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1.
Braz J Med Biol Res ; 36(2): 233-8, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12563526

ABSTRACT

The medial septum participates in the modulation of exploratory behavior triggered by novelty. Also, selective lesions of the cholinergic component of the septohippocampal system alter the habituation of rats to an elevated plus-maze without modifying anxiety indices. We investigated the effects of the intraseptal injection of the cholinergic immunotoxin 192 IgG-saporin (SAP) on the behavior of rats in an open-field. Thirty-nine male Wistar rats (weight: 194-230 g) were divided into three groups, non-injected controls and rats injected with either saline (0.5 microl) or SAP (237.5 ng/0.5 microl). Twelve days after surgery, the animals were placed in a square open-field (120 cm) and allowed to freely explore for 5 min. After the test, the rats were killed by decapitation and the septum, hippocampus and frontal cortex were removed and assayed for acetylcholinesterase activity. SAP increased acetylcholinesterase activity in the septum, hippocampus and frontal cortex and decreased the total distance run (9.15 +/- 1.51 m) in comparison to controls (13.49 +/- 0.91 m). The time spent in the center and at the periphery was not altered by SAP but the distance run was reduced during the first and second minutes (2.43 +/- 0.36 and 1.75 +/- 0.34 m) compared to controls (4.18 +/- 0.26 and 3.14 +/- 0.25 m). SAP-treated rats showed decreased but persistent exploration throughout the session. These results suggest that septohippocampal cholinergic mechanisms contribute to at least two critical processes, one related to the motivation to explore new environments and the other to the acquisition and storage of spatial information (i.e., spatial memory).


Subject(s)
Acetylcholinesterase/drug effects , Antibodies, Monoclonal/pharmacology , Cholinergic Agents/pharmacology , Exploratory Behavior/drug effects , Immunotoxins/pharmacology , Septal Nuclei/drug effects , Acetylcholinesterase/analysis , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Exploratory Behavior/physiology , Hippocampus/drug effects , Hippocampus/enzymology , Male , Memory/drug effects , N-Glycosyl Hydrolases , Rats , Rats, Wistar , Ribosome Inactivating Proteins, Type 1 , Saporins , Septal Nuclei/enzymology
2.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;36(2): 233-238, Feb. 2003. graf
Article in English | LILACS | ID: lil-326422

ABSTRACT

The medial septum participates in the modulation of exploratory behavior triggered by novelty. Also, selective lesions of the cholinergic component of the septohippocampal system alter the habituation of rats to an elevated plus-maze without modifying anxiety indices. We investigated the effects of the intraseptal injection of the cholinergic immunotoxin 192 IgG-saporin (SAP) on the behavior of rats in an open-field. Thirty-nine male Wistar rats (weight: 194-230 g) were divided into three groups, non-injected controls and rats injected with either saline (0.5 æl) or SAP (237.5 ng/0.5 æl). Twelve days after surgery, the animals were placed in a square open-field (120 cm) and allowed to freely explore for 5 min. After the test, the rats were killed by decapitation and the septum, hippocampus and frontal cortex were removed and assayed for acetylcholinesterase activity. SAP increased acetylcholinesterase activity in the septum, hippocampus and frontal cortex and decreased the total distance run (9.15 ± 1.51 m) in comparison to controls (13.49 ± 0.91 m). The time spent in the center and at the periphery was not altered by SAP but the distance run was reduced during the first and second minutes (2.43 ± 0.36 and 1.75 ± 0.34 m) compared to controls (4.18 ± 0.26 and 3.14 ± 0.25 m). SAP-treated rats showed decreased but persistent exploration throughout the session. These results suggest that septohippocampal cholinergic mechanisms contribute to at least two critical processes, one related to the motivation to explore new environments and the other to the acquisition and storage of spatial information (i.e., spatial memory)


Subject(s)
Animals , Male , Rats , Acetylcholinesterase , Antibodies, Monoclonal , Cholinergic Agents , Exploratory Behavior , Immunotoxins , Septal Nuclei , Acetylcholinesterase , Cerebral Cortex , Exploratory Behavior , Hippocampus , Memory , Rats, Wistar , Septal Nuclei
3.
Behav Brain Res ; 117(1-2): 97-105, 2000 Dec 20.
Article in English | MEDLINE | ID: mdl-11099762

ABSTRACT

The effect of intraseptal injection of the cholinergic immunotoxin 192-IgG-saporin on behavior in the elevated plus maze was investigated. A 5-min test-retest paradigm, with minute-by-minute analysis of the first session, was used to evaluate both anxiety and memory in this task. Biochemical analyses revealed a decrease in acetylcholinesterase (AChE) activity in the hippocampus (HPC), septum, and frontal cortex of animals injected with IgG-192 saporin (237.5 ng) when compared with controls. No statistical differences were found between groups in terms of behaviors associated with locomotor activity, conventional measures of anxiety, or ethological behaviors during either session 1 or 2. During test session 2 the controls exhibited decreased exploratory activity and increased indices of anxiety. In contrast, the saporin-treated rats did not exhibit these experience-dependent behavioral changes from session 1 to 2. The minute-by-minute analysis showed a significant decrease in exploratory as well in anxiety associated behaviors during the first session for the control group, but not for the saporin-treated group. These results suggest that the cholinergic innervation of the HPC, the frontal cortex, or both forebrain structures, modulate the initiation of exploratory activity which, results in the acquisition and retention of spatial information, but does not affect the expression of anxiety in the elevated plus-maze.


Subject(s)
Acetylcholinesterase/drug effects , Antibodies, Monoclonal/adverse effects , Anxiety , Cholinergic Agents/adverse effects , Exploratory Behavior , Hippocampus/metabolism , Immunotoxins/adverse effects , Memory/drug effects , Prosencephalon/metabolism , Septum of Brain/metabolism , Acetylcholinesterase/metabolism , Animals , Hippocampus/drug effects , Hippocampus/enzymology , Male , Maze Learning , N-Glycosyl Hydrolases , Neural Pathways , Prosencephalon/drug effects , Prosencephalon/enzymology , Rats , Rats, Wistar , Ribosome Inactivating Proteins, Type 1 , Saporins , Septum of Brain/drug effects , Septum of Brain/enzymology
4.
J Pediatr ; 120(6): 987-93, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1593362

ABSTRACT

To evaluate the safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases, we studied fluconazole in 26 children, aged 5 to 15 years, with normal renal function who were receiving treatment for cancer. The patients received fluconazole, 2, 4, or 8 mg/kg per day for 7 days intravenously for a 2-hour period. Patients had no nausea or vomiting related to fluconazole; three patients had an asymptomatic rise in hepatic aminotransferase values after four to six doses (one patient at 2 mg/kg per day and two patients at 8 mg/kg per day), which returned to normal within 2 weeks after discontinuation of the drug. Fluconazole showed linear first-order kinetics over the dosage range tested and during multiple dosing. After the first dose, mean clearance was 22.8 +/- 2.3 ml/min, volume of distribution 0.87 +/- 0.06 L/kg, and terminal elimination half-life 16.8 +/- 1.1 hours. Similarly, after the last dose, clearance was 19.4 +/- 1.3 ml/min, volume of distribution 0.84 +/- 0.04 L/kg, and terminal elimination half-life 18.1 +/- 1.2 hours. Patients receiving their first fluconazole dose of 8 mg/kg achieved peak serum levels of 9.5 +/- 0.4 microgram/ml and trough levels of 2.7 +/- 0.5 microgram/ml 24 hours later, and an area under the serum concentration-time curve from time zero to infinity of 186 +/- 16 micrograms.hr per milliliter. Renal clearance of fluconazole was 65% +/- 5% of total clearance and demonstrated the predominantly renal excretion of this drug. We suggest that the shorter serum half-life and the higher frequency of aminotransferase elevations in comparison with those of adults warrant careful investigation of fluconazole in controlled clinical trials.


Subject(s)
Fluconazole/pharmacokinetics , Fluconazole/toxicity , Leukemia, Myeloid, Acute/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Soft Tissue Neoplasms/metabolism , Child , Drug Administration Schedule , Drug Evaluation , Female , Humans , Kidney/metabolism , Liver/metabolism , Liver Function Tests , Male
7.
J Pediatr ; 117(4): 531-40, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2170609

ABSTRACT

Because polymorphonuclear neutrophils are the most important component of host defense against bacteria, we assessed their function in 13 children with asymptomatic and 12 with symptomatic infection with human immunodeficiency virus type 1 (HIV-1), and compared their values with healthy adult control values. The functions assessed were (1) chemotaxis, (2) bacterial phagocytosis, (3) superoxide generation, and (4) bactericidal activity. Chemotaxis of polymorphonuclear neutrophils toward the chemoattractant N-formylmethionyl leucyl phenylalanine (FMLP) was significantly decreased in symptom-free infected children compared with control subjects (p less than 0.0001), but was increased in children with symptomatic infection (p less than 0.025). Bactericidal activity of the neutrophils against Staphylococcus aureus was defective in 8 of 12 children with asymptomatic infection (p = 0.016), and in 8 of 9 children with symptomatic infection (p less than 0.00001). Superoxide generation by polymorphonuclear neutrophils on stimulation with FMLP and phagocytosis of S. aureus were normal. Serum from patients with symptomatic HIV-1 infection was not as efficient in low concentrations as normal serum in the ability to opsonize S. aureus. The in vitro bactericidal defect was partially corrected by granulocyte-macrophage colony-stimulating factor (GM-CSF). The results suggest that both cellular (neutrophils) and humoral defects contribute to the increased incidence of bacterial infections in HIV-1-infected children, and that GM-CSF may improve the defective bactericidal activity of polymorphonuclear neutrophils in these patients.


Subject(s)
Chemotaxis, Leukocyte/immunology , HIV Infections/blood , HIV-1 , Neutrophils/immunology , Phagocyte Bactericidal Dysfunction , Adolescent , Bacterial Infections/immunology , Chemotaxis, Leukocyte/drug effects , Child , Child, Preschool , Female , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , HIV Infections/immunology , Humans , Infant , Male , N-Formylmethionine Leucyl-Phenylalanine/metabolism , Phagocytosis , Superoxides/metabolism
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