Effects of mercury vapor inhalation on reactive oxygen species and antioxidant enzymes in rat brain and kidney are minimal

Metals are known to induce the formation of reactive oxygen species (ROS) that initiate oxidative stress, an important mechanism of cell injury. The brain is particularly sensitive to oxidative attack because of its high level of unsaturated lipids and high rate of oxidative metabolism. The objective of this study was to determine if elemental mercury (Hg(0)) vapor inhalation increases ROS production and affects activities or levels of antioxidant-related biomolecules in the rat brain and kidney. Adult female Sprague-Dawley rats were exposed for 2 h per day for 11 consecutive days to Hg(0) vapor (1, 2, and 4 mg Hg(0) m(-3)). Brain regions (frontal cortex, cerebellum, brain stem) and kidney were assayed for total Hg, ROS and glutathione (GSH) levels, and for enzyme activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD). Marked exposure-related increases (2500-5600-fold) in total Hg were detected in the brain regions and in kidney. A statistically significant increase in ROS production (ca. 30% above controls) was observed only in the cortex of rats exposed to 1 mg m(-3) Hg vapor, but no significant changes were apparent at other exposures. Although a trend towards increasing ROS production was observed in the kidney, these effects were not statistically significant. Mercury vapor exposure had no significant effects on GSH levels or GPx activity in the three brain regions, however, statistically significant decreases in GSH and GPx activity were detected in the kidneys of rats exposed to 2 mg m(-3). Mercury exposure did not cause significant effects on SOD activity in the brain or kidney. The data indicate that oxidative stress and changes in GSH and activities of antioxidant enzymes do not play a major role in Hg(0) vapor toxicity in brain and kidney.     

Effects of vibrissae removal on methamphetamine-induced damage to rat somatosensory cortical neurons

Repeated methamphetamine (mAMPH) damages forebrain monoamine terminals and causes degeneration of nonmonoaminergic cell bodies in rat primary somatosensory cortex (S1). These degenerating cortical neurons can be labeled with the fluorochrome dye Fluoro-Jade (FJ) and are found almost exclusively in layers II/III and IV of the vibrissae representation in S1. Within S1, layer IV is organized into discrete, anatomically identifiable units termed barrels, each of which receives information from a single whisker. We previously reported that mAMPH-damaged neurons in S1 were located within the whisker barrels, suggesting that the prolonged mAMPH-induced whisking contributes to S1 neuronal injury. Here, we investigate effects of vibrissae removal on mAMPH-induced damage to S1 neurons. Rats were anesthetized and vibrissae were trimmed from either the left, right, or neither side of the snout. The next day they were given four injections of either saline (1 ml/kg, s.c.) or mAMPH (4 mg/kg, s.c.) at 2-h intervals. Three days later, cortical sections were processed for FJ histochemistry. The hemivibrissotomy produces a hemispheric asymmetry in FJ-positive neurons in barrel cortex, with fewer damaged neurons contralateral than ipsilateral to whisker removal. Taken together with the demonstration that acute injection of this dose of mAMPH induces the immediate early gene zif/268 and Fos protein in barrel cortex, these data suggest that the prolonged behavioral activity involving the vibrissae contributes to the mAMPH-induced damage to S1 neurons. Thus, some of the injurious effects of drugs may depend on afferent activity occurring as a result of the abnormal behaviors evoked by their administration.     

Is Intrathecal Methotrexate Necessary in the Treatment of Primary CNS Lymphoma?

Systemic high-dose methotrexate (HD-MTX) is the most effective chemotherapeutic agent in the treatment of primary central nervous system lymphoma (PCNSL). Leptomeningeal involvement is common and intrathecal methotrexate (IT-MTX) is frequently used in combination with HD-MTX, but its benefits are not established. Using a case-controlled retrospective study, matching patients treated with HD-MTX with or without IT-MTX, we found no difference in survival, disease control, or neurotoxicity.     

Effects of Yizhi Capsule (益智胶囊) on Learning and Memory Disorder and β-amyloid Peptide Induced Neurotoxicity in Rats

Alzheimer sdisease(AD),adiseasethatse verelythreatenstheagedpopulation,ischaracte rizedbyprogressivelyloweringtherecognitionand memorycapabilitiesofthecentralnervoussystem(CNS).StudiesbyDiCarloA,etal(1)showedthat,inItaly,theincidencerateofdementiain1995was12.47‰,ofwhichADaccountedfor6.55‰andwasremarkablyhigherthantheincidencerateofanyotherkindofdementia.Itwasestimatedinan investigationconductedbyHebertLE,etal(2)thatfromtheyears2000through2050,thenumberofADpatientswasexpectedtobedoubled…     

Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P.

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injection of SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1-2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O(2))(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the "epileptic" pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use of global neurologic injury models.     

Wernicke-encephalopathy in children with cancer

In the last 4 years, 24 cases of neuroblastoma were treated in the Pediatric Hematology-Oncology Unit at the Chaim Sheba Medical Center, 8 of whom were under 1 year of age. Four of them were the product of a pregnancy-induced or preserved by gonadotropins, clomiphene citrate, or progestational hormones. These drugs are known to produce a higher than normal level of estradiol or progestrone in the early stages of pregnancy. Our observation led to the hypothesis that high levels of progestational hormones given during pregnancy are a risk factor for neuroblastoma in infancy. © 1994 Wiley-Liss, Inc.     

Interferon-induced organic mental disorders associated with unsuspected pre-existing neurologic abnormalities

Summary Eleven patients ranging in age from 52 to 80 years, undergoing treatment for cancer with various preparations of interferon received neurobehavioral evaluations after experiencing unexpectedly severe organic mental disorders. The reactions ranged from delirium to extrapyramidal symptoms, mania, and neurasthenia with catatonic episodes. Computed tomographic (CT) scans of the brain disclosed unsuspected pre-existing neurologic abnormalities in all patients, including cerebral atrophy (6/11), brain metastases (4/11), and evidence of head injury incurred 40 years earlier (l/11). These findings suggest that cancer patients with pre-existing neurologic dysfunctions are at increased risk for severe interferon neurotoxicity.     

Low-level lead exposure alters morphine antinociception in neonatal rats

Administration of lead (at 300 and 1000 ppm) in the maternal drinking water from conception to weaning impaired the antinociceptive activity of morphine in 10-day-old neonatal rats. Blood lead levels in these animals were below 50 μ/100 ml in the high lead dose group and below 35 μg/100 ml in the low lead dose group. The differences in the antinociceptive potency of morphine between normal and lead-exposed animals were not observed at later time points (21 and 30 days). It is suggested that lead disrupts the development of opioid receptor systems in the central nervous system and that this disruption occurs early in development.     

Chronic catheterization of the epidural space in rabbits: a model for behavioural and histopathological studies. Examination of meptazinol neurotoxicity

A technique of epidural catheterization in rabbits is described. Twelve albino rabbits received a totally implanted epidural catheter system. The system was implanted surgically, and the functioning of the system tested for a period of 3 months. X-ray examinations following epidural contrast injections showed a distribution up to Th4 following 1.5 ml and Th8–9 following 1.0 and 1.25 ml. Epidural injection of lidocaine throughout the study period proved the system to be functioning for all 3 months. Another 12 rabbits were included for the neurotoxicological examinations following epidural catheterization, without any injections (three rabbits), epidural injections of saline (four rabbits) and meptazinol (five rabbits) once a day for 14 days. Histopathological examinations showed a fibrous cocoon, at the tip of the catheter, in all rabbits. In the group of rabbits which did not receive any injections, the cocoon was slightly infiltrated with leukocytes and local depression of the spinal cord was observed in one rabbit. In the saline-injected group this infiltration was more pronounced and in one rabbit it extended into the meninges. Three rabbits showed local depression of the spinal cord and local myelopathy of the white matter in the area adjacent to the cocoon. In the group of rabbits receiving meptazinol, three out of five had local depression and myelopathy of the white matter. In this group these findings were more pronounced. In two rabbits the myelopathy extended transversely through the white matter into the grey matter of the spinal cord. The number of pathological changes in the group receiving meptazinol was significantly higher compared to the control and placebo groups. The epidural catheterization technique proved to be simple and reliable. Neurotoxicological examinations showed local effects following catheterization and injection of saline. Following injection of meptazinol, a significant neurotoxicological potential was shown.