Biomedical subjects

A Fredriksson

Publications and source records attributed to A Fredriksson.

At least 37 records · Page 2Linked to original sources

PubMed2001

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice.

The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Neonatal iron potentiates adult MPTP-induced neurodegenerative and functional deficits.

The interactive effects of neonatal iron and adult MPTP treatment groups of C57 Bl/6 mice were studied through adminustration of iron (Fe(2+)) 7.5mg/kg b.w., p.o. or vehicle (saline) on days 10-12 post partum, followed at 3months of age by administration of either MPTP (2x20 or 2x40mg/kg, s.c.) or saline. Neonatal iron administration to mice-induced hypoactivity during the first 20-min period of testing and hyperactivity during the 3rd and final 20-min period for all three parameters of motor activity tested at 4months of age. MPTP treatment caused a dose-related hypokinesia throughout the 3x20-min test periods; in the mice that received both neonatal iron and MPTP severe deficits of motor activity (akinesia) were obtained. Iron treatment impaired the ability of mice to habituate to the novel testing environment and later administration of MPTP potentiated the impairment markedly. Neurochemical analyses of striatal and frontal cortical dopamine (DA) and DA metabolites demonstrated that the depletions were potentiated under conditions of combined neonatal iron and adult MPTP. The analysis of total iron content (µg/g) in brain regions indicated notably elevated levels in the basal ganglia, but not in the frontal cortex, of mice administered Fe(2+). Iron-overload combined with MPTP treatment induced functional and neurochemical deficits with interactive consequences beyond a mere additive effect that may have implications for the neurodegenerative process in parkinsonism.

Journal Article↗

PubMed2001

Brominated flame retardants: a novel class of developmental neurotoxicants in our environment?

Brominated flame retardants are a novel group of global environmental contaminants. Within this group the polybrominated diphenyl ethers (PBDE) constitute one class of many that are found in electrical appliances, building materials, and textiles. PBDEs are persistent compounds that appear to have an environmental dispersion similar to that of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT). Levels of PBDEs are increasing in mother's milk while other organohalogens have decreased in concentration. We studied for developmental neurotoxic effects two polybrominated diphenyl ethers, 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47) and 2,2',4,4',5-pentabromodiphenyl ether (PBDE 99)--congeners that dominate in environmental and human samples--together with another frequently used brominated flame retardant, tetrabromo-bis-phenol-A (TBBPA). The compounds were given to 10-day-old NMRI male mice, as follows: PBDE 47, 0.7 mg (1.4 micromol), 10.5 mg (21.1 micromol)/kg body weight (bw); PBDE 99, 0.8 mg (1.4 micromol), 12.0 mg (21.1 micromol)/kg bw; TBBPA, 0.75 mg (1.4 micromol), 11.5 mg (21.1 micromol)/kg bw. Mice serving as controls received 10 mL/kg bw of the 20% fat emulsion vehicle in the same manner. The present study has shown that neonatal exposure to PBDE 99 and PBDE 47 can cause permanent aberrations in spontaneous behavior, evident in 2- and 4-month-old animals. This effect together with the habituation capability was more pronounced with increasing age, and the changes were dose-response related. Furthermore, neonatal exposure to PBDE 99 also affected learning and memory functions in adult animals. These are developmental defects that have been detected previously in connection with PCBs.

Age Factors↗

PubMed2000

Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice.

Neonatal exposure to low doses of nicotine has been shown to prevent the development of low-affinity nicotine-binding sites, and to elicit a different behaviour response to nicotine in the mice as adults. This study has identified a defined period during the development of neonatal mouse brain for the induction of these permanent changes. Neonatal mice, aged either 3, 10, or 19 days were exposed to nicotine, 66 micrograms nicotine-base/kg b.wt., s.c. twice daily, on 5 consecutive days. In the cerebral cortex, high- and low-affinity (HA and LA) nicotine-binding sites were assayed (3H-nicotine/nicotine) in neonatal male mice aged 8, 15, and 24 days and in adult mice aged 4 months. Spontaneous behaviour and nicotine-induced behaviour were observed in 4-month-old male mice. The spontaneous behaviour test did not indicate any difference between saline- and nicotine-treated mice, whereas the nicotine-induced behaviour test revealed a hypoactive response to nicotine, though only in mice given nicotine on days 10-14. The response of controls and the other age categories to nicotine was an increased activity. At no time during the neonatal period could LA nicotine-binding sites be found following nicotine treatment, but the persistence of this effect was evident only in adult mice exposed on days 10-14.

Animals↗

PubMed2000

Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period.

Newborn mice were administered Fe(2+) (iron succinate: 7.5 mg/kg, b. wt) on either Days 3-5, 10-12 or 19-21, or vehicle (saline) at the same times, postnatally. Spontaneous motor behaviour and radial arm maze learning were tested at the age of 3 months. It was found that mice treated with Fe(2+) during postnatal Days 10-12 were markedly hypokinetic during the 1st 20-min test period and hyperkinetic during the 3rd and final 20-min test period. These mice showed an almost complete lack of habituation of spontaneous motor activity parameters to the test chambers. In the radial arm maze, the Days 10-12 treatment group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets; these mice showed also a severe trial-to-trial retention deficit as indexed by retention quotients. These behavioural deficits were observed also in animals treated with Fe(2+) during postnatal Days 3-5, but the effects were less pronounced, indicating the higher susceptibility of the brain for Fe(2+)-induced damage during Days 10-12 postpartum. Treatment with Fe(2+) on Days 19-21 did not induce behavioural alterations in comparison with its respective control (vehicle) group. Analysis of total brain iron content indicated significantly more iron (microg/g) accumulation in the basal ganglia, but not frontal cortex, of mice from the Days 3-5 and 10-12 Fe(2+) (7.5 mg/kg) treatment groups. The contribution of iron overload during the immediate postnatal to later functional deficits seems to implicate symptoms of Parkinsonism but the kinetics of iron uptake to the brain and its regional distribution at this critical period of development awaits elucidation.

Animals↗

PubMed2000

Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice I: dose-, time- and parameter-dependency.

In three experiments the acute effects of clonidine administration upon locomotor and rearing behaviour of mice pretreated with the selective noradrenaline (NA) neurotoxin, DSP4 (1 x 75 mg/kg, i.p.) 10-12 days previously, were studied. Clonidine (0.01, 0.05, 0.25, 1.25 and 3.0 mg/kg, i.p.) induced a dose-dependent reduction of motor activity during the initial 30 min of testing in both DSP4-treated and control mice; this effect was attenuated by DSP4 treatment in the 0.01, 0.05, 0.25 and 3.0 mg/kg dose groups. By the third 30-min period of testing (60-90 min), each clonidine dose group, except the highest (3.0 mg/kg) dose for locomotion and the two highest (1.25 and 3.0 mg/kg) doses for rearing, induced increases in motor activity in the control mice. In DSP4-treated mice, a large increase in locomotor counts was produced by the 0.05 mg/kg dose of clonidine with lesser increases induced by the 0.01 mg/kg dose group, whereas a lesser effect of the 0.05 mg/kg group (30-60 min) was obtained for rearing but a larger effect of the 0.25 mg/kg group (60-90 min). Yohimbine (0.5 mg/kg, i.p., 15 min before clonidine) attenuated the suppressive effects of clonidine (0.01 and 0.05 mg/kg) during the initial 30 min of testing and markedly increased locomotor and rearing counts, both by itself and in combination with each dose of clonidine, in both DSP4-treated and control mice over the following 90 min of testing. Yohimbine treatment attenuated the large increase in locomotor counts induced by the 0.05 mg/kg dose of clonidine in the NA-denervated mice. Dihydroergotamine (0.5 mg/kg, i.p., 15 min before clonidine) did not antagonise either the initial suppressive effect or the later supersensitivity effect of the 0.05 mg/kg dose of clonidine. DSP4 treatment by itself reduced motor activity. The effects of clonidine, dose- and time-dependently, by itself or in co-administration with alpha-adrenoceptor antagonists, in DSP4-treated or control mice displayed denervation-induced supersensitivity that appear to reflect mainly postsynaptic alpha2-adrenoceptor mediation.

Journal Article↗

PubMed2000

Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine.

Adult mice were administered either the noradrenaline (NA) neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or distilled water (control), 10-12 days before motor activity testing, and 6 h before testing all the mice were administered reserpine (10 mg/kg), the monoamine-depleting agent. The interactive effects of (I) clonidine, the alpha(2)-adrenoceptor agonist, with the dopamine (DA) agonist, apomorphine, and the alpha(2)-antagonist, yohimbine, and (II) with either yohimbine or the alpha(1)-antagonist, prazosin, upon motor behaviour in activity test chambers were studied in reserpinized DSP4-treated and control mice. It was shown that apomorphine (3 mg/kg) increased locomotor and total activity in both reserpinized DSP4-treated and control mice but the effect was attenuated in the DSP4 mice. Co-administration of clonidine (3 mg/kg) with apomorphine potentiated the effects of apomorphine on motor activity and this effect was enhanced markedly by DSP4 pretreatment. Yohimbine (10 mg/kg) antagonized the motor activity-stimulating effects of apomorphine in both DSP4-treated and control mice. Co-administration of clonidine with apomorphine, following yohimbine, restored motor activity levels to those obtained in the absence of yohimbine and this effect upon locomotor activity was enhanced by DSP4 pretreatment. The effects of clonidine on motor activity were enhanced by NA-denervation. Prazzosin (3 mg/kg) enhanced the locomotor activity of both reserpinized DSP4-treated and control mice after the initial 30-min period but was not affected by DSP4 treatment. Analysis of post-decapitation convulsions (PDCs) indicated loss of the reflex by DSP4 pretreatment. Reserpine pretreatment abolished the initial, exploratory phase (30 min) of motor activity. These results demonstrate interactions between NA and DA systems that may bear eventual relevance to neurologic disorders such as parkinsonism.

Journal Article↗

PubMed2000

Restoration and putative protection in Parkinsonism.

Synergistic antiparkinsonian actions of different classes of putative therapeutic agents co-administered with a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-Dopa) (5 mg/kg) in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as well as the restorative actions of those compounds in suprathreshold L-Dopa-tolerant MPTP-treated mice subjected to "wearing-off" of L-Dopa efficacy were assessed in a series of experiments. The classes of compounds studied included the noncompetitive NMDA antagonists, memantine, amantadine and MK-801, the anticonvulsive and putative anticonvulsive agents, lamotrigine, FCE 26743, phenytoin, the monoamine oxidase inhibitors, L-Deprenyl, amiflamine, alpha-ethyltryptamine, clorgyline and guanfacine. In this final case, the restorative effects of clonidine and guanfacine were antagonized by the alpha(2)-adrenoceptor antagonist, yohimbine, but not the alpha(1)-adrenoceptor antagonist, prazosin. Within each class of potentially therapeutic agents a differential restorative efficacy was obtained, but the combination of different doses of apomorphine with clonidine failed to restore motor activity. Finally, the neuroprotective actions of acute and subchronic administration of the nitrone spin-trapping compound, alpha-phenyl-tert-butyl nitrone upon the spontaneous motor behaviour and striatal dopamine concentrations of MPTP-treated mice was examined.

Journal Article↗

PubMed2000

Neonatal nicotine administration influences ethanol-induced behaviors.

Neonatal mice were administered nicotine (66 microg (-)-nicotine base/kg body weight (bw) s.c. twice daily at 0800 and 1700 h on postnatal days 10 and 14) and control mice received saline (10 ml 0. 9% NaCl/kg bw s.c.) on the same occasions. Behavioral testing was initiated 3 months after birth. In Experiment 1, neonatal nicotine administration did not affect spontaneous motor activity but altered the peak dose stimulatory effect of ethanol upon locomotion and rearing activity from 3.0 mg/kg, in the control mice, to 1.5 mg/kg. Administration of the nicotine antagonist, mecamylamine (MEC, 2.0 mg/kg), had no effect upon the peak dose stimulatory effect (i.e., 1. 5 mg/kg) evidenced in the nicotine-treated mice, but attenuated the stimulatory effect of the 3.0 mg/kg dose of ethanol in the control mice. In Experiment 2, the effects of neonatal nicotine administration upon ethanol intake and preference were assessed. In the single fluid access (one-bottle) test, nicotine-treated mice consumed both more ethanol (2%, 4%, or 6% concentrations) and more tap water than control mice. In the two-bottle ethanol preference test, nicotine-treated mice consumed more ethanol and tap water. Further analysis of the high-preferring (HP) ethanol mice indicated higher ethanol intake and preference in the nicotine-treated mice but no differences in tap water or total fluid intake. The present findings are considered together with prevailing notions of nicotine receptor alterations and possible cross-sensitization effects modulating substance abuse.

Animals↗

PubMed2000

Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa.

Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1999

Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice.

Excess iron in the brain has been implicated in the pathogenesis of several human neurodegenerative disorders, i.e., Parkinson's and Alzheimer's disease. The neonatal period is critical for the establishment of normal iron content in the adult brain. In the present study, the long-term neurobehavioral effects of iron exposure during this period were assessed by treating NMRI mice orally with 0.0, 3.7, or 37.0 mg Fe(2+)/kg body wt on postnatal days 10-12. Spontaneous motor behavior and radial arm maze learning were tested at the age of 3 months. It was found that the mice treated with the higher dose of Fe(2+), 37.0 mg/kg body wt, were hypoactive during the first 20 min of testing but hyperactive during the final 20 min, showing an almost complete lack of habituation of spontaneous activity in the test chambers. These changes were also seen in animals treated with the lower dose of Fe(2+), 3.7 mg/kg body wt, but the effects were less pronounced, indicating a dose-response relationship. In the radial arm maze, the Fe(2+) 37.0 mg/kg group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets. Both dose groups showed attenuated performance increments on successive trials. Analysis of brain iron content indicated significantly more total iron (microgram/g) in the basal ganglia, but not frontal cortex, of the higher, 37 mg/kg, dose group. The knowledge of the long-term effects of iron entering the brain during this critical period of rapid brain growth is limited. Increased amounts of iron in the brain, especially in the basal ganglia, may contribute to neurodegenerative processes.

Animals↗

PubMed1999

Behavioural and morphological outcome of mild cortical contusion trauma of the rat brain: influence of NMDA-receptor blockade.

The authors studied the effect of a mild cortical contusion to the rat brain on behavioural and morphological outcome and the influence of NMDA-receptor blockade (MK-801, 0.5 mg/kg i.v. 30 min prior to trauma). Spontaneous motor activity was assessed 16-18 days post trauma. Saline treated traumatised rats showed a significant (p < 0.01) hyperactive behaviour compared to animals without injury. MK-801 treated rats performed significantly better than the saline treated animals (p < 0.05). For histopathological evaluation hippocampal hilar neurons were counted, cortical thickness under the impact was measured and microtubule-associated protein 2 (MAP2) immunoreactivity in the dentate hilus was quantified 1, 3 and 21 days post trauma. In traumatised rats scattered loss of nerve cells, oedema and minute haemorrhages were present at the site of the impact one and three days after injury. At day 21 there was a significant reduction of cortical thickness at the site of impact. One day after trauma there was a bilateral, significant loss of neurons and MAP2 immunostaining in the dentate hilus of the hippocampus. MK-801 pretreated rats showed similar morphological changes. The disturbed spontaneous motor behaviour may be caused by hippocampal damage and a reduction of somatosensory cortical neurons. NMDA-receptor blockade improved the outcome assessed by the functional tests but failed to influence the morphological changes, suggesting that this behavioural test is a more sensitive indicator of outcome after mild traumatic brain injury (TBI).

Animals↗

PubMed1999

Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists.

Three experiments were performed to study the development and manipulation of tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the 13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no stimulatory effects of the drug) by the 16th administration (Test Day 10). Administration of L-Dopa to control mice reduced locomotor and rearing activity throughout the tolerance development period (Test Days 1-12) during the first hour after injection, and then increased locomotor activity during the second hour. The effects of combining either a noncompetitive, MK-801, or a competitive, CGP 40116, glutamate antagonist with L-Dopa, following tolerance development, were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day 13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range 0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to offer a useful parkinsonian model also for the examination of different aspects of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the putative glutamatergic involvement. The clinical consequences may be far-reaching for the utility of L-Dopa in Parkinson's disease, whether the effects demonstrated be of a reinstatement or synergistic nature, once therapeutically adequate glutamate antagonists are more readily available.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1999

Effects of co-administration of anticonvulsant and putative anticonvulsive agents and sub/suprathreshold doses of L-dopa upon motor behaviour of MPTP-treated mice.

The effects of co-administration of the dopamine precursor, L-Dopa, with anticonvulsant and putative anticonvulsive agents upon the motor activity of hypoactive MPTP-treated C57 BL/6 mice were measured in six experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered four to six weeks prior to behavioural testing. Thus, the effects of these agents combined with either a single acute, subthreshold dose (5 mg/kg, s.c.) of L-Dopa, or, with chronically-administered, suprathreshold doses (20 mg/kg, s.c.) of L-Dopa were studied. In the former, lamotrigine, FCE 26743 and L-Deprenyl, injected 60 min before subthreshold L-Dopa (5 mg/kg), each induced an antiparkinsonian action in MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. In the latter, lamotrigine (all three measures of activity at 3 mg/kg), FCE 26743 (locomotion and total activity at 3; rearing at 1 and 3 mg/kg) and L-Deprenyl (locomotion and total activity at 1 and 3mg/kg), but not phenytoin (neither at 1 nor 3 mg/kg), reinstated the motor activity-stimulating effects of the threshold dose of L-Dopa (20 mg/kg) in L-Dopa-tolerant, MPTP-treated mice. Neurochemical analyses confirmed severe DA depletions in MPTP-treated mice. Since neither lamotrigine, FCE 26743 nor L-Deprenyl, nor subthreshold L-Dopa, by themselves increased the motor behaviour of MPTP-treated mice, a synergistic effect of the co-administration is concluded. Further, since the suprathreshold dose of L-Dopa by itself failed to stimulate motor activity in the MPTP mice following chronic (25 daily injections) administrations of the compound, it is suggested that a restorative effect, in combination with lamotrigine, FCE 26743 or L-Deprenyl was evidenced. The potential therapeutic benefits of anticonvulsant or putative anticonvulsive compounds for parkinsonian symptoms are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1999

In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.

Animals↗

PubMed1998

Evidence indicating that the extracellular loops of the mouse MC5 receptor do not participate in ligand binding.

The mMC5 receptor was cloned from a genomic library, mutated in the extracellular loops (EL's), expressed and tested for binding to melanocyte stimulating hormone (MSH) peptides. The EL's show low amino acid homology within the MC receptor family. Two mutants of the mMC5 receptor were created in order to investigate the participation of these regions in ligand binding. The EL1 and EL3 were separately altered by multiple mutagenesis so that their amino acid sequences became identical with the hMC1 receptor. The mutants were expressed in COS cells and found to bind peptide ligands in the same fashion as the wild type mMC5 receptor clone. The results indicate that the amino acids that were mutated in the mMC5 receptor do not participate in binding of MSH peptides. Comparison of the wild type mMC5 receptor with the hMC5 receptor showed that it has the same potency order for the MSH peptides but considerably higher affinity than the hMC5 receptor.

Amino Acid Sequence↗

PubMed1997

MPTP-induced deficits in motor activity: neuroprotective effects of the spintrapping agent, alpha-phenyl-tert-butyl-nitrone (PBN).

In Experiment 1, groups of mice were administered either saline or MPTP (2 x 30 mg/kg, s.c., separated by a 24-hr interval) 30 min after being injected either PBN (15, 50 or 150 mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0 mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150 mg/kg) or L-Deprenyl (10.0 mg/kg); lower doses of PBN (15 mg/kg) and L-Deprenyl (0.25 mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN (15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50 mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1997

Functional changes induced by neonatal cerebral 6-hydroxydopamine treatment: effects of dose levels on behavioral parameters.

Male Sprague-Dawley rats were treated neonatally with either of three different doses of 6-hydroxydopamine (6-OHDA): 50 micrograms i.c., 75 micrograms i.c., or 2 x 100 micrograms i.c.v., 30 min after a subcutaneous injection of desipramine (DMI, 25 mg/kg), in order to obtain selective lesions of mesencephalic dopamine (DA) neurons to different extents. From juvenile ages onwards, rats in each dose condition were tested for spontaneous motor activity and exploration in an openfield/holeboard setting measuring ambulation, rearing and head-dips. Between 77 and 78 days, the animals were tested in a modified, enclosed radial arm maze, followed 1 week later by tests in the circular swim maze. Finally, motor activity was tested in automated activity test chambers. In the openfield/holeboard setting, hyperactivity was seen for both rearing and ambulation in rats administered 50 micrograms 6-OHDA, whereas the 75 micrograms and 2 x 100 micrograms groups showed hyperactivity for ambulation, but hypoactivity for rearing and head-dips. All three dose groups demonstrated a retardation of learning in the radial arm maze. The 75 and 2 x 100 micrograms groups, but not the 50 micrograms group, showed impairments of acquisition in the swim maze. In the activity test chambers locomotion and rearing behavior varied as a function of 6-OHDA dose, being negatively and positively, respectively, related to DA concentration in striatum. These results show that the extent of the neonatal DA lesion determines both changes in motor- and exploratory activity as well as the occurrence and severity of acquisition impairment in spatial learning tasks.

Animals↗