Effects Of Metrifonate Research Articles

P.5.009 Effects of metrifonate on rats with model of hypoxia-induced impaired memory

P.5.009 Effects of metrifonate on rats with model of hypoxia-induced impaired memory

Effects of metrifonate on the hippocampal theta rhythm of freely moving intact and MS-lesioned mice

Changes in hippocampal electroencephalogram (EEG) have been suggested to be closely associated with spatial learning ability. Spatial learning can be improved in medial septal (MS)-lesioned mice by metrifonate, a cholinesterase inhibitor. We designed this study to investigate the effects of metrifonate on the hippocampal theta oscillation of intact and MS-lesioned mice. Intact and MS-lesioned C57BL mice were treated with acute injections of metrifonate (doses: 15, 50 and 100 mg/kg ip). These included a dose that considerably improved spatial memory of MS-lesioned mice in our earlier study. In addition, subtype selective muscarinic agents, BIBN-99, AF267B and AF150(S) were used. Recordings of hippocampal theta during movement and awake immobility revealed a dramatic reduction of theta in the lesioned animals. Metrifonate induced prominent changes in the EEG of intact mice, but not of MS-lesioned mice. The effect of metrifonate was not mimicked by two selective M 1-agonists and was augmented by a combined injection of a selective M 2-antagonist. These data suggest that improved spatial learning by the cholinesterase inhibitor metrifonate is unrelated to its effects on the hippocampal EEG. These two effects may be mediated through different muscarinic receptor subtypes.

Metrifonate

Acetylcholinesterase (AChE) inhibitors are currently the most promising drugs available for the treatment of Alzheimer's disease (AD). Their efficacy is based on the cholinergic hypothesis of AD which links reduced levels of cerebral acetylcholine (ACh) with declining cognitive function in affected individuals. AChE inhibitors are believed to work by increasing the level of ACh in the synaptic cleft by binding to local AChE and preventing the hydrolysis of ACh. Metrifonate differs from other AChE inhibitors in that it is a prodrug which is, non-enzymatically converted in vivo to the active moiety 2,2-dichlorovinyl dimethylphosphate (DDVP). DDVP administered alone has a very short plasma elimination half-life, but small amounts released from metrifonate are sufficient to inhibit AChE activity in vivo. DDVP is an irreversible inhibitor of AChE and activity is maintained for several weeks. Metrifonate has been used as an anthelmintic since 1962 and has been under investigation as a treatment for the symptoms of AD since 1990. Randomised, placebo-controlled clinical trials, using a variety of dose regimens, have demonstrated that metrifonate produces a significant, but modest, improvement in the 3 domains of AD: cognition, behaviour and function. However, it should be noted that with some assessment instruments in some trials, the improvement' was actually a reduction in the rate of worsening of symptoms compared with placebo. Weekly and daily schedules, with and without loading doses, have been evaluated and the research supports a fixed daily dose of 40 to 50mg, administered to supply approximately 0.65 mg/kg. In studies of up to 6 months' duration, metrifonate was well tolerated, and adverse events were mild and predominantly gastrointestinal. In clinical practice it is likely that metrifonate will be administered for several years and long term monitoring of adverse events will be important to further define the drug's tolerability profile. Muscle weakness occurred in a dose-related fashion in 20 of 3000 patients taking part in long term trials, and in some patients respiratory support was required. The mechanism of muscle weakness is not well defined and requires further investigation. Conclusions: Clinical data support the use of metrifonate in patients with AD. However, the improvements noted are modest and to date there is no evidence that metrifonate is more effective than other currently approved AChE inhibitors. The unique pharmacokinetic/pharmacodynamic profile of metrifonate may endow the agent with some advantages over other therapies, but this has yet to be evaluated in comparative trials. Moreover, long term studies evaluating the effects of metrifonate on maintenance of independence are required. While the clinical future of metrifonate is uncertain, it is one of a small group of drugs that have been shown to improve the outlook of patients with AD. Metrifonate is administered orally and after absorption is nonenzymatically converted to the active compound 2,2-dichlorovinyl dimethylphosphate (DDVP), at neutral or alkaline pH. After a short reversible phase, DDVP irreversibly binds to acetylcholinesterase (AChE). With the exception of nicotinic receptors, metrifonate does not bind to neurotransmitter receptors or binding sites associated with ion channels. Therefore, the pharmacological action of metrifonate is through inhibition of AChE and a consequent increase in levels of acetylcholine (ACh).

Metrifonate was effective in mild-to-moderate Alzheimer disease

Source Citation Raskind MA, Cyrus PA, Ruzicka BB, Gulanski BI, for the Metrifonate Study Group. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's di...

Metrifonate improves working but not reference memory performance in a spatial cone field task

The effects of metrifonate (3, 10 and 30 mg/kg, p.o.) on the working and reference memory performance of the rat were assessed in a spatial cone field task. The highest dose of metrifonate (30 mg/kg) improved the working memory performance, whereas none of the doses affected the reference memory performance. Other parameters of spatial discrimination performance were not affected by metrifonate treatment. The present results suggest that metrifonate has cognition-enhancing properties which are likely to be related to aspects of (spatial) working memory.

Characterization of learning and memory behaviors and the effects of metrifonate in the C57BL strain of mice

In the near future, a number of transgenic mouse models with neuropathological characteristics of Alzheimer's disease are expected to become widely available. It will be important to characterize their behavior in models for learning and memory. As a first step, we have characterized normal, medial septal-lesioned and hippocampal-lesioned C57BL mice, in different behavioral tests, i.e., water maze spatial navigation, Y-maze and passive avoidance behavior. These experiments were complemented by an investigation of the effects of acute treatment with an acetylcholinesterase inhibitor, metrifonate, in these behavioral tests. Normal C75BL mice perform very well in the water maze and the Y-maze, but suboptimally in the passive avoidance task. Lesioning of the medial septum or the dorsal hippocampus clearly impaired the performance of the mice. In medial septal-lesioned mice, metrifonate stimulated spatial navigation and alleviated the loss of activity in the Y-maze and passive avoidance. In hippocampal-lesioned mice, metrifonate had no effect on spatial navigation. It is concluded that C75BL mice are useful for testing in classical models for learning and memory, and that septohippocampal pathology is very likely to induce cognitive deficits in some of these models.

Metrifonate Increases Neuronal Excitability in CA1 Pyramidal Neurons from Both Young and Aging Rabbit Hippocampus

The effects of metrifonate, a second generation cholinesterase inhibitor, were examined on CA1 pyramidal neurons from hippocampal slices of young and aging rabbits using current-clamp, intracellular recording techniques. Bath perfusion of metrifonate (10-200 microM) dose-dependently decreased both postburst afterhyperpolarization (AHP) and spike frequency adaptation (accommodation) in neurons from young and aging rabbits (AHP: p < 0.002, young; p < 0.050, aging; accommodation: p < 0.024, young; p < 0.001, aging). These reductions were mediated by muscarinic cholinergic transmission, because they were blocked by addition of atropine (1 microM) to the perfusate. The effects of chronic metrifonate treatment (12 mg/kg for 3 weeks) on CA1 neurons of aging rabbits were also examined ex vivo. Neurons from aging rabbits chronically treated with metrifonate had significantly reduced spike frequency accommodation, compared with vehicle-treated rabbits. Chronic metrifonate treatment did not result in a desensitization to metrifonate ex vivo, because bath perfusion of metrifonate (50 microM) significantly decreased the AHP and accommodation in neurons from both chronically metrifonate- and vehicle-treated aging rabbits. We propose that the facilitating effect of chronic metrifonate treatment on acquisition of hippocampus-dependent tasks such as trace eyeblink conditioning by aging subjects may be caused by this increased excitability of CA1 pyramidal neurons.

Effects of metrifonate on radial arm maze acquisition in middle-aged rats

The efficacy of metrifonate, a well-tolerated cholinesterase (ChE) inhibitor, in attenuating the normal aging- and corticosterone-induced impairments of radial maze performance of rats was compared. Middle-aged Fischer 344 rats were screened for their spatial orientation performance in the Morris water escape task. Good and bad performers were selected: good performers ( N=22) were treated with subcutaneous sustained-release corticosterone pellets, resulting in hippocampal cell damage and impaired spatial orientation in the radial maze; age-induced bad performers ( N=20) were tested without additional pharmacological intervention. Metrifonate (MFT), administered daily during radial maze testing, 30 min before training, at a dose of 15 mg/kg p.o., facilitated the acquisition of the task in age-impaired rats, but not in corticosterone-impaired rats.

Cognition Enhancing Profile of CR 2249, a New NMDA‐Glycine Site Modulator

Memory processes have been widely studied in recent decades. Unfortunately, although several intriguing hypotheses about the possibility of modulating cognition have been developed, no conclusive result has been obtained (69). Two different neurotransmission models are of major interest in understanding how the brain can acquire and store a single cognitive event (3,23). The main neuronal agents involved in transferring this kind of information seem to be acetylcholine and glutamic acid. These two neurotransmitters are present in all the cerebral areas involved in the memory processes and both are responsible for the stimulation currents linked to the propagation of neuronal signals (1,4). The cholinergic hypothesis of memory ( 3 ) is based on the observation that a marked degeneration of the cholinergic neuronal pathway is often associated with the development of cognitive disorders ( 12). Moreover, it has been reported that one distinctive feature of Alzheimer’s disease (AD) consists of a progressive loss of either cholinergic or adrenergic neurons’ ability to transmit stimuli received from the limbic areas to the cerebral cortex (10,12,21,75). To help preserve high levels of acetylcholine in the synaptic cleft, several antiacetylcholinesterase agents have been synthesized and tested on both biochemical and behavioral models of learning (32,46). Tacrine is certainly the most studied among these agents ( 13). Clinical trials with tacrine revealed some interesting pro-mnemic properties of this compound (42,68), but tacrine exhibits major hepatotoxicity that strongly restricts its use ( 13,73). Donepezil (E2020) is another interesting compound of this family. Two recently published clinical studies (25,63) demonstrate both the efficacy of donepezil in patients with mild-to-moderate Alzheimer’s disease and its relative liver safety. Other potent acetylcholinesterase inhibitors, such as metrifonate and SDZ ENA 7 13, are currently under clinical evaluation (28,62,65). The glutamatergic hypothesis of memory is based on a particular characteristic of the glutamatergic neuronal pathway: long-term potentiation (LTP). LTP was first defined by Bliss and Collingridge (8) as a synaptic memory model expressed as a persistent increase in the size of the synaptic component of the evoked response. The

Corrigendum to ``Effects of metrifonate on memory impairment and cholinergic dysfunction in rats'' [Eur. J. Pharmacol. 322 (1997) 11–19

Corrigendum to ``Effects of metrifonate on memory impairment and cholinergic dysfunction in rats'' [Eur. J. Pharmacol. 322 (1997) 11–19

Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats

The effects of metrifonate were investigated in 4–6- and 22–24-month-old rats. Extracellular acetylcholine levels were measured by transversal microdialysis in vivo. Baseline extracellular acetylcholine levels in the cerebral cortex and hippocampus were 42% and 60% lower, respectively, in old than in young rats. Old rats did not discriminate between familiar and novel objects. In old rats, metrifonate (80 mg/kg p.o.) brought about 85% inhibition of cholinesterase activity in the cortex and hippocampus, a 4-fold increase in extracellular acetylcholine levels in the cortex only, and restored object recognition. In young rats, metrifonate caused 75% cholinesterase inhibition in the cerebral cortex and hippocampus, a 2-fold increase in cortical and hippocampal extracellular acetylcholine levels, and no effect on object recognition. The slight cholinesterase inhibition following metrifonate (30 mg/kg) in aged rats had no effect on cortical acetylcholine levels and object recognition. In conclusion, metrifonate may improve the age-associated cholinergic hypofunction and cognitive impairment.

Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats

Several studies have indicated the possibility of using cholinesterase (ChE) inhibitors as therapeutic drugs for Alzheimer's disease. Metrifonate (MTF) is an organophosphorus compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of MTF on the impairment of learning and memory, decreased ChE activity and extracellular acetylcholine (ACh) levels in basal forebrain (BF)-lesioned rats. The oral administration of MTF improved the BF-lesion-induced impairment of performance on passive avoidance task. Further, MTF reduced ChE activity in the cerebral cortex. In vivo brain microdialysis studies showed that MTF significantly increased the release of ACh, but decreased that of choline (Ch) in the cerebral cortex of BF-lesioned rats. These results indicated that MTF ameliorates the impairment of performance on passive avoidance task in BF-lesioned rats by increasing the extracellular ACh levels by inhibiting ChE. This suggested that MTF may be useful as a therapeutic drug for Alzheimer's disease.

Metrifonate Treatment Enhances Acquisition of Eyeblink Conditioning in Aging Rabbits

The cholinergic system is known to show deterioration during aging and Alzheimer's disease. In response, a therapeutic approach to Alzheimer's disease has been to attempt to compensate for the decrease in central cholinergic function by potentiating the activity of the remaining intact cholinergic cells with cholinesterase inhibitors. In this study treatment with the long-lasting cholinesterase inhibitor metrifonate enhanced acquisition of eyeblink conditioning in aging rabbits without producing interfering side effects. The effects of metrifonate on central and peripheral cholinesterase activity were evaluated, as was the involvement of plasma atropine esterase activity on the central and peripheral response to metrifonate. Results demonstrate that metrifonate can produce predictable, dose-dependent ChE inhibition. Associative learning in the aging rabbit was improved by metrifonate-induced steady state ChE inhibition within a range of 30–80%. Metrifonate was behaviorally effective in the absence of the severe side effects which typically plague cholinesterase inhibitors, suggesting that metrifonate is a possible treatment for the cognitive deficits resulting from normal aging and Alzheimer's disease.

Effects of metrifonate on escape and avoidance learning in young and aged rats

The present study assessed the effects of the indirect acetylcholinesterase inhibitor metrifonate on learning and memory functions in young (3-month-old) and aged (25-month-old) rats. In the shuttle box, metrifonate at a dose of 12.5mg/kg, p.o., 30min before each of the daily acquisition sessions, improved the acquisition of the active avoidance response, whereas a dose of 25mg/kg did not. Metrifonate, 12.5mg/kg, p.o., administered before each of the daily acquisition sessions, also facilitated the acquisition of the Morris water escape task in both young and aged rats: metrifonate-treated rats swam a shorter distance to reach the escape platform than did the vehicle-treated rats. The 3-month-old rats treated with metrifonate did not show the increase in swimming speed over training observed in vehicle-treated animals; no effects of metrifonate were found on the swimming speed of aged rats. In a probe trial carried out immediately after the fifth daily acquisition session, metrifonate treatment did not affect the bias of the aged rats for the quadrant in which the platform had been positioned during acquisition. It is concluded that metrifonate improves performance during the acquisition phase of two aversively motivated learning and memory tasks at the dose of 12.5mg/kg, p.o.

Effects of metrifonate and tacrine in the spatial morris task and modified irwin test: Evaluation of the efficacy/safety profile in rats

AbstractIn the present study we investigated the efficacy/safety profile of the cholinesterase inhibitors metrifonate (MTF) and tacrine [tetrahydroaminoacridine (THA)]. We tested the efficacy of MTF (12, 39, and 120 μmol/kg po) and THA (1.3, 4.3, and 13 μmol/kg po) in the spatial Morris task in 19‐month‐old rats. The modified Irwin test was used to evaluate the safety of both drugs, using in 19‐month‐old rats. In this observation test, higher doses of MTF (39, 120, and 390 μmol/kg) and THA (4.3, 13, and 43 μmol/kg) were tested. MTF was found to improve the performance of rats in the spatial Morris task. Independent of dose, MTF‐treated rats performed better than vehicle‐treated rats in the Morris task during the 2nd week of testing. THA treatment (1.3 μmol/kg) had only a minor effect on the spatial discrimination performance, i.e., effect on the probe trial after 2 weeks of training. In the modified Irwin test, both MTF and THA dose dependently induced side effects which were classified as being typically cholinergic. The threshold dose for the occurrence of side effects for acutely administered MTF and THA was 39 and 4.3 μmol/kg, respectively. Remarkably, repeated administration of 390 μmol/kg MTF (5 day treatment) resulted in fewer side effects. This was not observed for THA treatment. The data of the present study indicate that the efficacy/safety profile of MTF is more favorable than that of THA. © 1995 Wiley‐Liss, Inc.

P3-236 - Effects of metrifonate on cholinesterase activity, and the extracellular choline and acetylcholine levels in rodent brain

P3-236 - Effects of metrifonate on cholinesterase activity, and the extracellular choline and acetylcholine levels in rodent brain

Effects of metrifonate, a long‐acting cholinesterease inhibitor, in alzheimer disease: Report of an open trial

AbstractThis is the first study of a multiple‐dose trial of metrifonate (Met), a long‐acting cholinesterase (ChE) inhibitor, conducted over a prolonged period of time in humans. We have administered Met to 20 patients who met NINCDS‐ADRDA criteria for probable Alzheimer disease (AD). Patients were given, under open conditions, single oral doses of Met. 2.5, 5, 7.5, and 15 mg/kg/wk. A statistically significant improvement in the Alzheimer Disease Assessment Scale (ADAS) scores was observed with the 5 mg/kg/wk dose. Maximal improvement on the ADAS was associated with a mean 55.9% (± 12.6% standard deviation) activity level of red blood cell (RBC) acetylcholinesterase (AChE). Over 80% inhibition of plasma and RBC ChE was achieved with only minor side effects. Cholinesterate inhibition in the CSF of two patients was 37% and 47.5% 24 hr after a second dose of 5 mg/kg/wk of Met separated by 7 days from the first dose.Twenty‐seven minor side effects were reported: none on 2.5 mg, 5 on 5 mg, 9 on 7.5 mg, and 13 on the 15 mg dose. None of the side effects was clinically significant or drug related or required termination of treatment of dosage adjustment. We conclude that Met is a useful pharmacological probe of cholinergic function in the central nervous system and that double‐blind evaluation of Met in AD is warranted.