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Biomedical subjects

J Luthman

Publications and source records attributed to J Luthman.

At least 19 recordsLinked to original sources
PubMed1992

Occurrence and distribution of different neurochemical markers in the human dental pulp.

The occurrence and distribution of neuronal markers in human premolar and molar pulps were studied immunohistochemically. In the apical and central parts of the pulp, evenly distributed, thick neurofilament-immunoreactive nerve bundles predominated, which in many instances accompanied blood vessels. In the coronal parts, especially in the pulp horns, such nerve bundles formed a subodontoblastic plexus, while thin neurofilament-immunoreactive fibres projected into the odontoblastic region. In the coronal parts of the pulp, thin, varicose, calcitonin gene-related peptide (CGRP)- and occasionally substance P-immunoreactive fibres were observed in the pulp-dentine zone and also in the vicinity of blood vessels. Vasoactive intestinal polypeptide (VIP) fibres were distributed in several nerve bundles, while single VIP fibres were seen projecting into the odontoblastic region as well as in the vicinity of blood vessels. Peptide histidine isoleucine amide (PHI)-immunoreactive fibres showed a similar distribution as VIP, but were less common. Furthermore, neuropeptide Y-immunoreactive fibres occurred occasionally around blood vessels in the inner parts of the pulp. Tyrosine hydroxylase-immunoreactive nerve fibres with a varicose appearance were observed in some nerve bundles, but were also frequently seen around and in blood vessels. In premolar pulps obtained from teeth with open apices a less dense neurofilament innervation was seen in the coronal pulp. However, no apparent difference in the occurrence and distribution of the other neuronal markers was found compared to mature teeth. The human dental pulp, thus, seems to have a rich occurrence of neuropeptides and tyrosine hydroxylase in thin, varicose fibres. However, the distribution of the fibres expressing immunoreactivity to these neuronal markers seems to be sparse in comparison to neurofilament-immunoreactive fibres.

Biomarkers↗
PubMed1992

Effects of DM-9384, a pyrrolidone derivative, on ischemia-induced changes in the central monoamine systems.

Alterations in brain tissue levels of monoamines and monoamine metabolites were studied in gerbils 60 min after cerebral ischemia induced by 10 min carotid ligation after pretreatment with the antiischemic drug DM-9384 (1, 3, 10, 30 mg/kg, PO). The DA levels decreased in striatum after the ischemia, while cortical and hippocampal DA levels increased. The DOPAC levels increased in cortex, but were essentially unaffected in other regions. The HVA levels increased in all forebrain regions studied. NA levels decreased in hippocampus and superior colliculus, while a general increase in MHPG levels was seen. Decreases in 5-HT levels were seen in all forebrain regions except cortex. The 10 mg/kg and 30 mg/kg doses of DM-9384 counteracted the decrease in striatal 5-HT and hypothalamic MHPG/NA ratio, respectively. Thus pretreatment with DM-9384 exerted minor protective effects on the alterations induced in monoamine systems by transient forebrain ischemia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Postnatal lead exposure affects motor skills and exploratory behavior in rats.

The present study was undertaken to investigate the behavioral effects of postnatal lead exposure. Newborn male Sprague-Dawley rats were given 1 or 8 mg/kg lead acetate intraperitoneally daily for 20 days. Control rats received 1 mg/kg sodium acetate, or 8 mg/kg sodium acetate in oversized litters. The high dose lead acetate group and the high dose, oversized sodium acetate group showed impaired weight and length increment during the end of the treatment. Rats treated with the higher dose of lead showed delayed eye opening. The time required to turn in a negative geotaxis test was transiently longer in rats treated with the higher dose of lead. A tendency of reduced forepaw grasping ability was seen in lead-treated rats during the end of the lead exposure. Ambulation and rearing in an open field were lower for the rats treated with the higher dose of lead acetate during certain periods of development. Impaired performance in a balancing rod test was also seen in the rats treated with the higher dose of lead at the adult stage, while no difference was seen in ambulation or gnawing activity during tail pinch-induced stress. Thus, lead intoxication in rats during the early postnatal period, with doses that approximate those in children, induced transient as well as persistent dysfunctions in exploratory behavior and motor skills. These observed actions of lead may be related to impaired maturation of sensitive brain regions which develop postnatally.

Animals↗
PubMed1992

Mathematical description of the concentration of oxytetracycline and penicillin-G in tissue cages in calves as related to the serum concentration.

A mathematical model based on Fick's laws of diffusion describing the concentration of drug in tissue cage models was elaborated. The model takes into account differences in protein binding, tissue cage geometry and serum pharmacokinetics. The validity of the model was tested against experimental data obtained from a tissue cage model in calves by simultaneous fitting to serum and tissue cage fluid (TCF) data in a non-linear least-squares regression computer program. Concentrations of penicillin-G (pen-G) in serum and TCF following intravenous (i.v.) administration of potassium pen-G were adequately described by the mathematical model. Concentrations in TCF after intramuscular (i.m.) administration of the same drug and of procaine pen-G could be predicted by the mathematical model. Concentrations of oxytetracycline (OTC) in serum and TCF following i.v. administration and continuous i.v. infusions were also adequately described by the model, and TCF concentrations after i.m. administration of the same drug could be roughly predicted. The results indicate that pen-G and OTC have the same permeability coefficient for transport from serum to TCF.

Animals↗
PubMed1991

Enhanced adenylate cyclase activity in neonatally dopamine lesioned rats is related to increased Gs-protein coupling.

It has previously been shown that neonatal selective lesions of the central dopamine system with 6-hydroxydopamine lead to increased basal and dopamine-stimulated adenylate cyclase activity in striatum without any alterations of dopamine receptor binding characteristics. In the present study, it was shown that adenylate cyclase activity following G-protein stimulation by the GTP analogue 5-guanylimidodiphosphate (Gpp(NH)p) was increased in striatal preparations from neonatally 6-hydroxy-dopamine-lesioned rats, compared with control animals. No difference was seen in forskolin-stimulated enzyme activity between the two groups. These results indicate that neonatal dopamine lesions induce a selective functional supersensitivity at the D1 receptor complex by enhancing the coupling efficiency of the Gs protein to adenylate cyclase, without alterating the catalytic activity of the enzyme.

Adenylyl Cyclases↗
PubMed1991

Distribution of penicillin-G and spiramycin to tissue cages and subcutaneous tissue fluid in calves.

Antibacterial drug concentrations in serum, tissue cage fluid (TCF) and subcutaneous tissue fluid (SF), sampled either by filter paper discs or by microcapillaries, were measured after single intramuscular injections of potassium penicillin-G (KPG), procaine penicillin-G (PPG) and spiramycin adipate in calves. Concentration-time curves had essentially similar profiles in serum and SF, but peak levels were lower and occurred later in SF. From approximately four hours after drug administration, penicillin-G levels in SF were similar to levels in serum after KPG as well as after PPG administration. Elimination half-life (t1/2) of penicillin-G in serum was similar to t1/2 in SF after PPG administration but was longer in SF than in serum after KPG administration. Spiramycin concentrations were higher in SF than in serum and the t1/2 of spiramycin in SF was longer than in serum. For all three drugs, the t1/2 was longer in TCF than in serum and concentration-time curves in TCF were characterised by a slow rise and decline. The two methods of sampling SF, by filter paper discs and by microcapillaries, gave similar but not identical results. Penetration into SF and TCF, measured as the total area under curve ratio, was better for spiramycin than for penicillin-G, but the latter drug had a higher penetration ratio to TCF in the first 12 hours.

Animals↗
PubMed1991

Immunohistochemical studies on the spinal dorsal horn of the turtle Chrysemys d'orbigny.

Immunohistochemical methods were used to characterize some of the systems of nerve fibers occurring in the spinal dorsal horns of the turtle Chrysemys d'orbigny. Substance P (SP), calcitonin gene-related peptide (CGRP) and leuenkephalin (Enk) immunoreactive fibers were found concentrated in the superficial horn region, termed here synaptic field Ia. From this zone the immunoreactive fibers project to deeper dorsal horn regions. Comparison with histological images obtained after HRP labeling of dorsal root axons indicates that SP-, CGRP- and Enk-immunoreactive fibers are small-diameter primary sensory fibers entering the cord via synaptic field Ia. It is posulated here that these three substances may coexist in the same fibers. Enk-positive fibers also occur randomly scattered in the lateral funiculi, showing a conspicuous increase in density at the perimedullary plexus level. Tyrosine hydroxylase (TH) immunoreactive fibers were found in the more compact dorsal horn neuropil (synaptic field II) and also forming bilateral conspicuous bundles in the lateral funiculi. TH-immunoreactive cell bodies were found in the epithelium lining the central canal. Taking into account data derived from Golgi impregnated material it is proposed that they represent epithelial cells undergoing neural differentiation.

Animals↗
PubMed1991

Combined lead acetate and disulfiram treatment-induced alterations of glial fibrillary acidic protein (GFA) immunoreactive astrocytes in brain smears.

Dithiocarbamates are known to form lipid-soluble complexes with lead and greatly increase brain lead levels. The present study was undertaken to investigate whether lead acetate, when administered together with disulfiram (Antabuse, metabolite of dithiocarbamate) during development, would induce morphological changes in brain astrocytes. Female Sprague-Dawley rats were given 0.25% lead acetate in the drinking water from day one of pregnancy and this treatment was continued after birth until the litters were 4 weeks old. In addition, some dams received disulfiram in a dose of 0.1 mmol/kg p.o. twice weekly and after parturition this dose was given s.c. directly to the offspring twice a week. Lead acetate and disulfiram treatments were discontinued at weaning and animals sacrificed 3 weeks later. Samples of parietal cortex, hippocampal formation and cerebellar cortex were dissected out and smeared onto glass-slides and astrocytes were visualized in toto using immunohistochemistry with antibodies against glial fibrillary acid protein (GFA), enabling morphometric analysis with a computerized image analyser. Animals treated with lead acetate showed a minor increase in the size of the GFA-immunoreactive astrocytes in parietal cortex smears, while animals treated with disulfiram showed no difference in size or form compared to controls. However, in combined lead acetate and disulfiram-treated animals a profound increase in astrocyte size and an increase in the number of processes of the individual GFA-immunoreactive astrocytes could be demonstrated in parietal cortex. No significant changes were noted in GFA-immunoreactive astrocytes of hippocampal smears following the different treatments, while GFA-immunoreactive astrocytes in cerebellar cortex smears were significantly smaller and had reduced number or processes following the combined lead acetate and disulfiram treatment compared to lead acetate treatment or controls. It is concluded that combined exposure to lead acetate and disulfiram during development induces regionally specific changes in GFA-immunoreactive astrocyte morphology. Furthermore, the present study demonstrates the usefulness of smear preparations combined with computerized image analysis to study the morphology of GFA-immunoreactive astrocytes as an index of toxic effects in CNS.

Animals↗
PubMed1991

Effects of long-term treatment with methyl mercury on the developing rat brain.

Sprague-Dawley rats were exposed to low doses of methyl mercury (3.9 mg mercury/kg diet), via their dams during gestation and lactation and directly via their diet until sacrifice at 50 days postpartum, in order to study possible detrimental effects on CNS development. The methyl mercury exposure of the rats resulted in a brain concentration of 1.45 +/- 0.06 mg mercury/kg wet weight (mean +/- SEM). No general toxic effects were observed; body weight was not affected, brain weight was only slightly increased. No discernible general morphological alterations were seen in the brain as evaluated using cresyl violet histology. Furthermore, no effects on GFA-positive astrocytes in brain sections were observed and computerized morphometry of smeared astrocytes from frontal cortex, hippocampus, and cerebellum did not reveal any effects of the methyl mercury treatment. The noradrenaline (NA) and dopamine (DA) systems were also studied. In cerebellum the NA levels were increased (117% of controls, P = 0.008), whereas in other regions analyzed NA and DA levels were unchanged. Thus, long-term low-dosage exposure of methyl mercury in rats during development does not appear to exert any major effects on the morphological maturation of neurons and astrocytes. However, the results indicate that effects may occur in specific transmitter-identified systems, such as the NA input to cerebellum. The results therefore underline the need for detailed biochemical analyses to study the effects of long-term low-dosage exposure to neurotoxic compounds.

Animals↗
PubMed1991

Distribution of oxytetracycline to tissue cages and granuloma pouches in calves and effect of acute inflammation on distribution to tissue cages.

The effect of acute inflammation on oxytetracycline (OTC) distribution was studied in a tissue cage model in calves. An acute inflammatory reaction was induced in tissue cages by injecting lipopolysaccharide (LPS) from Salmonella typhimurium. The distribution of OTC to tissue cage fluid (TCF) was also compared with distribution to fluid from granuloma pouches (GPF). Tissue from LPS-injected cages showed histological changes indicating an acute inflammatory reaction. Concentrations of OTC were higher in LPS cages than in controls; at 1, 2, 4 and 10 h the difference was statistically significant (P less than 0.05). Numerically the overall elimination rate constant (kel) was larger, elimination half-life (t1/2) shorter, peak concentration (Cmax) higher, and time of peak concentration (Tmax) shorter in LPS cages than in controls. The area under the curve (AUC) of OTC was greater and the ratio AUCTCF/AUCserum was higher in LPS cages than in controls. Although statistically significant differences were not found for all the pharmacokinetic parameters, it was concluded that distribution to and elimination from LPS cages were both faster than in controls. Concentration-time profiles of OTC were similar in TCF and GPF in that concentrations were lower and elimination was more prolonged than in serum. Levels were higher in GPF than in TCF up to 3 h after injection; thereafter the relationship was reversed. Distribution to and elimination processes from GPF appeared to be faster than from TCF as numerically kel was higher, t1/2 shorter and Tmax shorter in GPF than in TCF. It was concluded that the granuloma pouch model and the tissue cage model have similarities in distribution and elimination patterns and that differences are most probably due to differences in the ratio of the surface area to the volume.

Acute Disease↗
PubMed1991

Immunohistological study of neuronal markers in inflamed gingiva obtained from children with Down's syndrome.

The histological appearance of the gingiva in children with Down's syndrome (DS) was studied with special reference to inflammatory involvement and innervation. A dense infiltration of inflammatory cells was seen in the propria of most of the DS patients, including a few polymorphonuclear leucocytes. A hyperplasia of the epithelium was also found. The innervation of the gingiva was studied using immunohistochemistry. Nerve fibers as well as nerve bundles immunoreactive to neurofilament (NF) were seen in the propria, while occasionally intraepithelial NF fibers were observed. Calcitonin gene-related peptide (CGRP)-immunoreactive fibers and fiber bundles were also visualized, but they were less abundant than NF fibers. The density of NF and CGRP fibers and fiber bundles was estimated by semiquantitative evaluation. A higher density of NF and CGRP immunoreactive structures was observed in the propria of DS patients compared to the control subjects, while no obvious alteration was seen in their distribution in the propria. In addition, sparsely distributed fibers immunoreactive to peptide histidine isoleucine amide (PHI) and vasoactive intestinal polypeptide (VIP) fibers as well as neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were seen, mainly surrounding blood vessels. A few substance P (SP) fibers were also found, mostly close to the epithelium. No obvious differences of these sparsely distributed fibers were seen in the DS patients compared to controls. Thus, a profound inflammatory involvement of the gingiva of DS patients is seen concomitant with a hyperinnervation of the presumed sensory component of the gingival innervation. In contrast, no alterations were seen in the density of neuronal markers related to autonomic nerve fibers. The sensory hyperinnervation observed is probably not specifically related to DS, but may be due to a sprouting of afferent nerves induced by the inflammatory reaction. However, factors released from the sensory afferents could contribute to the gingival inflammation seen in DS.

Adolescent↗
PubMed1991

Serum factors induce C-fos expression and rapid cell proliferation in adolescent but not in infant rat proximal tubule cells.

Kidney epithelial cells in short-term primary culture have been studied with regard to proliferative rate and expression on the c-fos protooncogene. The experiments were performed on subconfluent renal proximal tubule cells isolated from infant and adolescent rats. Proliferation was determined by 3H-thymidine autoradiography and nuclear content of c-fos protein by semiquantitative immunofluorescence. The basal proliferative rates in infant and adolescent renal proximal tubule cells were the same after 48 h of primary culture in Dulbecco's modified Eagle's medium with 10% FCS. Serum deprivation for 24 h caused a significant growth inhibition in both infant and adolescent cells. C-fos was expressed to the same extent in infant and adolescent serum-deprived cells. The rapid response to the addition of serum was markedly different in infant and adolescent cells. In adolescent cells, addition of serum led to a transient significant increase in the nuclear expression of c-fos protein, reaching a peak at 60 min. No increase in c-fos was seen in infant cells. In adolescent cells, the rate of proliferation increased 11-fold and 3H-thymidine labeling index reached 26.7 +/- 4.3%. In infant cells, the proliferative response to serum addition was significantly lower; the labeling index reached only 4.2 +/- 1.2%. It could be excluded that the attenuated response in infant cells was due to cell death or impaired metabolic function. The results imply that the principles of growth regulation change postnatally.

Age Factors↗
PubMed1990

Neonatal dopamine lesion in the rat results in enhanced adenylate cyclase activity without altering dopamine receptor binding or dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) immunoreactivity.

Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 micrograms 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60-70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number of affinity of D1 and D2 receptor sites. Furthermore, the appearance of DARPP-32 seems to be independent of intact DA input during development.

Adenylyl Cyclases↗
PubMed1990

No apparent difference in the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the sympathetic system in NMRI and C57 BL/6 mice.

The parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to possess marked species as well as strain differences in toxicity on central catecholaminergic systems. In the present study the effects on the peripheral sympathetic nervous system following treatment with MPTP, as well as its metabolite 1-methyl-4-phenylpyridine (MPP+) and the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) were studied in mice of the NMRI and C57 BL/6 strains, two strains that possess marked difference in MPTP toxicity on central catecholaminergic neurons. No strain differences in the depletions of noradrenaline (NA) in iris and heart auricula and of NA and dopamine (DA) in superior cervical ganglion or in the reduction of the in vitro [3H]NA uptake in iris or heart auricula were found following MPTP treatment (2 X 40 mg/kg s.c., 2 and 7 days). Treatment with the NA uptake blocker desipramine (DMI) did not affect the MPTP-induced NA depletion in either strain. Following treatment with MPP+ (30 mg/kg i.v., 7 days) no differences in the two strains were seen on the reduction of NA levels in iris and heart auricula or decrease in [3H]NA uptake. In addition, no differences were found on NA levels in iris and heart auricula after 6-OHDA treatment (15 mg/kg i.v., 7 days). The data indicate that in the NMRI and C57 BL/6 mice peripheral NA neurons do not possess any notable strain difference in the vulnerability to MPTP or in the mechanism of action of MPTP.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Structural and neurochemical effects in mouse cerebellum following neonatal methylazoxymethanol and 6-hydroxydopamine treatment.

The effects of neonatal treatment with the antimitotic agent methylazoxymethanol and the catecholamine neurotoxin 6-hydroxydopamine on cerebellar morphology and monoamine innervation in the N.M.R.I. mouse has been studied. Methylazoxymethanol (25 mg/kg s.c.) treatment induced a cerebellar weight reduction of 40% as observed in the adult stage, while other CNS regions analysed were unaffected. An obvious atrophy of the cerebellar cortex was found, with an irregular distribution of the Purkinje cells, while Bergmann glia fibers deviated from their normal radial configuration and showed a tendency to form clusters. A 65% increase of tyrosine hydroxylase immunoreactive fiber density was found in the cerebellar cortex and 3H-5-hydroxytryptamine in vitro synaptosomal uptake was increased by 55%. Noradrenaline and 5-hydroxytryptamine concentrations in the cerebellum increased by 50 and 30%, respectively, whereas the total content of both neurotransmitters in cerebellum was approximately unchanged after methylazoxymethanol treatment. A significant reduction in total cerebellar in vitro binding of 3H-WB-4101 and 3H-dihydroalprenolol was also found, indicating compensatory receptor alterations following methylazoxymethanol treatment. The effect of combined treatment of methylazoxymethanol and the neurotoxin 6-hydroxydopamine (50 mg/kg s.c., day 1) showed a very pronounced reduction of noradrenaline concentration in cortex cerebri, while the noradrenaline concentration in cerebellum was increased by 185% and the tyrosine hydroxylase immunoreactive fiber density by 125%, indicating an additional relative hyperinnervation of cerebellar noradrenaline fiber due to a "pruning effect" of the 6-hydroxydopamine treatment. The results imply a relatively rigid development of terminal arborization of central nervous system monoamine neurons, relatively independent of neuronal and glial arrangement in the target area.

Animals↗
PubMed1990

Studies on brain monoamine and neuropeptide systems after neonatal intracerebroventricular 6-hydroxydopamine treatment.

In order to study the effects of a neonatal dopamine lesion on dopaminergic, serotonergic and peptidergic systems, Sprague-Dawley rats were treated by intracerebroventricular administration of 6-hydroxydopamine (100 micrograms, days 3 and 6) following desipramine pretreatment (25 mg/kg s.c.). At 60-70 days postnatally a profound reduction of dopamine- and 3,4-dihydroxyphenylacetic acid levels was found in striatal and limbic forebrain regions concomitant with an extensive loss of tyrosine hydroxylase-immunoreactive fibers, while no significant alteration in noradrenaline levels was seen. A marked loss of tyrosine hydroxylase-immunoreactive cell profiles was also observed in the substantia nigra and ventral tegmental area in mesencephalon. In striatum, but not in other regions analysed, an almost 100% increase in serotonin levels and serotonin-immunoreactive fiber density was observed following 6-hydroxydopamine treatment. However, the number of serotonin-immunoreactive cell profiles in the median and dorsal raphe nuclei was not altered. The 6-hydroxydopamine treatment also led to reductions in substance P levels in striatum, nucleus accumbens and ventral mesencephalon. The cholecystokinin level in nucleus accumbens and neurotensin level in ventral mesencephalon were also reduced. A neonatal intracerebroventricular 6-hydroxydopamine treatment thus leads to a lesion of dopamine neurons in the mesencephalon with extensive loss of dopamine fibers in several forebrain areas, while localized serotonin fiber sprouting is induced in striatum. Furthermore, concomitant reductions of the levels of peptides related to the dopamine system occur following the 6-hydroxydopamine treatment. Behavioral disturbances such as hyperactivity and cognitive deficiencies occurring after a dopamine lesion early in life might therefore be due to plastic alterations in several different transmitter/neuromodulator systems as a direct or indirect consequence of the lesion.

3,4-Dihydroxyphenylacetic Acid↗