Piracetam and fipexide prevent PTZ-kindling-provoked amnesia in rats

Genkova-Papazova, M.; Lazarova-Bakarova, M.

doi:10.1016/s0924-977x(96)00032-6

Cited by 14 publications

(5 citation statements)

References 39 publications

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“…Kindling is the neuroplasticity phenomenon suggested to be useful in the investigation of memory process 21 . Deficits in active and inhibitory avoidance responses have been found in PTZ‐kindled rats 22 . Many epidemiological studies have indicated that chronic use of non‐steroidal anti‐inflammatory drugs (NSAIDs) reduces the risk of developing Alzheimer's disease 23 .…”

Section: Discussionmentioning

confidence: 99%

Effect of Naproxen, a Non‐selective Cyclo‐oxygenase Inhibitor, on Pentylenetetrazol‐induced Kindling in Mice

Dhir

Naidu

Kulkarni

2005

Clin Exp Pharma Physio

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1. Epilepsy is one of the major neurological disorders of the brain, affecting approximately 0.5-1.0% of the population worldwide. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy. 2. Cyclo-oxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins and, as such, is a key target for many anti-inflammatory drugs. Cyclo-oxygenase has been reported to play a significant role in neurodegeneration. Recent studies have reported that COX plays a significant role in the pathophysiology of epilepsy. 3. The aim of the present study was to explore the possible role of COX and the effect of COX inhibitors in epilepsy. 4. Kindling is a chronic model of epilepsy. In the present study, kindling was induced in mice by chronic administration of a subconvulsive dose of pentylenetetrazole (PTZ; 40 mg/kg) on every other day for a period of 15 days. Naproxen was administered daily 45 min before PTZ or vehicle. The kindling score was recorded after PTZ administration. Seizure severity was measured according to a prevalidated scoring scale. Biochemical estimations were performed immediately after recording behavioural parameters on the 16th day of PTZ treatment. 5. Chronic treatment with PTZ significantly induced kindling in mice. Pretreatment with the non-selective COX inhibitor naproxen (7 and 14 mg/kg, i.p.) showed significant protection against PTZ-induced kindling in mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation and nitrite levels (NO levels), but decreased reduced glutathione (GSH) levels in brain homogenates. 6. In conclusion, the results of the present study strongly suggest that COX plays an important role in the pathophysiology of PTZ-induced kindling in mice and that COX inhibitors could be a useful neuroprotective strategy for the treatment of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Effect of Naproxen, a Non‐selective Cyclo‐oxygenase Inhibitor, on Pentylenetetrazol‐induced Kindling in Mice

Dhir

Naidu

Kulkarni

2005

Clin Exp Pharma Physio

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“…It is well established that there is a suppression of γ‐amino butyric acid (GABAergic) transmission during epileptogenesis [8] which may result in the amplification of excitatory neurotransmission, culminating in emotional disorders such as anxiety and amnesia. These behavioral excitations such as increased locomotor activity, hyperalgesia and loss of memory have been established by numerous in vivo experiments [9,10]. The oxidative stress imposed during seizures is an outcome of free radicals produced from the abnormal structural alterations of cellular proteins, membrane lipids, DNA and RNA [11].…”

Section: Introductionmentioning

confidence: 99%

Systemic administration of adenosine ameliorates pentylenetetrazol‐induced chemical kindling and secondary behavioural and biochemical changes in mice

Akula

Dhir

Kulkarni³

2007

Fundamemntal Clinical Pharma

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Adenosine is one of the inhibitory neuromodulators in the brain and is considered to be responsible for seizure arrest and postictal refractoriness. Adenosine, adenosine receptor agonists, and adenosine uptake blockers are known to reduce the severity and duration of amygdala-kindled seizures. The present study was carried out to elucidate the anticonvulsant and neuromodulatory effect of systemic adenosine on the pentylenetetrazol (PTZ)-induced chemical kindling in mice. Kindling was induced by chronic administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.) on every other day for a total period of 9 days. Adenosine was administered daily, 30 min before PTZ or vehicle. The kindling score was recorded immediately following PTZ administration according to a prevalidated scoring scale. Various behavioral and biochemical estimations were performed on day 10 (i.e. 24 h after the last dose of PTZ). Chronic PTZ treatment progressively increased the seizure score with the maximum score reached on day 9. Behavioral analysis found hyperlocomotor activity, anxiogenic response, hyperalgesia and amnesia in kindled mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation (malondialdehyde levels), nitrite (NO(2-) levels), adenosine deaminase (ADA) and total RNA levels and decreased catalase, reduced glutathione (GSH) levels in brain homogenates, and a depletion of adrenal ascorbic acid. Daily treatment with adenosine (25 and 50 mg/kg, i.p.) for 9 days led to a significant decrease in PTZ-induced kindling score and also reversed various behavioral and biochemical alterations produced by PTZ. The results of the present study suggested that systemic adenosine administration reversed the behavioral and biochemical alterations induced by chronic PTZ.

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“…Fipexide (Vigilor®, 1‐[2‐(4‐chlorophenoxy)acetyl]‐4‐(3,4‐methylenedioxybenzyl)piperazine, Fig. 1) is a nootropic compound (smart drug) that acts as a mild stimulant, affecting dopamine levels in the brain, and is said to improve short‐term memory, learning and cognition 1–6. It has been withdrawn from the market due to adverse side effects, including liver toxicity7, 8 and severe fever 9.…”

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confidence: 99%

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Sleno

Staack

Varesio

et al. 2007

Rapid Comm Mass Spectrometry

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The in vitro metabolism of the nootropic drug fipexide was studied using different liquid chromatography/mass spectrometry (LC/MS) techniques. This drug has been withdrawn from the market due to toxic effects. No previous reports have investigated the possible involvement of reactive metabolites in the toxicity of fipexide. The hydrolysis of this drug leads to the formation of two potentially toxic species, 3,4-methylenedioxybenzylpiperazine (MDBP) and 4-chlorophenoxyacetic acid (4-CPA). Here, we investigate the in vitro metabolism of fipexide in human, rat, mouse and dog, as well as of MDBP and 4-CPA in human and rat, while focusing on the formation of reactive metabolites. A combination of LC/MS analyses on a hybrid quadrupole-linear ion trap instrument and accurate mass data from QqTOF measurements was employed for the characterization of these metabolites. Microsomal metabolites of fipexide were MDBP, 4-CPA, fipexide N-oxide or hydroxyl, demethylenated fipexide and other minor ones, all of which were investigated by tandem mass spectrometry. Reactive metabolites were detected using several trapping procedures with small molecules such as glutathione, its ethyl ester derivative and N-acetylcysteine. The demethylenated metabolite, a catechol, formed its corresponding ortho-quinone, which readily reacts with these nucleophiles. MDBP was studied in a similar manner, due to its ability to form an analogous catechol. Because of its acidic nature, 4-CPA was assessed for possible acylglucuronide and acyl-CoA thioester metabolites, which could also be involved in bioactivation pathways. Several important metabolites were identified as potential mediators of toxicity via protein binding.

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Piracetam and fipexide prevent PTZ-kindling-provoked amnesia in rats

Cited by 14 publications

References 39 publications

Effect of Naproxen, a Non‐selective Cyclo‐oxygenase Inhibitor, on Pentylenetetrazol‐induced Kindling in Mice

Effect of Naproxen, a Non‐selective Cyclo‐oxygenase Inhibitor, on Pentylenetetrazol‐induced Kindling in Mice

Systemic administration of adenosine ameliorates pentylenetetrazol‐induced chemical kindling and secondary behavioural and biochemical changes in mice

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

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