Neuronal oxidative injury and dendritic damage induced by carbofuran: protection by memantine.

Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h.

Carbofuran-induced oxidative stress in slow and fast skeletal muscles: prevention by memantine and atropine.

Acute toxic effects of acetylcholinesterase (AChE) inhibitors on skeletal muscles are thought to involve oxidative stress with increased generation of free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Muscle hyperactivity with its increased oxygen and energy consumption appear to be the primary cause of oxidative stress. The present investigation was therefore undertaken to establish the normal levels of F(2)-isoprostanes (F(2)-IsoPs, specific markers of ROS/oxidative stress), citrulline (determinant of NO/NOS and marker of RNS), and high-energy phosphates (HEP: adenosine triphosphate, ATP and phosphocreatine, PCr) in slow (soleus) and fast (extensor digitorum longus, EDL) muscles of rats.

Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain regions.

Previous studies using the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E established the involvement of free radicals in kainic acid (KA)-induced neurotoxicity. In the present study, we examined the effects of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) to establish a possible role of nitric oxide (NO) in the neurotoxicity caused by KA-induced status epilepticus (SE). A single injection of KA (15 mg/kg, s.

Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity.

Oxidative stress, as determined by increased lipid peroxidation, has been implicated in the pathology of myotoxicity. As a model system to study the response of muscle to oxidative insults, we have studied the effects of diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity on levels of nitric oxide (NO) and energy metabolites in rat skeletal muscles. In in vivo experiments, citrulline levels as indicators of NO and NO synthase (NOS), and ATP and phosphocreatine (PCr) as indicators of mitochondrial dysfunction, were determined using HPLC methods 15 min, 30 min, 60 min, 2 h, and 24 h after intoxication.

Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain.

The involvement of nitric oxide (NO) in kainic acid (KA)-induced excitotoxicity was studied in rat brain. With the onset of KA (15 mg kg(-1), s.c.

Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E.

Acute effects of seizure-inducing doses of the organophosphate compound diisopropylphosphorofluoridate (DFP, 1.25 mg/kg s.c.

Alterations in cytochrome c oxidase activity and energy metabolites in response to kainic acid-induced status epilepticus.

The effects of kainic acid (KA)-induced limbic seizures have been investigated on cytochrome c oxidase (COx) activity, COx subunit IV mRNA abundance, ATP and phosphocreatine (PCr) levels in amygdala, hippocampus and frontal cortex of rat brain. Rats were killed either 1 h, three days or seven days after the onset of status epilepticus (SE) by CO2 and decapitation for the assay of COx activity and by head-focused microwave for the determination of ATP and PCr. Within 1 h COx activity and COx subunit IV mRNA increased in all brain areas tested between 120% and 130% of control activity, followed by a significant reduction from control, in amygdala and hippocampus on day three and seven, respectively.

Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants.

Status epilepticus (SE)-induced neuronal injury may involve excitotoxicity, energy impairment and increased generation of reactive oxygen species (ROS). Potential treatment therefore should consider agents that protect mitochondrial function and ROS scavengers. In the present study, we examined whether the spin trapping agent N-tertbutyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E (DL-alpha-tocopherol) protect levels of high-energy phosphates during SE.

N-tert-butyl-alpha-phenylnitrone, a free radical scavenger with anticholinesterase activity does not improve the cognitive performance of scopolamine-challenged rats.

Reversible inhibitors of acetylcholinesterase improve spatial learning and memory in animal models of cognitive impairment. Here we investigate if the beneficial effects of free radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on cognitive performance could be explained by its recently discovered anticholinesterase activity. Morris water maze experiment was performed to examine the effect of PBN on the impairment of spatial learning and memory induced by the antagonist of cholinergic muscarinic transmission scopolamine.

Seizure-induced changes in energy metabolites and effects of N-tert-butyl-alpha-phenylnitrone (PNB) and vitamin E in rats.

Impaired energy metabolism may play a critical role in the neuronal injury caused by kainic acid (KA) induced status epilepticus (SE). Following an acute dose of KA (15 mg/kg, s.c.

Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects.

The objective of this investigation was to determine the distribution of cholinergic and noncholinergic biomarkers in discrete brain regions (cortex, stem, striatum, hippocampus, and cerebellum) of rats treated with dimethyl sulfoxide (DMSO, controls), and insecticides such as carbofuran (CARB, 1.5 mg/kg, sc), or methyl parathion (MPTH, 5 mg/kg, ip). Both insecticides produced characteristic signs of anticholinesterase nature within 5-7 min after injection.

The effects of tetanus toxin on the orbicularis oculi muscle.

Purpose: Tetanus toxin can cause localized neuromuscular weakness, but it also can produce systemic tetany. The action of tetanus toxin on the orbicularis muscle has not been studied in animals immunized to prevent systemic tetany. Our objective was to determine whether tetanus toxin could be used to treat orbicularis oculi muscle spasms.

Atypical effect of some spin trapping agents: reversible inhibition of acetylcholinesterase.

N-tert-butyl-alpha-phenylnitrone (PBN), a widely used nitrone-based free radical trap was recently shown to prevent acetylcholinesterase (AChE) inhibitors induced muscle fasciculations and brain seizures while being ineffective against glutamergic or cholinergic receptor agonist induced seizures. In the present study we compared the effects on AChE activity of four free radical spin traps PBN, alpha-(4-pyridil-1)-N-tert-butyl nitrone (POBN), N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO). The kinetics of AChE inhibition were studied in vitro using a spectrophotometric kinetic assay with AChE from rat brain, diaphragm, electric eel and mouse brain.

Spin trapping agent phenyl-N-tert-butylnitrone prevents diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the rat.

Indirect evidence suggests that reactive oxygen species (ROS) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate (DFP). Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase (AChE) activity was reduced to less than 30% of control. The spin trapping agent phenyl-N-tert-butylnitrone (PBN) was used in vivo to directly assess the formation of ROS during DFP (1.

Nitrone spin trapping compound N-tert-butyl-alpha-phenylnitrone prevents seizures induced by anticholinesterases.

The neuroprotection afforded by spin trapping agents such as N-tert-butyl-alpha-phenylnitrone (PBN) has lent support to the hypothesis that increased production of reactive oxygen species (ROS) is a major contributing factor to excitotoxicity, aging and cognitive decline. Little is known, however, about the pharmacological properties of PBN. We have compared the acute effects of PBN on the development of seizures induced by the irreversible acetylcholinesterase (AChE) inhibitor diisopropylphosphorofluoridate (DFP), the reversible AChE inhibitor physostigmine (PHY), the muscarinic cholinergic receptor agonist pilocarpine (PIL) and the glutamatergic receptor agonist kainic acid (KA).

Seizure-induced changes in energy metabolites and effects of N-tert-butyl-α-phenylnitrone (PNB) and vitamin E in rats.

Impaired energy metabolism may play a critical role in the neuronal injury caused by kainic acid (KA) induced status epilepticus (SE). Following an acute dose of KA (15 mg/kg, sc) rats developed SE within 1 h. Rats were sacrificed 1 or 72 h after the onset of SE using a head focused microwave technique and the brain regions (pyriform cortex, amygdala, and hippocampus) were assayed for energy metabolites: ATP, ADP, AMP, phosphocreatine (PCr) and creatine (Cr) using reversed-phase HPLC (RP-HPLC).

Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP.

The contribution of carboxylesterase (CarbE) to toxicity and tolerance to the organophosphorus anticholinesterases (OP-antiChE) paraoxon (diethyl p-nitrophenyl phosphate) and DFP (diisopropylphosphorofluoridate) was investigated in rats. Daily injections (20 days) of paraoxon (0.33 micromol/kg) or DFP (2.

Prevention of tolerance to the organophosphorus anticholinesterase paraoxon with carboxylesterase inhibitors.

The contribution of carboxylesterase (CarbE) to the development of tolerance to the organophosphorus anticholinesterase (OP-ANTIChE) paraoxon (diethyl p-nitrophenyl phosphate) was investigated in rats. Daily injections (20 days) of paraoxon (0.09 mg/kg) led to a cumulative dose that was 9.

Lipid peroxidation and changes in cytochrome c oxidase and xanthine oxidase activity in organophosphorus anticholinesterase induced myopathy.

A possible role of radical oxygen species (ROS) initiated lipid peroxidation in diisopropylphosphorofluoridate (DFP)-induced muscle necrosis was investigated by quantifying muscle changes in F2-isoprostanes, novel and extremely accurate markers of lipid peroxidation in vivo. A significant increase in F2-isoprostanes of 56% was found in the diaphragm of rats 60 min after DFP-induced fasciculations. As possible source of ROS initiating lipid peroxidation, the cytocrome-c oxidase (Cyt-ox) and xanthine dehydrogenase-xanthine oxidase (XD-XO) systems were investigated.

Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid.

F2-isoprostanes are prostaglandin F2-like compounds that are formed nonenzymatically by free radical-induced oxidation of arachidonic acid. We explored whether oxidation of docosahexaenoic acid (C22:6omega3), which is highly enriched in the brain, led to the formation of F2-isoprostane-like compounds, which we term F4-neuroprostanes. Oxidation of docosahexaenoic acid in vitro yielded a series of compounds that were structurally established to be F4-neuroprostanes using a number of mass spectrometric approaches.

Common mechanism of toxicity: a case study of organophosphorus pesticides.

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ...

Diisopropylphosphorofluoridate-induced muscle hyperactivity associated with enhanced lipid peroxidation in vivo.

Acute exposure to acetylcholinesterase (AChE) inhibitors such as organophosphates and carbamates induces functional changes at the neuromuscular junctions, leading to fasciculations that ultimately cause muscle fiber necrosis. There is recent evidence that oxygen free radical formation may be a factor in the toxicity of these insecticides. One of the targets of free radical-induced injury is lipid peroxidation.

Diisopropylphosphorofluoridate-induced cholinergic hyperactivity and lipid peroxidation.

In the present study, the association between acetylcholine (ACh)-induced muscle necrosis and the appearance of lipid peroxidation products was investigated. Lipid peroxidation in this injury was quantified by the malondialdehyde-thiobarbituric acid complex (TBA-MDA) using HPLC. To induce muscle necrosis, rats were treated with 1.

Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat.

These experiments examined the changes in acetylcholinesterase (AChE) during tolerance development in rats exposed to paraoxon, an irreversible inhibitor of AChE. Rats were injected sc for 20 days with 0.09, 0.

Hydrolysis of tetriso by an enzyme derived from Pseudomonas diminuta as a model for the detoxication of O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX).

An enzyme termed organophosphorus hydrolase (OPH), derived from Pseudomonas diminuta, had been found previously to hydrolyze the powerful acetylcholinesterase (AChE) inhibitor O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX). This enzyme has now been shown to be correlated with the loss of AChE inhibitory potency (detoxication). OPH also hydrolyzed and detoxified the VX analogue, O,O-diisopropyl S-(2-diisopropylaminoethyl) phosphorothiolate (Tetriso), also a potent AChE inhibitor, about five times faster than VX.