Chronic methanesulfonyl fluoride enhances one-trial per day reward learning in aged rats

Malin, David H.; Plotner, Robert E.; Radulescu, Sarah J.; Ferebee, Robert N.; Lake, John R.; Negrete, Pilar G.; Schaefer, Peggy J.; Crothers, Marie K.; Moss, Donald E.

doi:10.1016/0197-4580(93)90127-w

Cited by 10 publications

(13 citation statements)

References 12 publications

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“…Compared to ischemic animals, MSF treatment in sham operated animals produced no obvious increase in septal ChAT immunoreactivity or enhancement of passive avoidance performance. Although we found here and in our previous studies [25,26,29] that MSF resulted in brain AChE activity inhibition in normal animals, MSF neither altered septal ChAT immunoreactivity nor impaired passive avoidance performance in nonischemic animals. Some studies have reported memoryenhancing effects of AChE inhibitors in normal rodent subjects [21,22], as well as in healthy humans [16].…”

Section: Discussioncontrasting

confidence: 47%

“…Because MSF is a selective inhibitor of AChE [33], this minimizes toxic side effects seen with non-selective AChE inhibitors. Indeed, chronic MSF treatment even at the low dose of 0.22 mg/kg given three times per week produces a significant decrement (about 50%) in brain AChE activity, but without discernable locomotor side effects and no liver damage [26]. Similarly, brain AChE activity is reduced by 70% after a single systemic injection of 1.5 mg/kg MSF with no observable behavioral alterations [28].…”

Section: Discussionmentioning

confidence: 92%

“…reward learning task in mid-adult and aged rats [25,26]. Because MSF is a selective inhibitor of AChE [33], this minimizes toxic side effects seen with non-selective AChE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…All tests were run blind, and the animal codes were revealed only at the end of the behavioral and histological analyses. In the present experiment, the 0.3 mg/kg dose of MSF, which was previously reported as efficacious in ameliorating cognitive deficits in animals [25,26,29], was used to examine the potential protective effects of MSF in stroke animals. Sixteen animals underwent MCAo surgery, while another sixteen animals underwent sham surgery; these two groups were further subdivided into animals that received either MSF or vehicle (see Fig.…”

Section: Experimental Protocolmentioning

confidence: 99%

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Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats

2005

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Methanesulfonyl fluoride (MSF), a highly selective CNS inhibitor of acetylcholinesterase, has been recently demonstrated to promote improvement in cognitive performance in patients with senile dementia of Alzheimer type. Because a similar cognitive impairment may accompany stroke, we investigated in the present study whether treatment with MSF could produce beneficial effects in adult rats subjected to an experimental stroke model. Sprague-Dawley rats received transient 60 min intraluminal occlusion of the right middle cerebral artery (MCAo) and were given i.p. injections of either MSF (1 mg/kg at 24 and 48 h post-MCAo and 0.3 mg/kg thereafter every other day) or the vehicle, peanut oil, for 4 weeks. Behavioral tests and biochemical assays were performed at 28 days post-surgery. MSF treatment produced about 90% inhibition of acetylcholinesterase in the brain. Ischemic animals that received the vehicle displayed significant elevated body swing biased activity (84.8 F 10%) and significantly prolonged acquisition (398 F 62 s) and shortened retention (79 F 26 s) of the passive avoidance task. Interestingly, while the ischemic animals that received the MSF exhibited elevated body swing biased activity (87.7 F 8%), they performed significantly better in the passive avoidance task (255 F 36 s and 145 F 18 s in acquisition and retention) than the vehicletreated animals. Moreover, whereas brains from both groups of animals revealed similar extent and degree of cerebral infarction, the MSFtreated ischemic animals showed more intense immunoreactivity, as well as a significantly higher number (10-15% increase) of septal choline acetyltransferase-positive cells than the vehicle-treated ischemic animals. These results show that MSF, possibly by preserving a functional cholinergic system, attenuated stroke-induced deficits in a simple learning and memory task. Published by Elsevier B.V.Theme: Disorders of the nervous system Topic: Ischemia

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 92%

“…reward learning task in mid-adult and aged rats [25,26]. Because MSF is a selective inhibitor of AChE [33], this minimizes toxic side effects seen with non-selective AChE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Section: Experimental Protocolmentioning

confidence: 99%

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Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats

2005

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“…This approach is well grounded in the findings that dementia in Alzheimer’s is due, at least in part, to a severe loss of acetylcholine in the nucleus basalis of Meynert, as well as in other midbrain nuclei, cortex and hippocampus [2 – 4]. Recent evidence also suggests that cholinesterase inhibitors may be useful in treating vascular cognitive impairment [5 – 7], Parkinson’s disease dementia and Lewy body dementia [8, 9], and for age-related memory impairment as suggested by animal experiments [10]. In addition, a wide variety of preclinical and clinical studies show that AChE inhibitors may have neuroprotective effects that can delay or modify the course of the disease [11 – 17].…”

Section: Introductionmentioning

confidence: 99%

Cholinesterase Inhibitor Therapy in Alzheimer’s Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates

Moss

Perez

Kobayashi

2016

JAD

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Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer’s patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ~ 80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ~ 12 days. A single IM dose of 1.5 mg/kg MSF produced ~ 59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ~ 80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.

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Hippocampal Injections of Amyloid β-Peptide 1-40 Impair Subsequent One-Trial/Day Reward Learning

Malin

Crothers

Lake

et al. 2001

Neurobiology of Learning and Memory

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Chronic methanesulfonyl fluoride enhances one-trial per day reward learning in aged rats

Cited by 10 publications

References 12 publications

Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats

Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats

Cholinesterase Inhibitor Therapy in Alzheimer’s Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates

Hippocampal Injections of Amyloid β-Peptide 1-40 Impair Subsequent One-Trial/Day Reward Learning

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