|
ACTIVITY: Former
Insecticide (Organophosphate)
Structure:
DFP is a structural
analog of sarin.
Ref: Sarin
(nerve agent GB)-induced differential expression of
mRNA coding for the acetylcholinesterase gene in the
rat central nervous system; by Damodaran TV, Jones KH,
Patel AG, Abou-Donia MB. Biochemical Pharmacology Volume
65, Issue 12 , 15 June 2003,
Pages 2041-2047.
|
79
Reports available
from
The National Technical Information Service
(NTIS)
Order from NTIS by: phone at 1-800-553-NTIS (U.S. customers);
(703)605-6000 (other countries); fax at (703)605-6900; and
email at orders@ntis.gov. NTIS is located at 5285 Port Royal
Road, Springfield, VA, 22161, USA. |
| Order
No. |
Title |
Abstract or Keywords |
| NTIS/02210010 |
2004
-
Toward Optically Monitored Cytosensors.
Authors:
McFadden PN
Oregon
State Univ., Corvallis. |
Final rept. 1 Mar 1996-28 Feb 1999.
Fish scales display arrays of thousands of colored living
cells known as chromatophores. In this study, the
use of color changes in isolated lish scales was evaluated
as a rapid warning signal for delayed neurotoxic agents.
The focus was on detecting delayed effects of organophosphate
nerve agents like sarin, though the less toxic diisopropylfluorophosphate
(DFP) was used as a sirnulant. DFP
caused rapid and long-lasting scale color changes. These
signals were readily visible and quantifiable, especially
for the brightly iridescent scale colors. DFP induced
color changes in scales at similar dose-sensitivity and
about 300 times more rapidly than in standard animal models.
Scales thus showed promise as toxicity monitors. |
NTIS/00860015
43p |
2001
-
Prevention of Organophosphorous Lethality with OPA Anhydrolase
(OPAA-2) Containing Stealth Liposomes.
Authors:
Leong-Way J
Texas
A and M Research Foundation, College Station. |
Annual rept. 15 Sep 2000-14 Sep 2001.
This research is focused on the use of various liposome-like
drug carrier systems containing recombinant organophosphorus
(OP) hydrolyzing enzymes (OPH = Organophosphorus Acid
Hydrolase; OPAA = Organophosphorus Acid Anhydrolase) to
prevent organophosphorus poisoning. The objective is to
provide long term protection against OP intoxication by
using OP-hydrolyzing enzymes with various liposome-based
enzyme carrier Systems such as sterically stabilized liposomes
(SL) and modified liposome-like carriers (NT). Present
research is focused on: studying and optimizing of the
in vitro efficacy of the OP-comlex- hydrolyzing enzymes;
optimizing the carrier systems; studying the in vivo efficacy
of the encapsulated enzymes; studying the blood cholinesterase
level in the presence of OPs, 2-PAM, and the OP-hydrolyzing
enzymes and to monitor and attempt to predict the OP toxicity
and antagonism. OPH enzyme has, highly efficient substrate
specificity to paraoxon but in general it is less efficient
to diisopropylfluorophosphate (DFP), soman and satin.
However, OPAA can hydrolyze DFP, soman and satin with
a relatively high efficiency. DFP and paraoxon were used
as model substrates to study the in vitro OP-hydrolyzing
efficiency and the in vivo antidotal efficiency of the
encapsulated OPAA and OPH. Hydrolysis of DFP was followed
by measuring the amount of the fluoride ions formed by
using a fluoride ion selective electrode, Hydrolysis of
paraoxon was determined spectrophotometrically by measuring
the p-nitrophenol formation. The paraoxon hydrolysis displayed
saturation kinetics with increasing substrate concentration
both with free OPH and encapsulated OPH. The kinetic parameters
suggest that paraoxon can freely enter and exit the enzyme
carrier systems. Preliminary toxicology studies indicate
that the encapsulated OPH and OPAA, (NT- OPH and NT-OPAA),
may strikingly enhance the antidotal effects of the clinically
proven OP antidotes, 2-PAM and atropine.
|
NTIS/03240098
272p |
2000
- Neurophysiologic and Neuropathologic Effects in Monkeys
of Low Level Exposures to Sarin, Pryidostigmine, Pesticides,
and Botulinum Toxoid.
Authors:
Olson CT, Podell M, Sahenk Z, Lordo R, Kinney P
Battelle
Memorial Inst., Columbus, OH. |
Final rept. 30 Sep 1997-30 Jun 2000.
Of approximately 700,000 U.S. military personnel serving
in the Persian Gulf region during Operations Desert Storm/Shield,
about 30,000 have had a range of unexplained complaints
including chronic fatigue, muscle and joint pain, loss
of concentration, forgetfulness, headaches, and rashes.%'%
In response to concerns about health effects resulting
from service in the Persian Gulf area and to investigate
the nature of illnesses reported by veterans, the Department
of Defense initiated the Comprehensive Clinical Evaluation
Program (CCEP) for Persian Gulf War veterans. Clinical
examinations have been performed on more than 10,000 individuals.
The major categories of primary diagnoses were psychological,
musculoskeletal, and nonspecific conditions.%1% The question
arises whether these nonspecific symptoms were due to
service in the Persian Gulf War or are comparable to the
number and type of symptoms expected in a population with
similar demographics that did not serve in the Persian
Gulf War.
Among
the keywords:
Dip(Diisopropylfluorophosphate) |
| NTIS/ADA363604 |
1998
- Chronic Organophosphorus Exposure and Cognition.
Authors:
Buccafusco JJ
Medical
Coll. of Georgia, Augusta. |
Chronic,
low-level exposure to acetylcholinesterase (AChE) inhibitor
organophosphorus (OP) insecticides or chemical warfare
agents produces abnormalities in the function of brain
acetylcholine (ACh) neurons, and in humans they may be
associated with impaired cognitive function well after
withdrawal from such exposure. The purpose of the present
study was to identify the severity of cognitive impairment
of rats and monkeys following protracted withdrawal from
chronic, Low-level exposure to the OP agent diisopropylfluorophosphate
(DFP). Assessment of spatial learning (water maze task)
in rats began 1 - 17 days after completion of either a
14 day once daily DFP (50,250, or 500 microngram/kg) or
vehicle treatment regimen. During the 14 day regimen,
prior to withdrawal, spontaneous activity and olfactory
behaviors were initially suppressed during DFP exposure,
effects to which the subjects became tolerant after receiving
the 'standard' (250 microngram/kg dose) regimen. Performance
of the spatial memo [abstract truncated] |
| NTIS/AD-A332-510/7 |
1996
- Chronic Organophosphorus Exposure and Cognition.
Authors:
Buccofusco JJ
Medical
Coll. of Georgia, Augusta. Research Inst. |
Chronic,
low-level exposure to acetyleholinesterase (AChE) inhibitor
organophosphate (OP) insecticides or chemical warfare
agents produces abnormalities in CNS acetyicholine (ACh)
function, and in humans, may be associated with impaired
cognitive function well after withdrawal from such exposure.
The purpose of the present study was to identify the severity
of inipairment in spatial learning of rats and monkeys
following protracted withdrawal from chronic, low-level
exposure to the OP agent diisopropylfluorophosphate (DFP).
Annual rept 15 Apr 95-14 Mar 96. |
NTIS/PB95-148979
13p |
1994
- Repeated Inhibition of Cholinesterase by Chlorpyrifos
in Rats: Behavioral, Neurochemical and Pharmacological
Indices of Tolerance.
Authors:
Bushnell PJ, Kelly KL, Ward TR
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div.
ManTech
Environmental Technology, Inc., Research Triangle Park,
NC.
|
Daily
subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate
caused prolonged inhibition of cholinesterase (ChE) activity
in whole blood and brain and downregulation of muscarinic
receptors in the central nervous system; these changes were
accompanied by progressive, persistent deterioration of
working memory and motor function. Further, a single
s.c. injection of the organophosphate insecticide chlorpyrifos
(O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate,
CPF), caused neurochemical changes of the same magnitude
and duration, but transient impairment of working memory
and motor slowing. In the present study, weekly injections
of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity
in whole blood of rats by 60% to 90% after 5 weeks; the
highest dose also induced tremor, working memory impairment
and motor slowing in daily delayed matching-to-position/visual
discrimination tests. Reducing the CPF injection frequency
to every other week relieved the inhibiti [abstract truncated] |
NTIS/AD-A290
426/6
17p |
1994
- Genetic and Biochemical Manipulation of a Broad-Spectrum
Organophosphate Degrading System.
Authors:
Wild JR
Texas
A and M Research Foundation, College Station.
|
Recent
studies on the plasmid-borne organophosphorus-degrading
gene of Pseudomonas diminuta and its enzyme have sought
to define both the genetic organization and the protein
chemistry involved in this system. The bacterial gene encodes
a single, unique enzyme, a phosphotriesterase (organophosphorus
anhydrase), which is capable of hydrolyzing a wide spectrum
of organophosphorus neurotoxins ranging from insecticides
such a parathion, orthene, coumaphos and diazinon to mammalian
neurotoxins such as diisopropylfluorophosphate (DFP), sarin,
soman and mipafox. The organophosphorus degrading genes
(opd) from two different plasmids in the soil bacteria P.
diminuta and Flavobacterium have been sequenced andtheir
structural organizations are being characterized. The cloned
geneshave been expressed in a number of biological systems
from bacteria to insect tissue culture, and the enzyme has
been purified and characterized from several different sources.
The catalytic reaction has been determined to involve [abstract
truncated] |
NTIS/AD-A290
571/9
Pub.
in Applied Microbiology and Biotechnology, v41 p352-358,
1994., 8p |
1994
- Expression of Organophosphate Hydrolase in the Filamentous
Fungus Gilociadium Virens.
Authors:
Dave KI, Lauriano C, Xu B, Wild JR, Kenerley CM
Texas
A and M Univ., College Station. Dept. of Biochemistry
and Biophysics.
|
The
broad-spectrum organophosphate hydrolase (OPH; EC 3.1.8.1)
encoded by the organophosphate-degrading gene (opd) from
Pseudomonas diminuta MG and Flavobacterium sp. ATCC 27551
possesses capabilities of both P-O bond hydrolysis (e.g.
paraoxon) and P-F bond hydrolysis E.G. SARIN AND DIISOPROPYLFLUOROPHOSPHATE
(DFP). In the present study a 9.4-kb plasmid, pCL1, was
used to transform the saprophytic fungus Gliocladium virens.
pCL1 was derived from pJS294 by placing the fungal promoter
(prom1) from Cochliobolus heterostrophus upstream and the
trpC terminator from Aspergillus nidulans downstream of
the opd gene. Southern analysis of restricted genomic DNA
from various transformants indicated that integration occurred
non-specifically at multiple sites. Western blot analysis
of mycelial extracts from transformants confirmed the production
of a processed form of the enzyme in the fungus. Maximal
levels of OPH activity (rate of p-nitrophenol production
from paraoxon) were observed after 168 h of cultur [abstract
truncated] |
NTIS/PB95-148045
10p |
1994
- 24-Hour Control of Body Temperature in the Rat. 2. Diisopropyl
Fluorophosphate-Induced Hypothermia and Hyperthermia.
Authors:
Gordon CJ
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div.
|
Diisopropyl
fluorophosphate (DFP) and other anticholinesterase (antiChE)
agents have been found to induce marked hypothermic responses
in laboratory rodents. To characterize the effects of DFP
on autonomic and behavioral thermoregulation, rats of the
Long-Evans strain were injected with DFP while housed in
a temperature gradient. The gradient allowed for the measurement
of selected ambient temperature T(sub a) and motor activity
(MA) over a 6- to 7-day period. Core temperature T(sub c)
and heart rate (HR) were also monitored simultaneously using
radiotelemetry. Injection of the peanut oil vehicle led
to transient elevations in T(sub c), HR, and MA, but no
change in selected T(sub a). The next day animals were injected
with 0.25, 1.0, or 1.5 mg/kg DFP. DFP (1.0 and 1.5 mg/kg)
led to a marked reduction in T(sub c). The decrease in T(sub
c) was accompanied by reductions in HR, MA, and selected
T(sub a). During the first night after DFP, selected T(sub
a) remained elevated as T(sub c) recovered to i [abstract
truncated] |
NTIS/PB93-229003
8p |
1993
-
Effect of Repeated Organophosphate Administration on Carbachol-Stimulated
Phosphoinositide Hydrolysis in the Rat Brain.
Authors:
Mundy WR, Ward TR, Dulchinos VF, Tilson HA
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div. |
The
effects of repeated exposure to two organophosphates on
the turnover of phosphoinositides, the second messenger
system coupled to the M1 and M3 subtypes of muscarinic
receptors, were examined in the
rat hippocampus. Repeated diisopropylfluorophosphate (DFP)
exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase
activity and muscarinic receptor density. The incorporation
of (3H)myoinositol into brain slices was also decreased.
Phosphoinositide turnover was measured as the accumulation
of (3H)inositol phosphates (IP) in the presence of lithium.
DFP did not affect basal IP accumulation, but decreased
carbachol-stimulated IP accumulation in the hippocampus
after 0.4 and 0.8 mg/kg. The effects of repeated
disulfoton administration (2.0 mg/kg, IP) were also examined
in the hippocampus. Similar to DFP, repeated disulfoton
exposure decreased acetylcholinesterase activity, receptor
density, and carbachol-stimulated IP accumulation. The
incorporation of myoinositol, however, was increased i
[abstract truncated] |
NTIS/AD-A279-000/4
7p |
1993
- Monoclonal Antibody AE-2 Modulates Carbamate and Organophosphate
Inhibition of Fetal Bovine Serum Acetylcholinesterase.
Authors:
Wolfe AD, Chiang PK, Doctor BP, Fryar N, Rhee JP
Walter
Reed Army Inst. of Research, Washington, DC. Div. of Biochemistry. |
The
monoclonal antibody AE-2 raised against the human erythrocyte
acetylcholinesterase (AChE) dimer (acetylcholine acetylhydrolase,
EC 3.1.1.7), binds to other mammalian AChEs, including
the tetramer that occurs in fetal bovine serum (FBS).
AE2 partially inhibited the rate of hydrolysis of the
charged substrate acetylthiocholine by FBS AChE, whereas
it increased the rate of hydrolysis of the neutral substrate
indophenyl acetate. Present results show that AE-2 decreases
the rate of inhibition of FBS AChE by the positively charged
organophosphate amition-p-toluene sulfonate and the positively
charged carbamates pyridostigmine and neostigmine but
accelerate inhibition of FBS AChE by neutral organophosphates
paraoxon and diisopropylfluorophosphate. Results suggest
that AE-2 may allosterically modulate an anionic site
in the catalytic center of FBS AChE.
|
NTIS/AD-A275
433/1
Pub.
in Biochemistry, v32 n49 p13441-13450, 1993., 11p |
1993
- Direct Observation and Elucidation of the Structures
of Aged and Nonaged Phosphorylated Cholinesterases by
31P NMR Spectroscopy.
Authors:
Segall Y, Waysbort D, Barak D, Ariel N, Doctor BP
Walter
Reed Army Inst. of Research, Washington, DC. |
31P
NMR spectroscopy of butyrylcholinesterase (BChE), acetylcholinesterase
(AChE), and chymotrypsin (Cht) inhibited by pinacolyl
methylphosphonofluoridate (soman), methylphosphonodifluoridate
(MPDF), and diisopropyl phosphorofluoridate (DFP) allowed
direct observation of the OP-linked moiety of aged (nonreactivatable)and
nonaged organophosphorus(OP)-ChE conjugates. The 31P NMR
chemical shifts of OP-ChE conjugates clearly demonstrated
insertion of a P-0 bond into the active site of aged OP-ChE
adducts. The OP moiety of nonaged OP-ChEs was shown to
be uncharged. The OP-bound pinacolyl moiety of soman-inhibited
and aged AChE was detached completely, whereas only partial
dealkylation of the pinacolyl group was observed for soman-inhibited
BChEs. This suggests that the latter enzyme reacted with
the less active stereoisomer(s) of soman. In the case
of soman-inhibited Cht, no dealkylation could be experimentally
detected for any of the four stereoisomers of OP-Cht adducts.
Results are consistent with [abstract truncated]
|
NTIS/AD-P008
828/6
10p |
1993
- Effects of Soman on Visual Processing.
Authors:
Townsend AT, Clarke T, Evans G, Pope C, Tomberlin J
Army
Aeromedical Research Lab., Fort Rucker, AL. |
We
have demonstrated previously that diisopropylfluorophosphate
(DFP) causes a preferential loss of low spatial frequency
information in the visual evoked response (VER) of the
adult cat. The effect is dose related, can be reversed
with atropine, is closely related to acetylcholinesterase
(AChE) activity, and shows spontaneous recovery to baseline
conditions over 15-20 hours without recovery of AChE activity.
After DFP, dopamine (DA) turnover increases and there
are consistent changes in gamma-aminobutyric acid (GABA),
and muscarinic, DA, and GABA receptors in visual cortex.
The experiments described here were designed to investigate
the effect of soman on visual processing in the adult
cat. The VER was used as our response measure, and all
drugs were given i.v. Following soman (1-5 ug/kg), there
is a preferential loss to low spatial frequencies in the
VER. The loss is dose related, can be reversed with atropine,
seems closely linked to AChE activity, but shows no tendency
for spontaneous recove [abstract truncated] |
NTIS/AD-P008
811/2
9p |
1993
- Modulation of Acetylcholinesterase by Monoclonal Antibody
AE-2.
Authors:
Wolfe AD, Chiang PK, Doctor BP, Rhee JP, Saeed M
Walter
Reed Army Inst. of Research, Washington, DC. |
The
monoclonal antibody AE-2 was raised against the human
erythrocyte dimer acetylcholinesterase (AChE; acetylcholine
acetyl-hydrolase, EC 3.1.1.7), but bound to other mammalian
AChEs, including the tetramer which occurs in fetal bovine
serum (FBS). AE-2 partially inhibited the rate of hydrolysis
of the charged substrate acetylthiocholine (ATC) by FBS
AChE, while it increased the rate of hydrolysis of the
neutral substrate, indophenyl acetate (IPA). Present results
show AE-2 to decrease the rate of inhibition of FBS AChE
by the positively charged organophosphate (OP), amiton-p-toluene
sulfonate, and the positively charged carbamates (CB)
pyridostigmine and neostigmine, but, consistent with its
effects upon ATC and IPA, to accelerate inhibition of
FBS AChE by the neutral OPs, paraoxon and diisopropylfluorophosphate
(DFP). Results suggest that AE-2 may allosterically modulate
an anionic site facilitating access to the catalytic center
of FBS AChE. This article is from 'Proceedings of the
Medical [abstract truncated]
Keywords:
Acetylcholinesterase
Monoclonal antibodies |
NTIS/PB94-137130
13p |
1993
- Behavioral and Neurochemical Effects of Acute Chlorpyrifos
in Rats: Tolerance to Prolonged Inhibition of Cholinesterase.
Authors:
Bushnell PJ, Pope CN, Padilla S
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div.
Northeast
Louisiana Univ., Monroe. School of Pharmacy. |
To
determine whether these functional effects of diisopropylfluorophosphate
(DFP) resulted from inhibition of cholinesterase (ChE)
and downregulation of muscarinic cholinergic receptors,
rats were dosed with chlorpyrifos (CPF), an OP pesticide
which inhibits blood and brain ChE of rats for weeks after
a single injection. Long-Evans rats were trained to perform
an appetitive test of memory and motor function and were
then injected s.c. with 0, 60, 125 or 250 mg/kg of CPF
in peanut oil and tested 5 days/week for 7 weeks. Unconditioned
behavior was also rated for signs of cholinergic toxicity.
CPF inhibited ChE activity in whole blood in a dose-related
manner for more than 53 days. The degree and time course
of ChE inhibition in blood and brain and the downregulation
of muscarinic receptors in brain after 125 mg/kg of CPF
closely paralleled the previously reported effects of
25 daily injections of 0.2 mg/kg of DFP. In addition,
CPF-treated rats were subsensitive to oxotremorine-induced
hypothermia [abstract truncated] |
NTIS/PB93-228971
14p |
1993
-
Acute and Delayed Effects of Diisopropyl Fluorophosphate
on Body Temperature, Heart Rate and Motor Activity in
the Awake, Unrestrained Rat.
Authors:
Gordon CJ
Health Effects Research Lab., Research Triangle Park,
NC. Neurotoxicology Div. |
Acute
exposure to diisopropyl fluorophosphate (DFP) causes irreversible
inhibition of acetylcholinesterase activity, leading to
various behavioral and autonomic sequelae including hypothermia,
reduced motor activity, and other neurological dysfunctions.
To
characterize the acute response and recovery of autonomic
and behavioral processes to DFP exposure, rats of the Long-Evans
strain were implanted with radiotransmitters that allowed
the monitoring of core temperature, heart rate, and motor
activity in unrestrained animals 24 h/d. These parameters
were monitored for 96 h following subcutaneous injection
of DFP at a dose of 0, 0.1, or 1.0 mg/kg. Rats given 0 and
0.1 mg/kg DFP displayed an increase in core temperature
and motor activity during the first 24 h postinjection.
Core temperature decreased a maximum of 1.9 C by 5 h after
DFP and then started to recover, reaching control levels
by 17 h after DFP treatment. Motor activity was also depressed
during the first 24-h period in the 1.0 mg/kg gro [absract
truncated] |
NTIS/PB93-228609
15p |
1993
- Strain Comparisons of DFP Neurotoxicity in Rats.
Authors:
Gordon CJ, MacPhail RC
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div.
|
The
purpose of the study was to assess intraspecies differences
in behavioral and autonomic function in three strains of
rat following administration of diisopropyl fluorophosphate
(DFP), an irreversible inhibitor of acetylcholinesterase
activity. Male rats of the Long-Evans (LE), Fischer 344
(F344), and Sprague-Dawley (SD) strains were administered
DFP at doses of 0 to 1.5 mg/kg (s.c.). The animals were
placed 60 min later into one of two motor activity chambers
and tested for 30 min. Motor activity was measured using
either a Doppler-based system or a commercial photocell
device. Following measurement of motor activity in the Doppler
system, body temperature was measured and blood was then
withdrawn by cardiac puncture and analyzed for serum cholinesterase
activity. The remaining rats were retested 24 hr after DFP
administration in the photocell device. The
results showed a significant influence of strain on the
effects of DFP. Motor activity of LE rats was reduced
by DFP at doses of 1.0 and 1 [abstract truncated] |
NTIS/AD-A257 540/5
17p |
1992
- Cholinesterase Assay for Monitoring the Kinetics of
the JD6.5 Organophosphorus Acid Anhydrase in Detoxification
of Diisopropylfluorophosphate.
Authors:
Yeh HR, Cheng TC, DeFrank JJ
Chemical
Research, Development and Engineering Center, Aberdeen
Proving Ground, MD. |
In
the present studies, cholinesterase was used for monitoring
the enzymatic activities of the JD6.5 organophosphorus
acid anhydrase. The kinetic data indicated that: (1) the
first order of kinetic constants (k) and Vmax values of
the enzymatic reactions increased as the concentrations
of the enzyme increased; (2) while the half-life (tl/2)
of diisopropylfluorophosphate (DFP) hydrolysis decreased
as the enzyme concentrations increased; (3) the minimum
time required for hydrolysis of 9mM of DFP was 3 min at
the concentrations of the enzyme present; Km values of
DFP were found to be in range of 5mM; and (4) both MnCl2
and NaCl were found to be required for the optimal activity
of the enzyme. Final rept. Jan-Jun 88. |
NTIS/AD-A244
435/4
17p |
1991
- Effect of Diisopropylfluorophosphate on Muscarinic and
Gamma-Aminobutyric Acid Receptors in Visual Cortex of
Cats.
Authors:
Townsend AT, Adams DK, Lopez JB, Kirby AW
Army
Aeromedical Research Lab., Fort Rucker, AL. |
Administration
of diisopropylfluorophosphate (DFP), an organophosphorus
(OP) compound, irreversibly inhibits
acetylcholinesterase (AChE) and results in cholinergic hyperactivity.
This study investigated muscarinic and gamma aminobutyric
acid (GABA) receptor changes in visual cortex of cats following
an acute exposure to DFP. A single acute administration
of DFP (4 mg/kg) decreased the number of muscarinic receptors
at 2, 10, and 20 hours after treatment. GABA receptors were
elevated at 2 and 10 hours but returned to within control
levels at 20 hours. No significant alteration in muscarinic
or GABA receptor affinity was noted. In all cases cortical
AChE activity was inhibited 60-90%. These findings show
a down regulation of muscarinic receptors after DFP associated
with low AChE activity. GABA receptors also are altered,
and may be part of a compensatory mechanism to counteract
excess cholinergic stimulation. Final rept.
Keywords:
Acetylcholinesterase
Visual cortex
Diisopropylfluorophosphate
GABA receptors
Muscarinic receptors |
NTIS/PB91-200238
11p
|
1991
-
Behavioral and Neurochemical Changes in Rats Dosed Repeatedly
with Diisopropylfluorophosphate.
Authors:
Bushnell PJ, Padilla SS, Ward T, Pope CN, Olszyk VB
Health
Effects Research Lab., Research Triangle Park, NC. Neurotoxicology
Div.
Northeast
Louisiana Univ., Monroe. School of Pharmacy.
Northrop
Services, Inc., Research Triangle Park, NC. |
Behavioral
effects of organophosphates (OPs) typically decrease with
repeated exposure, despite persistence of OP-induced inhibition
of acetylcholinesterase (AChE) and downregulation of muscarinic
acetylcholine (ACh) receptors. To characterize this tolerance
phenomenon, rats were trained to perform an appetitive
operant task which allowed daily quantification of working
memory (delayed matching-to-position), reference memory
(visual discrimination) and motor function (choice response
latencies and inter-response times (IRTs) during delay).
Findings indicate that animals showing a definitive sign
of tolerance to OP administration (subsensitivity to a
cholinergic agonist) were also functionally
impaired on both the motoric and mnemonic demands of a
working memory task. The nature of this impairment
suggests further that it results from compensatory changes
in the CNS, e.g., muscarinic receptor downregulation,
considered to produce 'tolerance' to OPs in exposed animals.
Journal article. Pub. in J [abstract truncated] |
NTIS/PB92-124668
17p |
1991
- Acute Effects of Diisopropyl Fluorophosphate (DFP) on
Autonomic and Behavioral Thermoregulatory Responses in
the Long-Evans Rat.
Authors:
Gordon CJ, Fogelson L, Lee L, Highfill J
Health
Effects Research Lab., Research Triangle Park, NC.
|
Experiments
were designed to assess the mechanisms of diisopropyl fluorophosphate
(DFP)-induced changes in thermoregulation of the rat. In
one study, male rats of the Long-Evans strain were injected
with DFP (s.c.) at doses ranging from 0 to 2.0 mg/kg while
maintained at an ambient temperature (Ta) of 20-24C. Body
(Tb) and tail skin (Tt) temperatures were recorded for 5
h post-injection. DFP doses of > or = 1.0 mg/kg resulted
in significant decreases in Tb lasting up to 5 h and increases
in Tt lasting up to 1 h post-injection. In a second study,
metabolic rate (MR), evaporative water loss (EWL), motor
activity (MA), Tb, and Tt, were measured at 2 h post-injection
of 0, 0.5, 1.0, and 1.5 mg/kg DFP (s.c.) at Ta values of
10, 20, and 30 C. DFP treatment resulted in hypothermia
at all three Ta values, but the effect was attenuated at
30 C. MR was significantly reduced at a Ta of 20 C following
1.5 mg/kg, unaffected by DFP at a Ta of 30 C, and stimulated
at 10 C following 0.5 mg/kg DFP. EWL was si [abstract truncated] |
NTIS/AD-A239
635/6
56p |
1991
- Nicotinic Cholinergic Receptors in Rat Brain.
Authors:
Kellar KJ
Georgetown
Univ., Washington, DC. School of Medicine. |
Nicotinic
cholinergic receptors in rat brain were studied to determine
their dependence on intact disulfide bonds, their relationship
to catecholamine and serotonin axons, and their regulation
by cholinesterase inhibitors and nicotinic agonists. Reduction
of disulfide bonds with dithiothreitol decreased the number
of nicotinic binding sites labeled by (3H)acetylcholine
(3 HAC). This effect was reversed by reoxidation of the
reduced sulfhydryl groups to disulfide bonds. Lesioning
catecholamine or serotonin axons with specific neurotoxins
resulted in a decrease in the number of nicotinic receptor
binding sites in the striatum and hypothalamus, indicating
that in those brain areas the receptors are located on these
axons. The number of nicotinic receptors
is decreased by chronic inhibition of cholinesterase enzymes
with diisopropylfluorophosphate or soman. In contrast,
the receptor number is increased by chronic treatment with
nicotine. Final rept. 1 May 83-31 Oct 86. |
NTIS/PB92-158658
10p |
1991
- Relationship between Cholinesterase Inhibition and Thermoregulation
Following Exposure to Diisopropyl Fluorophosphate in the
Rat.
Authors:
Gordon CJ, Fogelson L, Richards J, Highfill J
Health
Effects Research Lab., Research Triangle Park, NC.
NSI
Technology Services Corp., Research Triangle Park, NC.
|
The
study examined the relationship between inhibition of cholinesterase
activity (CA) and thermoregulatory response in the rat following
exposure to the organophosphate (OP), diisopropyl fluorophosphate
(DFP). Male Long-Evans rats were injected with DFP dissolved
in peanut oil in doses ranging from 0 to 1.5 mg/kg (s.c.).
Colonic T(sub col) and tail skin temperature T(sub tail)
were recorded at 0, 1, 2, and 3 hr post-injection. At 3
hr post-injection the rat was sacrificed and a blood sample
was taken by cardiac puncture and analyzed for CA. There
was a biphasic dose effect of DFP on T(sub col) with slight
but significant elevation in T(sub col) in the dose range
of 0.01 to 0.5 mg/kg and a significant depression in T(sub
col) at doses of 1.0 and 1.5 mg/kg. There
was a dose-dependent fall in CA with DFP administration
in the erythrocyte, plasma, and whole blood fractions.
Hypothermia was associated with 80 to 87% inhibition in
CA, whereas the elevation in T(sub col) was associated with
20 to 70% [abstract truncated] |
NTIS/PB91-217893
24p |
1991
- Mechanism of Spontaneous Recovery of Neuromuscular Transmission
after Acetylcholinesterase Inhibition in the Rat Neuromuscular
Junction (Onderzoek naar het Herstelmechanisme van Neuromusculaire
Transmisna Acetylcholinesterase Remming).
Authors:
Melchers BPC, van der Laaken AL
Medical
Biological Lab. RVO-TNO, Rijswijk (Netherlands).
|
Neuromuscular
transmission shows a significant degree of spontaneous recovery
after being impeded by acetylcholinesterase inhibition.
Part of the recovery can be ascribed to de novo synthesis
of acetylcholinesterase but another part is independent
of enzyme activity. To unravel the mechanism underlying
the synaptic adaptation to acetylcholinesterase inhibition
a study compared a number of electrophysiological parameters
in diaphragms taken from animals that were sacrificed within
15 minutes after a 2xLD50 dose of the acetylcholinesterase
inhibitor diisopropylfluorophosphate and from similarly
treated animals killed after being kept alive for 3h under
artificial respiration. The study found no differences in
the quantal content. There was a significantly smaller degree
of endplate potential rundown at tetanic stimulation and
the mepp amplitude was smaller in the 3h adapted animals.
In addition, the desensitization induced by carbachol appeared
to be less in the group. It is concluded that postsyn [abstract
truncated] |
NTIS/DE92004442
8p |
1991
- Supercritical fluid extraction and organic solvent microextraction
of chemical agent simulants from soil.
Authors:
Griest WH, Ramsey RS, Ho C, Caldwell WM
Oak
Ridge National Lab., TN.
Sponsored
by Department of Energy, Washington, DC.
|
Experiments
with chemical warfare agent simulants suggest that supercritical
fluid extraction can achieve good extraction recoveries
of agents in soil and produce less laboratory waste than
current organic solvent extraction methods. Two-ppm spikes
in 1 g of Rocky Mountain Arsenal Standard Soil were extracted
using 5% methanol in carbon dioxide at 300 atm for 2 min
at 60(degrees)C. Recoveries (n=3) were 79(plus minus)23%
for dimethylmethylphosphonate, 93(plus minus)14% for 2-chlorethylethylsulfide,
92(plus minus)13% for diisopropylfluorophosphate, and 95(plus
minus)17% for diisopropylmethylphosphonate. A 5 min ultrasonic
micro-scale extraction using methanol is more reproducible
but less efficient. 1991 U.S. Army chemical research conference
on chemical defense, Aberdeen Proving Ground, MD (United
States), 19-22 Nov 1991. |
NTIS/AD-A236
870/2
43p |
1990
- Central Neuronal Mechanisms Involved in the Cardiorespiratory
Effects of Organophosphorous Agents.
Authors:
Gillis R, Dretchen KL
Georgetown
Univ., Washington, DC. |
The
organophosphorous anticholinesterase agents diisopropylfluorophosphate
(DFP) and soman were applied topically, by way of cotton
pledgets placed bilaterally to three different chemosensitive
areas of the ventral medulla of the cat, and the effects
on cardiorespiratory activity were monitored. The dose range
was 6.25-25.0 microgram/side DFP and 0.004-0.5 micrograms/side
soman. Comparison of dose-response data upon application
to the three areas indicated that both agents exerted their
greatest effect at the intermediate area. Oxotremorine,
a specific agonist for muscarinic receptors, also had a
much greater effect on cardiorespiratory activity when applied
to the intermediate area as compared to its effects after
application to either the caudal or the rostral areas. Further
evidence indicating the role of a muscarinic receptor in
mediating the respiratory depressant effects of DFP and
soman at the intermediate area was the finding that atropine
counteracted the toxic effects of these compound [abstract
truncated] |
NTIS/AD-A228
521/1
9p
Pub.
in Chirality and Biological Activity, p169-175 1990. |
1990
- Catalytic Properties of Nonstereospecific Diisopropylfluorophosphatases.
Authors:
Lenz DE, Little JS, Broomfield CA, Ray R
Army
Medical Research Inst. of Chemical Defense, Aberdeen Proving
Ground, MD.
|
Enzymes
that catalyze the hydrolysis of organophosphorus compounds
(Mazur, 1946) have been classified as diisopropylfluorophosphatases
(DFPase, EC 3.8.2.1). These enzymes often vary in their
substrate selectivities depending on their source. Some,
isolated from cephalopods, show a preference for diisopropylfluorophosphate
(DFP) as the substrate (Hoskin, 1971; Garden et al., 1975),
whereas those from mammalian sources tend to hydrolyze other
organophosphorus esters such as tabun (GA), soman (GD),
or sarin (GB) (Augustinsson and Heimburger, 1954; Mounter,
1963; Hoskin, 1971; Hoskin and Long, 1972; Gay and Hoskin,
1979) in preference to DFP. Tabun, sarin, and soman each
has a center of asymmetry at the phosphorus atom giving
rise to stereoisomers. (js) |
NTIS/AD-A218
409/1
14p |
1989
-
Actions of Organophosphates on the Mammalian Spinal Cord.
Authors:
Warnick JE
Maryland
Univ. at Baltimore. Dept. of Pharmacology and Experimental
Therapeutics.
|
The
characteristics of monosynaptic transmission in the isolated
spinal cord of the neonatal rat were established to determine
optimal temperature and analysis. It was determined that
25 C was suitable and that the area of the reflex was the
best measure of motoneuron activity. The action of diisopropylfluorophosphate
(DFP) was examined on monosynaptic transmission in the spinal
cord of the neonatal rat, in vitro. DFP
caused a dose-dependent depression of the monosynaptic reflex
which could be prevented or reversed by atropine.
Initial experiments suggest that the depression is independent
of acetylcholinesterase inhibition. Diazepam was examined
in pilot experiments and found to be ineffective in preventing
DFP-induced depression. It also appeared that diazepam was
only moderately effective in reversing such depression.
On the other hand, the tripeptide thyrotropin-releasing
hormone effectively and completely reversed the depression
caused by DFP. Frequency-dependent depression of the monosynap
[abstract truncated] |
NTIS/AD-A215
077/9
24p |
1989
- Cellular Actions and Interactions of Anticholinesterases
and Their Antidotes in Mammalian Autonomic Neurons.
Authors:
Dun NJ
Stritch
School of Medicine, Maywood, IL. |
The
effects of organophosphorus anti-cholinesterase (anti-ChE)
agents, soman, tabun, diisopropylfluorophosphate (DFP) and
non-organophosphorus anti-ChE agents, eserine and neostigmine
on sympathetic neurons and on ganglionic transmission were
investigated. Intracellular recordings were obtained from
sympathetic neurons of isolated rabbit and guinea pig superior
cervical ganglia by means of glass microelectrodes. DFP,
soman and eserine increased and blocked nicotinic cholinergic
transmission at low and high concentrations, respectively.
These agents at lower concentrations, i.e. 1 micro M or
lower, facilitated nicotinic transmission by inhibiting
ganglionic cholinesterases. Whereas, these agents at higher
concentrations, i.e. 1 or 10 micro M appeared to block nicotinic
transmission by different mechanisms. The effects
of pyridinealdoxine (2-PAM), a cholinesterase reactivator,
on sympathetic neurons and on ganglionic transmission were
also studied and found to be concentration-dependent as
well. T [abstract truncated] |
NTIS/AD-A213
677/8
8p |
1989
- Biochemical Characterization and Protein Crystallography
of OPA Anhydrase.
Authors:
Ward KB, Deschamps JR, Zuk WM
Naval
Research Lab., Washington, DC.
|
Squid,
Loligo pealii, hepatopancreas organophosphorous acid anhydrase
(OPAase) hydrolyzes and detoxifies nerve agents, such as
diisopropylfluorophosphate (DPF) and Soman. Refinements
in the purification of OPAase produce an enzyme with a specific
activity greater that 300 U/mg, and yield of about 1 mg
purified enzyme from a typical purification. Based on results
obtained from atomic absorption spectroscopy, only zinc
is present in the native active enzyme. Only zinc can completely
reactivate the metal free enzyme. The relationship between
pH and enzyme activity led to the hypothesis that cysteine
may be involved in enzyme activity, however attempts to
modify cysteine residues had no effect on enzyme activity.
Preliminary results from this study suggest that tyrosine
or histidine may be the active site residue. The sequence
of the first 15 N-terminal residues has been determined.
Experiments to produce polyclonal antibodies against squid
OPAase have shown signs of success. The robotics system
we [abstract truncated] |
NTIS/AD-A212
968/2
50p |
1989
- Effect of Organophosphorus Compounds on the Conformation
of Acetylcholinesterase and Acetylcholine Receptor: Tacrine
Protection of Acetylcholinesterase from Inactivation by
Diisopropylfluorophosphate and Interaction of Acetylcholinesterase
and Acetylcholine Receptor with Soman and Tabun.
Authors:
Yang JT, Wu CSC, Sun X
California
Univ., San Francisco. |
Tacrine
showed an apparent noncompetitive inhibition of actylcholinesterase
(AChE) from Torpedo californica with a dissociation constant,
K1, of 8.5 nM. It altered the CD bands of AChE in the near-UV
region, which monitor the local conformation of aromatic
side groups, but not those in the far-UV region, which measure
the secondary structure. With this band as a probe, the
bound tacrine could be displaced by edrophonium or decamethonium,
both of which are known to bind to the anionic site at the
active center of AChE, but not by propidium, which binds
to the peripheral site of the enzyme. The inactivation of
AChE by potent, irreversible inhibitors such as soman and
tabun could be slowed down by adding reversible inhibitors
such as tacrine and hexamethonium bromide. Acetylcholine
receptor (AChR) seemed to bind soman, which, however, did
not alter the conformation of the AChR (based on far- and
near-UV CD spectrum). The addition of acetylcholine induced
a local conformational change of AChR; this [abstract truncated] |
NTIS/AD-A208
405/1
37p |
1989
- Effect of Organophosphates on Cholinergic and Other
Neurotransmitter Dynamics in Brain.
Authors:
Dewey WL, Brase DA
Medical
Coll. of Virginia, Richmond. Dept. of Pharmacology and
Toxicology.
|
The
effects of physostigmine, diisopropylfluorophosphate (DFP),
sarin, tabun, and soman on a number of neurotransmitter
and effector systems in mouse brain after iv administration
were studied, in addition to effects on lethality, spontaneous
activity, and body temperature in mice. Less extensive studies
were also carried out in rats with DFP and soman and in
guinea pigs with soman. The order
of potency of the irreversible acetylcholinesterase (AChE)
inhibitors for both lethality and AChE inhibition was DFP
< tabun < sarin < soman. However, there
was not a good correlation between the LD50 values and ED50
values of AChE inhibition among these agents. Guinea pigs
were much more sensitive to soman-induced lethality than
were mice or rats, but none of the six brain areas examined
appeared to be uniquely sensitive to soman-induced AChE
inhibition. All agents decreased spontaneous activity and
body temperature in doses causing inhibition of AChE. Except
for physostigmine, the duration of ACh [abstract truncated] |
NTIS/AD-A225
636/0
101p |
1989
- Tolerance Following Organophosphate Poisoning of Tracheal
Muscle.
Authors:
Farley JM, Dwyer TM
Mississippi
Univ. Medical Center, Jackson. Dept. of Pharmacology and
Toxicology. |
The
effects of subacute exposure to the organophosphate acetylcholinesterase
diisopropylfluorophosphate (DFP) soman, sarin and (VX) were
studied on the binding properties of muscarinic receptors
of swine tracheal smooth muscle, and on the contractile
response and the electrophysiological properties of the
muscle. There is no difference between weanling and young
adult swine in the density of receptors in tracheal smooth
muscle. The nonselective muscarinic antagonists atropine,
scopolamine and quinuclidinyl benzilate (3H)QNB competitively
inhibited (3H)QNB binding to the homogenate with Hill coefficients
of 0.9-1.9 and inhibition constants (Ki) of nanomolar range.
Competition with selective antagonists pirenzepine and 3-quinuclicinyl
xanthene-9-carboxylate (QNX) gave Ki values of 0.26 Mm and
0.78 nM, respectively, and Hill coefficients of approximately
1. There was a single population of (3H)QNB binding sites
of the M3 subtype for all tested muscarinic antagonists.
Competition with the selective [abstract truncated] |
NTIS/AD-A218
732/6
49p |
1989
-
Acetylcholinesterase Inhibitors on the Spinal Cord.
Authors:
Warnick JE
Maryland
Univ., Baltimore. School of Medicine. |
This
report concerns ongoing studies on the mechanism and site
of action of organophosphate (OP) and carbamate inhibitors
of acetylcholinesterase (AChE) in the mammalian spinal cord
and the reversal of those effects by known and putative
antagonists. Spinal cords isolated from neonatal rats 5-
to 9-days old were hemisected and placed in experimental
chambers. Recordings were made from ventral roots under
varying stimulation and recording paradigms to characterize
the actions of these agents. Parallel studies on AChE were
performed to determine the role of enzyme inhibition in
the observed effects. A full dose-response curve for alteration
of synaptic transmission and AChE in the isolated rat spinal
cord by diisopropylfluorophosphate (DFP) was completed and
studies were expanded to include sarin, other organophosphates
and carbamates. The dose-response curve for sarin was extended
into the picomolar range, completed and compared with initial
results on soman, VX and tabun. In addition, the action
[abstract truncated] |
NTIS/AD-A208 214/7
9p |
1989
- Partial Characterization of an Enzyme That Hydrolyzes
Sarin, Soman, Tabun, and Diisopropyl Phosphorofluoridate
(DFP),
Authors:
Little JL, Broomfield CA, Fox-Talbot MK, Boucher LJ, MacIver
B
Army
Medical Research Inst. of Chemical Defense, Aberdeen Proving
Ground, MD. |
The
properties of a rat liver enzyme that hydrolyzes organophosphorus
(OP) inhibitors of Cholinesterases were studied. The rates
of hydrolysis of OP inhibitors were determined by continuous
titration of released hydrogen ions, using a pH stat method.
Centrifugation of homogenates at 205,000g for 30 min demonstrated
that the activity was in the soluble fraction. Hydrolysis
of sarin, soman, and diisopropyl
phosphorofluoridate (DFD), but not of tabun, was
stimulated by the addition of Mn(2+) and Mg(2+). Unlike
other OP hydrolases that preferentially hydrolyze the
non-toxic isomers of soman, this enzyme hydrolyzed all
four soman isomers at approximately the same rate. This
results was obtained in vitro by gas chromatographic analysis
of enzyme-catalyzed soman hydrolysis and confirmed in
vivo by demonstrating reduced toxicity in mice of soman
partially hydrolyzed by this enzyme. Km and Vmax were
determined by fitting V vs (S) to a hyperbolic function
using regression analysis. Elution profiles from g [abstract
truncated] |
NTIS/AD-A208
150/3
10p |
1988
- Specific Soman-Hydrolyzing Enzyme Activity in a Clonal
Neuronal Cell Culture,
Authors:
Ray R, Boucher LJ, Broomfield CA, Lenz DE
Army
Medical Research Inst. of Chemical Defense, Aberdeen Proving
Ground, MD. |
An
enzymatic activity that specifically hydrolyzes the highly
toxic organophosphorus anticholinesterase compound soman
(pinacolyl methylphosphonofluoridate) has been identified
and partially characterized in the clonal neuronal neuroblastoma-glioma
hybrid NG108-15 cell line. Using the whole cell homogenate
as the enzyme source and 1 mM substrate, the relative
rate of hydrolysis of two other toxic anticholinesterase
compounds sarin (isopropyl methylphosphonofluoridate)
and tabun (ethyl-N-dimethyl phosphoramidocyanidate) is
approximately one-tenth the rate of hydrolysis of soman,
while DFP (diisopropyl phosphorofluoridate), paraoxon
(p-nitrophenyl diethylphosphate), and a phosphinate PNMPP
(p-nitrophenyl methyl (phenyl)phosphinate) are not hydrolyzed.
Analysis of the kinetics of soman hydrolysis reveals two
components of the enzyme activity with different affinities
and reaction rates. Unlike previously reported enzymes
of ths type, this enzyme lacks chiral specificity and
thus hydrolyzes both tox [abstract truncated] |
NTIS/AD-A188
368/5
10p |
1987
- Effects of Chronic Diisopropylfluorophosphate Treatment
on Spatial Learning in Mice,
Authors:
Upchurch M, Wehner JM
Colorado
Univ. at Boulder.
Supporting
Agency: Air Force Office of Scientific
Research, Bolling AFB, DC. |
The
Morris water task was used to measure the effects of chronic
diisopropylfluorophosphate (DFP) treatment on C57BL/6Ibg
mice. Control mice showed good task acquisition and searched
accurately for the platform after it was removed from
the pool, suggesting that they had formed a spatial map
of the platform's location relative to distal cues.
In contrast, mice chronically treated with DFP prior to
training showed a marked deficit in spatial learning.
Chronic DFP treatment did not affect ability to locate
a visible platform and did not impair task retention in
mice trained to find the hidden platform prior to DFP
treatment. The chronic DFP treatment
decreased muscarinic binding in cortex, hippocampus, and
striatum. These results indicate that C57BL mice
are capable of spatial learning in the water task. The
ability of chronic DFP treatment to impair place but not
cue learning suggests that the cholinergic dysfunction
produced by DFP is similar to those produced by lesions
of central cholinergic s [abstract truncated]
|
NTIS/AD-A181
921/8
9p |
1987
-
Sex Differences in the Recovery of Brain Acetylcholinesterase
Activity Following a Single Exposure to DFP (Diisopropylphosphofluoridate),
Authors:
Smolen A, Smolen TN, Han PC, Collins AC
Colorado
Univ. at Boulder. Inst. of Behavioral Genetics.
Supporting
Agency: Air Force Office of Scientific Research, Bolling
AFB, DC. |
Male
and female C57BL, DBA, and C3H mice were injected intraperitioneally
with a single 6.33 mg/kg dose of diisopropyl-phosphofluoridate
(DFP). The time course of recovery of acetylcholinesterase
(AchE) activity as well as effects on choline acetyltransferase
(ChAT) activity and brain muscarinic and nicotinic receptors
were measured. DFP treatment did not affect ChAT activity
or the muscarinic an nicotinic receptors were measured.
DFP treatment did not affect ChAT activity or the muscarinic
and nicotinic receptors. Near control levels of AChE activity
were regained in female mice within the first 20 days. However,
levels of whole brain AChE acitivity remained depressed
for as long as 40 days following a single dose of DFP in
male mice. An analysis of the recovery of AChE acitivity
in several brain regions indicated that control activity
was regained in striatrum, hindbrain, and hippocampus, but
not in cortex, midbrain, and hypothalamus. These data are
discussed in terms of potential neurotoxicit [abstract truncated] |
NTIS/AD-A221
118/3
12p |
1987
- Recovery of the Visual Evoked Response in the Cat Following
Administration of Diisopropylfluorophosphate: An Irreversible
Cholinesterase Inhibitor.
Authors:
Kirby AW, Harding TH, Wiley RW
Army
Aeromedical Research Lab., Fort Rucker, AL. |
Visual
evoked responses (VER) to counterphased gratings were
recorded from area 17 of cat visual cortex prior to and
following administration of diisopropylfluorophosphate
(DFP). The VER and acetylcholinesterase (AChe) activity
of blood, retina, and visual cortex were reduced significantly
following DFP administration. Approximately 2 hours after
exposure to 4 mg/kg DFP, the VER began to recover and
in some cats returned to base line levels. In contrast,
blood, retina, and cortex AChe activity showed little,
if any, tendency for recovery throughout the experiment.
Since atropine sulfate provided at least partial recovery
of the VER following DFP without affecting AChE inhibition,
an accumulation of acetylcholine (ACh) probably is involved
in the initial visual loss. However, recovery of the VER
over time while AChE remained severely inhibited implicates
mechanisms other than, or in addition to, accumulation
of ACh at receptor sites. Keywords: Toxicity. (kt) Final
rept. Pub. in Life Sciences, v [abstract truncated] |
NTIS/AD-A255
300/6
30p |
1987
- Effects of Organophosphate Nerve Agents on Visual Cortical
Function.
Authors:
Bonds AB, DeBruyn EJ
Vanderbilt
Univ., Nashville, TN. |
The
effects of intravenous administration of the anticholinesterase
agent soman (pinacolyl methylphosphonofluoridate, 5-15
ug/kg) on the visual evoked potential (VEP) were examined
in cats using phase-reversed sine wave grating stimuli
of different spatial frequencies and contrasts. Soman
doses of 5-7 u7/kg caused a depression of the VEP across
all spatial frequencies in an abrupt, non-graded fashion.
Studies in which contrast was varied showed that VEP depression
resulted primarily from a decrease in the response system
gain rather than a change in the contrast sensitivity.
Administration of a pretreatment regimen of physostigmine
(0.25 mg/kg), atropine (0.8 mg/kg) and mecamylamine (0.8
mg/kg) raised the effective soman dose level by a factor
of at least 8. The impact of iontophoretically applied
physostigmine, pyridostigmine and diisopropylfluorophosphate
(DFP) on single neurons in striate cortex was also studied.
Of 23 cells in which physostigmine was applied, 2 showed
no changes in firing ra [abstract truncated] |
NTIS/AD-A224
005/9
38p |
1987
- Effects of Organophosphate Nerve Agents on Visual Cortical
Function.
Authors:
Bonds AB, DeBruyn EJ
Vanderbilt
Univ., Nashville, TN. |
The
effects of intravenous administration of the anticholinesterase
agents physostigmine, pyridostigmine, diisopropylfluorophosphate
(DFP), and soman (pinacolyl methylphosphonofluoridate)
on the visual evoked potential (VEP) in cats were examined
using phase-reversed sine wave grating stimuli of different
spatial frequencies and contrasts. All four agents caused
a depression of the VEP across all spatial frequencies
and at low (1-8 Hz) temporal frequencies. Studies in which
contrast was varied showed that VEP depression resulted
primarily from a decrease in the response system gain
rather than a change in the contrast sensitivity. Physostigmine,
pyridostigmine, and DFP yielded response losses that were
graded with increasing dosages, while soman acted in an
abrupt, nongraded fashion with a threshold dose of 5-7
ug/kg. (jes) Final rept. 15 Jul 83-15 Jan 87. |
NTIS/PB89-106819
9p |
1987
- Triphenyl Phosphite: In vivo and In vitro Inhibition
of Rat Neurotoxic Esterase (Journal Version).
Authors:
Padilla SS, Grizzle TB, Lyerly D
Health Effects Research Lab., Research Triangle Park,
NC.
Northrop
Services, Inc., Research Triangle Park, NC. |
Organophosphorus
compounds which, after acute administration, inhibit neurotoxic
esterase (NTE) by > or = 65% and undergo a subsequent
'aging' reaction, produce a delayed neuropathy characterized
by degeneration of large and long nerve fibers. The present
studies examine in detail the NTE-inhibiting properties
of triphenyl phosphite (TPP), a plasticizer which produces
ataxia and degeneration of the spinal cord in animals.
A neurotoxic dosing regimen (1184 mg/kg/week, sc, for
2 weeks) inhibited both brain and spinal cord NTE (<
or = 40%) only marginally 4 and 48 hr postdosing. By
contrast, TPP was shown in vitro to be a potent inhibitor
of rat brain NTE relative to Mipafox or diisopropyl phosphorofluoridate.
Preincubation of 10 micromolar TPP in buffer (37
deg C) resulted in a time-dependent loss of TPP's ability
to inhibit NTE. In summary, TPP is a powerful NTE inhibitor
in vitro, but only a marginal NTE inhibitor after in vivo
administration. These results raise questions as to the
causal [abstract truncated] |
NTIS/AD-A211
259/7
32p |
1987
- Organophosphate Anticholinesterases: Their Effects on
Sleep and Vigilance in a Rodent Model.
Authors:
Meighen G, Pegram GV, Gnadt J, Atwood C, Crowson J
Alabama
Univ. in Birmingham. |
Cholinergic
mechanisms have been implicated in the control of sleep
and its various physiological parameters. These systems
were manipulated using the organophosphate acetylcholinesterase
inhibitors diisopropylfluorophosphate (DEP) and o,1,2,2-trimethyl
propyl methylphosphonofluroidate (soman). Results
of the DFP studies indicated increased rapid eye movement
(REM) sleep in rats administered chronic doses of DFP.
In the acute DFP study, the treated rats showed a dose-dependent
decrease in all stages of sleep; most likely due to DFP's
toxic effects. Results of acute administration
of soman included the disturbance of normal sleep patterns
and revealed a dose- dependent effect upon the different
stages of sleep.Keywords: Cholinesterase inhibitor; Sleep;
Toxicity; DFP; Organophosphate; RA 5%. (KT). Final rept.
15 Jan 83-14 Jan 85. |
NTIS/AD-A200
182
38p |
1987
- Studies on the Effects of Anticholinesterase Compounds
on Functions of Neuroglia.
Authors:
19HK
Albany
Medical Coll., NY. |
The
purpose of this work was to determine whether selected
anticholinesterase compounds are likely to have effects
on normal astroglial function in the mammalian center
nervous system (CNS). To do this, the authors studied
the effect of three organophosphates, diisopropyl-fluorophosphonate
(DFP), paraoxon, and parathion, and the carbamat physostigmine
on the ion transport, volume control, electrophysiological
and monoamine transmitter uptake properties of primary
astrocyte cultures. Compounds were studied at 1 micrometer
-1 mM concentrations and both acute and chronic effects
were observed. Physotigmine and parathion inhibited uptake
of tritium-labelled serotonin at 10 micrometers, but had
no effects at concentrations of 1 micrometer of less.
The effects of paration and paraoxon were irreversible
within at least 1 hour after removal of the inhibitor.
In conclusion, it seems that some acetylcholinesterase
(AChE) inhibitors have marked effects on monoamine transmitter
uptake, ion transport, and vo [abstract truncated] |
NTIS/AD-A199
157/9
38p |
1987
- Effect of Organophosphorus Compounds on the Conformation
of Acetylcholinesterase and Acetylcholine Receptor. Reconstitution
of Globular Dimer of Acetylcholinesterase and Interaction
of Acetylcholinesterase and Receptor with Diisopropylfluorophosphate.
Authors:
Yang JT, Wu CSC, Gan L, Reed WD
California
Univ., San Francisco. |
The
detergent-soluble globular dimer of acetylcholinesterase
from Torpedo californica was reconstituted through dialysis
into egg phosphatidylcholine vesicles. The size of the
reconstituted particles depended on the ionic strength
of the buffer as well as the molar lipid/protein ration
(R). The solution of the protein-lipid complex was turbid
at R = 5,000 and I = 0.13, and the particles became heterogeneous
at R < 2,000. The enzyme was unstable at R = 1,000
and I = 0.05. Based on circular dichroism studies, the
conformation of the enzyme reconstituted at R = 4,000
and I = 0.07 remained unaltered. The enzymatic activity
and the Michaelis-Menten constant were also unchanged.
The reconstituted enzyme seemed to be more stable against
thermal denaturation than in detergent solution. Acetylcholinesterase
is irreversibly inhibited by diisopropyl fluorophosphate
(DFP). The three isozymes, buffer-soluble globular
dimer, asymmetric dodecamer and its derived globular tetramer,
had essentially the same b [abstract truncated] |
NTIS/AD-A179
677/0
7p |
1986
- Strain Comparison of Physiological and Locomotor Responses
of Mice to Diisopropylfluorosphosphate,
Authors:
Smolen A, Smolen TN, Oh EI, Collins AC
Colorado
Univ. at Boulder. Inst. of Behavioral Genetics.
Supporting
Agency: Air Force Office of Scientific Research, Bolling
AFB, DC. |
The
effects of acute treatment with the organophosphate, diisopropylfluorophosphate
(DFP), were studied in three inbred mouse strains, C57BL,
DBA and C3H. A battery of physiological and locomotor tests
including respiratory rate, heart rate, body temperature,
Y-maze activity and rotarod performance was used. Dose-response
and time course studies were carried out. Approximately
15 min after injection the animals were markedly affected
by the drug with maximal effects occurring approximately
2 hours after injection. Strain comparisons were
made at the 2 hr time point. In all strains, males and females
were affected about equally except for respiratory rate
and rotarod performance in which females were slightly more
effected. Strain comparisons revealed that for most of the
test the C57BL mice were most affected by the DFP and the
C3H mice were least affected. For the heart rate test the
DBA mice were the most sensitive. Previous studies form
our laboratory have demonstrated a similar rank ordering
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