues from pregnant mice at 24 and 48 hr after exposure to 30 mg/kg of 14C-SAD, i.p., in NaHCO3 (control) or in 20% DMSO. Compared with those not receiving DMSO, maternal exposure to DMSO: 1) significantly reduced (42-75%) radioactivity in fetal heads and bodies, placenta, and maternal tissues other than liver; 2) significantly increased (up to 222%) the radioactivity in maternal liver; and 3) significantly reduced (44-58%) fecal and urinary elimination of SAD-derived radioactivity. These results suggest that the antiteratogenic effect of DMSO against SAD may be at least partly mediated by increased SAD (or its metabolites) retention by maternal liver leading to reduced SAD uptake by the fetus.     

Repeated Cocaine Administration Alters Extracellular Glutamate in the Ventral Tegmental Area

Abstract: The present study determined if repeated cocaine injections alter the effect of cocaine on extracellular glutamate in the ventral tegmental area (VTA). All rats were treated with daily cocaine (15 mg/kg i.p. × 2 days, 30 mg/kg i.p. × 5 days) or saline for 7 days. At 21 days after discontinuing the daily injections, a dialysis probe was placed into the VTA and the extracellular levels of glutamate were estimated. A systemic injection of cocaine (15 mg/kg i.p.) elevated extracellular glutamate in the VTA of rats pretreated with daily cocaine but not in the daily saline-pretreated subjects. No significant change in glutamate was produced by a saline injection in either pretreatment group. In a group of rats pretreated with daily cocaine, the D₁ antagonist SCH-23390 (30 µ M ) was infused through the dialysis probe prior to the acute injections of saline and cocaine. SCH-23390 prevented the increase in extracellular glutamate associated with the acute administration of cocaine. Behavioral data were collected simultaneously with the measures of extracellular glutamate. The behavioral stimulant effect of cocaine was greater in cocaine-pretreated than saline-pretreated subjects, and the behavioral augmentation in cocaine-pretreated rats was partly blocked by SCH-23390. These data support the hypotheses that repeated cocaine administration produces an increase in the capacity of D₁ receptor stimulation to release glutamate in the VTA and that this mechanism partly mediates behavioral sensitization produced in rats treated with daily cocaine injections.     

A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.     

Cross-tolerance of dopamine metabolism to baclofen, γ-butyrolactone and HA-966 in the striatum and olfactory tubercle of the rat

Rats received 7 daily injections with baclofen (40 mg/kg), GBL (750 mg/kg) or HA-966 (100 mg/kg). Dopamine (DA) was measured in the striatum and olfactory tubercle (OT) of rats, sacrificed 0.5 h or 1 h after the last injection. Marked tolerance and cross-tolerance for the DA-elevating effect of these drugs was seen in the striatum, but not in OT. When on day 7 a unilateral lesion of the nigrostriatal pathway was made, also some tolerance to the DA increase in the striatum on the lesioned side was seen in HA-966-pretreated rats, but it was small compared to the tolerance after an additional drug administration in non-lesioned animals. A low dose of apomorphine (0.25 mg/kg, i.p.) had no effect on DA, dihydroxyphenylacetic acid DOPAC) or homovanillic acid (HVA) levels in the lesioned striata, whether the rats had been pretreated for 6 days with HA-966 or not. However, this dose of apomorphine had a significantly more lowering effect on striatal DOPAC and HVA levels on the unlesioned side of HA-966 pretreated rats. The results show that tolerance develops to the increase of DA synthesis, which is possibly receptor-mediated. This tolerance develops more readily in the striatum than in the olfactory tubercle.     

Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-induced in vivo oxidative stress and striatal lesions: insights into Huntington's disease

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of complex II in the mitochondria. 3-NP toxicity has gained acceptance as an animal model of Huntington's disease (HD). In the present study, we confirmed that rats injected with 3-NP (20 mg/kg, i.p., daily for 4 days) exhibit increased oxidative stress in both striatum and cortical synaptosomes as well as lesions in the striatum. Synaptosomal membrane proteins from rats injected with 3-NP exhibited a decrease in W/S ratio, the relevant electron paramagnetic resonance (EPR) parameter used to determine levels of protein oxidation, and western blot analysis for protein carbonyls revealed direct evidence of increased synaptosomal protein oxidation. Treatment of rats with the brain-accessible free radical spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO; 30 mg/kg, i.p., daily 2 h before 3-NP injection) or with N-acetylcysteine (NAC; 100 mg/kg, i.p., daily 2 h before 3-NP injection), a known glutathione precursor, before 3-NP treatments protects against oxidative damage induced by 3-NP as measured by EPR and western blot analysis for protein carbonyls. Furthermore, both DEMPMPO and NAC treatments before 3-NP administration significantly reduce striatal lesion volumes. These data suggest oxidative damage is a prerequisite for striatal lesion formation and that antioxidant treatment may be a useful therapeutic strategy against 3-NP neurotoxicity and perhaps against HD as well.     

Compartive behavioral effects of dibutyryl cyclic AMP and prostaglandin E1 in mice.

Three behavioral tests, spontaneous locomotor activity (SLMA), exploratory behavior (EB) and rotarod performance (RP), a measure of neuromuscular coordination, were used to stuey the interaction of PGE1 (1 mg/kg i.p., 10 min. pretreatment) with DBcAMP (25 mg/kg i.p., 25 min. pretreatment) in mice. A dose-response relationship of PGE1 (0.01-5.0 mg/kg) to SLMA was determined, with a significant decrease in SLMA produced by a dose of 0.1 mg/kg. decreases in SLMA were produced by PGE1 (79%), DBcAMP (41%) and DBcAMP-PGE1 combination (71%). Similar decreases in EB were observed. Although no significant difference between controls and DBcAMP was observed in RP, 52% of mice tested were RP failures following PGE1 and a 100% failure rate was induced by the combination. Mice were treated with a second injection of DBcAMP or PGE1 or the combination 24 hr following the first injection. Behavioral activity of these mice was observed 25 min (DBcAMP) or 10 min (PGE1) after the second dose was administered. A second injection of DBcAMP failed to decrease SLMA and EB from controls; moreover, SLMA began to return towards control levels as early as 2 hr between injections. The second injection of PGE1 or DBcAMP+PGE1 produced the same behavior as that produced by the first injection. On the basis of these results, the relationship of cyclic nucleotides and PGs to behavioral activity is discussed.