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PubMed2000

Dendrite loss is a characteristic early indicator of toxin-induced neurodegeneration in rat midbrain slices.

In rat brain substantia nigra catecholamine neurons in vitro, a sensitive indicator of excitatory amino-acid-induced damage is dendritic degeneration that precedes the loss of the cell body. The present study has shown that dendritic loss is not specific for excitatory amino acids and is an early indicator of neurodegeneration produced by numerous agents that initiate damage by different primary cellular actions. Rats were anesthetised by fluothane inhalation and killed, and the brain was rapidly removed. Three-hundred-micrometer-thick slices containing substantia nigra were incubated for 2 h at 35 degrees C in the presence or absence of kainic acid (50 microM), 1-methyl-4-phenylpyridinium ion (10 or 50 microM), ouabain (10 or 30 microM), 6-hydroxydopamine (10 or 100 microM), potassium cyanide (100 microM or 1 mM), or elevated extracellular potassium chloride (25, 50, or 100 mM). The slices were fixed and recut into thin sections (30 micrometer) and substantia nigra dopamine neurons were immunolabeled for tyrosine hydroxylase coupled to diaminobenzidine. Both the cell body and the extensive dendritic projections were immunolabeled. Each agent caused a similar pattern of toxicity including loss of tyrosine-hydroxylase-immunolabeled dendrites at lower concentrations and damage to, or disintegration of, the cell bodies at higher concentrations. For example, 100 microM potassium cyanide reduced the proportion of substantia nigra neurons which exhibited dendrites from 66 +/- 4% (SEM) in controls to 54 +/- 7%, without obvious changes in cell bodies. After 1 mM potassium cyanide, only 13 +/- 2% of substantia nigra neurons retained dendrites and cell bodies were shrunken or disintegrated. Loss of dendrites was also evident in substantia nigra neurons stained with cresyl violet or immunolabeled for microtubule-associated protein 2. The findings suggest that disruption of the dendritic arbor is an early indicator of neurodegeneration, irrespective of how this is initiated. The approach that we have developed may therefore prove valuable in investigating the mechanisms of degeneration of catecholamine neurons.

Animals↗

PubMed2000

Progressive metabolic changes underlying the chronic reorganization of brain circuits during the silent phase of the lithium-pilocarpine model of epilepsy in the immature and adult Rat.

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. In the present study, we explored the correlation between metabolic changes, neuronal damage, and epileptogenesis during the silent phase following status epilepticus (SE) induced by Li-Pilo in 10- (P10) and 21-day-old (P21) and adult rats. Cerebral metabolic rates for glucose (CMR(glcs)) were measured at 14 and 60 days after SE by the 2-[(14)C]deoxyglucose method and neurodegeneration was assessed by the silver staining and cresyl violet techniques. In P10 rats, there was no damage and no metabolic consequences at any time after SE. In P21 rats, metabolic decreases were recorded at 14 days after SE, mainly in damaged forebrain regions. Conversely at 60 days after SE, P21 rats exhibited metabolic increases in both forebrain-damaged and brain-stem-intact areas. Finally, in adult rats studied at 14 days after SE, CMR(glcs) decreased in damaged forebrain areas involved in the circuitry of spontaneous seizures and increased in nondamaged brain-stem areas involved in the remote control of epilepsy. The increase in CMR(glcs) in damaged forebrain areas of P21 rats at 60 days after SE may reflect the genesis of a new circuitry underlying the occurrence of spontaneous seizures. The metabolic increase recorded in nondamaged brain-stem areas of P21 and adult rats occurs in regions involved in the remote control of seizures and might underlie a process of protection against the occurrence of seizures.

Age Factors↗

PubMed2001

Smaller amounts of antiretroviral drugs are needed when combined with an active ribozyme against HIV-1.

We have tested for combined anti-HIV-1 effects of a hammerhead ribozyme and antiretroviral drugs and the possibility of reducing the drug burden of patients on highly active antiretroviral therapy (HAART). The antiretroviral compounds used represent the three groups in HAART: nucleoside analogue reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors. A human T cell line (HUT78), stably expressing a hammerhead ribozyme targeted to nef (hhRz.nef(9016-9029)), was infected with HIV-1(SF2) in the presence of a single drug. The combined effects on HIV-1 replication were measured by p24 antigen determinations over a 2-week period. In the presence of the ribozyme, smaller amounts of antiretroviral drugs were required to reduce the HIV-1 p24 levels equally as much as when only drugs were present. The results support a strategy of combining ribozyme gene therapy with HAART to improve the long-term outcome of anti-HIV-1 therapy.

Alkynes↗

PubMed1997

Developmental features of human striatal tissue transplanted in a rat model of Huntington's disease.

Areas of striatal grafts which contain neurons that are characteristic of the striatum are called P-zones. We have investigated whether the paucity of P-zones in human xenografts of lateral ganglionic eminence (LGE) tissue in a rat model of Huntington's disease is due (i) to an absence of the appropriate target cells of LGE neurons or (ii) to the persistence of an immature morphology. Striatal tissue from human embryos of varying sizes (21, 24, and 30 mm in crown-to-rump length) was grafted into the ibotenate-lesioned striatum of immunosuppressed rats, which were killed after 15-17 weeks. In most cases, tissue from the LGE and medial ganglionic eminence (MGE) was transplanted together, whereas some rats received grafts of only LGE tissue. Both types of grafts exhibited positive immunostaining for PCNA (proliferating cells), Vimentin (immature astrocytes), and GAP-43 (outgrowing fibers), which indicates that graft maturation is still ongoing up to 4 months after grafting. Graft survival seemed better when MGE was cografted with LGE, suggesting that the MGE may provide trophic support for LGE neurons and can affect the overall survival of human striatal xenografts. However, the extent of P-zone formation was not increased in MIXED, i.e., LGE plus MGE, grafts.

Acetylcholinesterase↗

PubMed1999

Inhibitory effects of cannabinoid receptor ligands on electrically-evoked responses in rat isolated tracheal ring segments.

We have examined the possible existence of cannabinoid receptors in the isolated rat tracheal ring segments by studying the effects of some cannabinoid receptor ligands on electrically-induced contractions. Anandamide (10(-8)-3 x 10(-5)m), an endogenous ligand for cannabinoid receptors, and WIN 55,212-2 (10(-9)-3 x 10(-5)m), a moderately selective CB(2)agonist, inhibited electrically evoked contractions of the rat tracheal ring segments in a concentration-related manner. Addition of phentolamine (10(-6)m) to Krebs Henseleit solution to block alpha(2)-adrenoceptors did not affect anandamide-induced inhibition of the electrically evoked contractions. The EC(25)(-log m) values were 5.25+/-0.2 and 5.8+/-0. 4 for anandamide and WIN 55,212-2, respectively. The maximal inhibition produced by the highest concentration of the agonists used was 51.4+/-5.8% for anandamide and 35.1+/-19.5% for WIN 55, 212-2. WIN 55,212-3 also produced a concentration-dependent inhibition of the electrically evoked contractions. The maximal inhibition produced by WIN 55,212-3 was 15.8+/-2.4. The inhibitory effects of anandamide and WIN 55,212-2 were not attenuated by SR141716A (10(-6)m), a selective CB(1)receptor antagonist. Anandamide (10(-8)-3 x 10(-5)m) did not relax rat tracheal ring segments pre-contracted with carbachol (10(-6)m). These results suggest that anandamide and WIN 55,212-2 produce pre-junctional inhibitory effects in the rat trachea and that these effects were likely mediated through cannabinoid CB(2)receptors. These effects were probably non-cannabinoid receptor-mediated considering the high concentrations of the agents required to produce inhibitory responses and the effectiveness of WIN 55,212-3.

Animals↗

PubMed2000

The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats.

Efavirenz, a potent nonnucleoside reverse transcriptase inhibitor widely prescribed for the treatment of HIV infection, produces renal tubular epithelial cell necrosis in rats but not in cynomolgus monkeys or humans. This species selectivity in nephrotoxicity could result from differences in the production or processing of reactive metabolites, or both. A detailed comparison of the metabolites produced by rats, monkeys, and humans revealed that rats produce a unique glutathione adduct. The mechanism of formation and role of this glutathione adduct in the renal toxicity were investigated using both chemical and biochemical probes. Efavirenz was labeled at the methine position on the cyclopropyl ring with the stable isotope deuterium, effectively reducing the formation of the cyclopropanol metabolite, an obligate precursor to the glutathione adduct. This substitution markedly reduced both the incidence and severity of nephrotoxicity as measured histologically. Further processing of this glutathione adduct was also important in producing the lesion and was demonstrated by inhibiting gamma-glutamyltranspeptidase with acivicin pretreatment (10 mg/kg, IV) prior to dosing with efavirenz. Again, both the incidence and severity of the nephrotoxicity were reduced, such that four of nine rats given acivicin were without detectable lesions. These studies provide compelling evidence that a species-specific formation of glutathione conjugate(s) from efavirenz is involved in producing nephrotoxicity in rats. Mechanisms are proposed for the formation of reactive metabolites that could be responsible for the renal toxicity observed in rats.

Alkynes↗

PubMed1997

Population dynamics studies of wild-type and drug-resistant mutant HIV in mixed infections.

We have studied the population dynamics in response to selective drug pressure of mixtures of wild-type and mutant HIV viruses exposed to either an inhibitor of the viral protease or a nonnucleoside allosteric inhibitor of the viral reverse transcriptase. In order to quantitate mutant virus present in a mixed population, we developed a selective plaque assay, which appears to be generally applicable to population dynamics studies where the viruses in question differ in the sensitivity to a given drug by at least 10-fold. In this assay system, the titer of virus in a mixture is measured in the absence and presence of a concentration of a specific inhibitor known to suppress virus replication by 99%. Virus detected in the presence of inhibitor corresponds to mutant virus, whereas detection in the absence of drug results in quantitation of the total virion population. Wild-type virus is then estimated by difference. Utilizing this system we studied the fate of mixtures of wild-type and the protease-resistant mutant variant I84V in the presence and absence of the cyclic urea HIV protease inhibitor, DMP 450. We also examined the dynamics of mixtures of wild-type and the resistant mutant variant, L100I, in the presence and absence of the drug DMP 266. In both systems we demonstrated that in the absence of drug, mutant virus is at a selective disadvantage for growth compared to wild-type, whereas in the presence of a specific inhibitor, mutant virus exhibits the selective growth advantage over wild-type virus. Better understanding of HIV population dynamics may allow the development of superior inhibitors and the careful application of combination therapy in the clinical setting.

Alkynes↗

PubMed1995