Neurotoxicology of chemotherapy in relation to cytokine release, the blood-brain barrier, and cognitive impairment.

Purpose/objectives: To review the effects of chemotherapeutic agents on the blood-brain barrier as related to cytokine release and cognitive impairment.

Data Sources: PubMed database.

Data Synthesis: The recent findings that standard doses of chemotherapy agents reach higher than expected levels in the brain and cerebral spinal fluid are being investigated as a potential etiology for the cognitive impairment seen in patients receiving chemotherapy for cancer.

Basal local cerebral glucose utilization is not altered after behavioral sensitization to quinpirole.

Sensitization to psychostimulants results in a behavioral response of a greater magnitude than that produced by a given single dose. Previously, we have shown that sensitization to the D(2)/D(3) dopamine receptor agonist quinpirole produces alterations in quinpirole-stimulated local cerebral glucose utilization (LCGU) in ventral striatal and limbic cortical regions. To determine whether basal neuronal activity is altered in the sensitized animal, this study examined the effects of a sensitizing course of quinpirole on basal neuronal activity using the [(14)C]-2-deoxyglucose (2-DG) method in rats with verified sensitization.

Clorgyline-induced modification of behavioral sensitization to quinpirole: effects on local cerebral glucose utilization.

Sensitization refers to augmented behavioral responses produced by repeated, intermittent injections of dopaminergic psychostimulants. The locomotor manifestations observed after a sensitizing course of quinpirole, a D(2)/D(3) dopamine agonist, can be modified by the MAO(A) inhibitor clorgyline, by a mechanism apparently unrelated to its actions on MAO(A). Alterations in regional neuronal activity produced by quinpirole in quinpirole-sensitized rats with or without clorgyline pretreatment were assessed based on LCGU using the [(14)C]-2-deoxyglucose (2-DG) method.

Altered quinpirole-induced local cerebral glucose utilization in anterior cortical regions in rats after sensitization to quinpirole.

Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as "sensitization." Most studies of sensitization have focused on the "motive circuit"; however, some additional anterior cortical regions also appear to be affected. In this study, alterations in regional neuronal activity in anterior cortical brain areas produced by quinpirole, a D(2)/D(3) agonist, were assessed on the basis of local cerebral glucose utilization (LCGU) using the [(14)C]-2-deoxyglucose (2-DG) method.

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method.

Alterations in brain glutathione homeostasis induced by the nerve gas soman.

Public awareness of the dangers of chemical and biological warfare has been heightened in recent times. In particular, chemical nerve agents such as soman and its analogs have been developed and used in war as well as recent incidents, such as in Iraq and Japan. Soman, a rapid acting acetylcholinesterase inhibitor, produces a status epilepticus that leads to extensive neuropathology in vulnerable brain regions (eg, piriform cortex and hippocampus).

Recovery of metabolic activity in retinofugal targets after traumatic optic nerve injury is independent of retinofugal input.

Traumatic injury of the adult optic nerve causes a progressive degeneration of retinal ganglion cells. Despite this ongoing degeneration, a partial recovery of visual behavioral function and of local cerebral glucose use (LCGU) has been observed. To evaluate whether this partial recovery of LCGU is due to a recovery of visual conductance (extrinsic) or intrinsic neuronal activity, visual stimulation alone and combined with physostigmine,an acetylcholinesterase inhibitor, were used to activate the retinofugal pathway.

Differences in quinpirole-induced local cerebral glucose utilization between naive and sensitized rats.

Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as 'sensitization'. Alterations in regional neuronal activity produced by quinpirole, a D(2)/D(3) agonist, in quinpirole-naive and quinpirole-sensitized rats were assessed on the basis of local cerebral glucose utilization (LCGU) using the [14C]2-deoxyglucose (2-DG) method. Adult, male Long-Evans rats (180-200 g, n=7-9/group) were subjected to ten injections of quinpirole (0.

From mainframe to Web-based: 30 years of experience in computer-aided instruction of pharmacology.

This review describes 30 years of experience at the University of Kansas Medical Center in using computers in the teaching of pharmacology to medical students and other health professionals. The Computer-Assisted Teaching System contains both Computer-Assisted Instruction (CAI) and Computer-Managed Instruction (CMI). The system has evolved from mainframe to microprocessors to the current World Wide Web system.

Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins.

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage.

Measurement of loosely-bound iron in brain regions using redox cycling and salicylate.

A sensitive iron assay was developed for measuring non-heme and loosely bound iron in regions of rat brain. The method is based on the salicylate trapping of hydroxyl radicals generated from ascorbate-driven redox cycling of Fe3+-EDTA. This assay has high sensitivity (about 20 nM) because of amplification obtained with redox-cycling and fluorescent detection of the salicylate hydroxylation product, 2,5-dihydroxybenzoate.

Effects of hypoxia preconditioning on expression of metallothionein-1,2 and heme oxygenase-1 before and after kainic acid-induced seizures.

Global hypoxia preconditioning provides neuroprotection against a subsequent, normally damaging challenge. While the mechanistic pathways are unknown, changes in the expression of stress-related proteins are implicated. Hypoxia preconditioning attenuates the brain edema and neuropathology associated with kainic acid-induced status epilepticus in a protein synthesis-dependent manner when a kainic acid challenge is given up to one week post-preconditioning.

Reactive oxidant species in piriform cortex extracellular fluid during seizures induced by systemic kainic acid in rats.

Kainic acid (KA) administered systemically to rats produces seizures and brain damage. We measured an increase in reactive oxidant species (ROS) during KA-induced seizures in the extracellular fluid (ECF) of the piriform cortex, a brain region known to be subsequently damaged. Intracerebral microdialysis samples were collected and assayed for isoluminol-dependent chemiluminescence before and after injection of KA (16 mg/kg, i.

A global hypoxia preconditioning model: neuroprotection against seizure-induced specific gravity changes (edema) and brain damage in rats.

Hypoxia preconditioning states that a sublethal hypoxia episode will afford neuroprotection against a second challenge in the near future. We describe and discuss a procedure for the development of global hypoxia preconditioning in adult male Wistar rats, using a mildly hypoxic (9% O(2), 91% N(2)) atmospheric exposure of 8 h. The persistence of neuroprotection was analyzed using a kainic acid (KA) model of brain injury.

Hypoxia preconditioning attenuates brain edema associated with kainic acid-induced status epilepticus in rats.

Kainic acid (KA)-induced seizures elicit edema associated with necrosis in susceptible brain regions (e.g., piriform cortex and hippocampal CA1 and CA3 regions).

Alterations in local cerebral glucose utilization produced by D3 dopamine receptor-selective doses of 7-OH-DPAT and nafadotride.

The D3 dopamine receptor, localized primarily in limbic brain areas, is a potential antipsychotic site. The effects of D3 receptor stimulation or blockade on neuronal activity were determined using the [14C]-2-deoxyglucose method. Freely-moving, adult, male, Sprague-Dawley rats were injected s.

Kainic acid causes redox changes in cerebral cortex extracellular fluid: NMDA receptor activity increases ascorbic acid whereas seizure activity increases uric acid.

Kainic acid (KA) causes seizures and extensive brain damage in rats. To study the effects of KA on the redox state in cerebral cortex extracellular fluid (ECF), ascorbic and uric acid concentrations were measured in intracerebral microdialysis samples before and after systemic KA administration (ip). During seizures, concentrations of ascorbic and uric acid increased 500 and 100%, respectively.

Cerebral penetration injury leads to H2O2 generation in microdialysis samples.

Delayed tissue damage is proposed to be caused by reactive oxygen species. We investigated the effects of microdialysis probe penetration into rat piriform cortex on hydrogen peroxide (H2O2) in brain extracellular fluid (ECF). H2O2 decreased immediately after probe insertion into the brain, but increased over 300% in samples within minutes after collection.

Redox changes in perfusates following intracerebral penetration of microdialysis probes.

Microdialysis probe insertion into rat cerebral cortex significantly affects the levels of redox-active substances in brain extracellular fluid. Ascorbic acid levels are high immediately after probe insertion, decline rapidly, and then rise as the rat recovers from anesthesia 5-8 hours after surgery. Uric acid is at a low level for 5 hours and then rapidly increases in parallel with ascorbic acid.

Nitric oxide detection with intracerebral microdialysis: important considerations in the application of the hemoglobin-trapping technique.

Nitric oxide (NO.) is involved in processes such as neurotransmission, memory, brain injury, vessel relaxation, etc. To study the functional and pathological roles of NO.

Loss and subsequent recovery of local cerebral glucose use in visual targets after controlled optic nerve crush in adult rats.

A mild crush of the adult rat optic nerve serves as a model to study the restoration of function after traumatic brain injury. It causes a progressive degeneration of retinal ganglion cells, but visually guided behavior is partially restored within 2-3 weeks. The purpose of this study was to determine to what extent local cerebral glucose use (LCGU) decreases and if it recovers in retinofugal targets following unilateral optic nerve crush.

Temporalspatial patterns of expression of metallothionein-I and -III and other stress related genes in rat brain after kainic acid-induced seizures.

Kainic acid-induced seizures in the rat brain cause severe brain damage that is thought to result, in part, from oxidative stress. In this study, we examine the consequences of systemic administration of kainic acid on expression of several genes that encode proteins thought to play roles in protection from oxidative stress, including metallothionein-I, and -III. Kainic acid causes an increase in metallothionein-I and heme oxygenase-I mRNAs, as well as an increase in c-fos, heat shock protein-70, and interleukin-1 beta mRNAs.

Is there an energy conservation "system" in brain that protects against the consequences of energy depletion?

A poorly understood marked decrease (circa 50% of control) in local cerebral glucose utilization is caused by sublethal doses of NaCN. The decrease is global, occurring in essentially all brain regions and is entirely reversible within hours, leaving no obvious pathology. This event is not unique to NaCN in so far as a strikingly similar pattern of decreased glucose utilization occurs with some other toxins.

Patterns of glucose use after bicuculline-induced convulsions in relationship to gamma-aminobutyric acid and mu-opioid receptors in the ventral pallidum--functional markers for the ventral pallidum.

Bicuculline-induced convulsions increased glucose use throughout the brain and sharply demarcated the ventral pallidum and globus pallidus. Glucose use in the nucleus accumbens also increased after bicuculline-induced convulsions, except for a circumscribed region in the dorsomedial shell. Since the projection from the nucleus accumbens to the ventral pallidum contains gamma-aminobutyric acid (GABA) and the opioid peptide, enkephalin, the pattern of increased glucose use in the ventral pallidum and nucleus accumbens after bicuculline-induced convulsions was compared to the topography of GABAA and mu-opioid receptors.

The osmotic/calcium stress theory of brain damage: are free radicals involved?

This overview presents data showing that glucose use increases and that excitatory amino acids (i.e., glutamate, aspartate), taurine and ascorbate increase in the extracellular fluid during seizures.