Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of clinical observations suggest that certain forms of epilepsy are due to long-term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. Recently, there has been growing evidence that serotonergic neurotransmission modulates experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in some genetically epilepsy-prone animals. Generally, agents that elevate extracellular serotonin (5-Hydroxytryptamine, 5-HT) levels, such as 5-hydroxytryptophan, and 5-HT reuptake blockers inhibit both limbic and generalized seizures. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically-evoked convulsions. More specifically, the recent finding that the 5-HT2B/2C receptor agonist, 1-(m-chlorophenyl)-piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5-HT2C receptor subtype as a potential target for the treatment of epilepsy. Further pharmacological evaluation of selective activation or inactivation of the 5-HT2C receptor subtype with selective agonist/positive modulators and antagonists will provide important information about the therapeutic contribution of this receptor to the epileptic circuitry in the brain. Future development of serotonergic antiepileptic drugs will be a significant addition to the therapeutic armamentarium against epilepsy.
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PMID:Serotonergic 5-HT2C receptors as a potential therapeutic target for the design antiepileptic drugs. 1563 78

Fast oscillations at approximately 200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA(A) receptor antagonist picrotoxin (50 microM) to mouse hippocampus-entorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 +/- 146.1 msec, mean +/- SD; interval of occurrence 14.8 +/- 3.3 sec, n = 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 +/- 23.4 Hz (n = 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in "minislices" only of the dentate gyrus, were unaffected by application of the mu-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 microM; n = 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 microM; n = 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM; n = 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA(B) receptor agonist baclofen (0.01-0.5 microM; n = 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n = 6) or octanol (0.2-0.5 mM; n = 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at approximately 200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA(A) receptor-mediated or gap-junction mechanisms.
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PMID:Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices. 1574 60

Various 1,4-substituted derivatives of piperazine (I-XII) were synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet)--induced seizures and for neurotoxicity (TOX) in the rotorod test in mice and rats. The most promising compounds seem to be 1-[(2,4,6-trimethyl)-phenoxyethyl]-4-(2-hydroxyethyl)-piperazine dihydrochloride (II) and 1,4-bis-[(4-chloro-3-methyl)-phenoxyethyl]-piperazine dihydrochloride (X) which displayed anti-MES activity with their protective index (PI) higher than that for valproate II (rats), X(mice)).
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PMID:Synthesis and anticonvulsant activity of some piperazine derivatives. 1588 10

The K+ channel blocker 4-aminopyridine (4-AP) stimulates the release of glutamate from nerve endings and induces seizures and neurodegeneration when perfused by microdialysis in rat hippocampus. In addition, there is a temporal correlation between the progress of neurodegeneration in the perfused hippocampus and the expression of the inducible cellular stress marker heat shock protein 70 (HSP70) in the non-damaged contralateral hippocampus. All these effects of 4-AP are prevented by the NMDA receptor antagonists 3-phosphonopropyl-piperazine-2-carboxilic acid (CPP) and (+)5-methyl-10,11-dyhydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), indicating that they are due to NMDA receptor overactivation by excessive extracellular synaptic glutamate. We hypothesized that the induction of HSP70 in the non-damaged contralateral hippocampus should have a protective action against this excitotoxic effect. Here we demonstrate that 4-AP perfusion in one hippocampus prevented the neurotoxic effect of 4-AP when perfused by microdialysis in the contralateral hippocampus 24h later. However, both the stimulation of glutamate release and the EEG epileptiform discharges, which occur immediately after 4-AP perfusion, were similar after the first and the second perfusions. When CPP was coperfused with 4-AP during the first microdialysis, HSP70 induction in the contralateral hippocampus was prevented and the protection against the second 4-AP perfusion was abolished in 50% of the rats. These results suggest that HSP70 induction is an important cellular mechanism to protect vulnerable neurons from excitotoxic overactivation of glutamate receptors by endogenous glutamate, and may be relevant to pathological conditions in which extracellular endogenous glutamate is augmented, such as ischemia.
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PMID:HSP70 expression protects against hippocampal neurodegeneration induced by endogenous glutamate in vivo. 1878 52

A series of 1,4-piperazine derivatives was synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The compounds were only moderately effective. The anticonvulsant activity was accompanied by neurotoxicity. 1-[(4-Chlor-3-methylphenoxy)-acetyl]-4-(2-methoxyphenyl)-piperazine was also evaluated in six hertz seizure test (6-Hz) and showed good activity. At the dose of 100 mg/kg b. w. the compound produced 100% protection after 0.5 h without neurotoxic effect.
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PMID:Preliminary evaluation of anticonvulsant activity and neurotoxicity of some 1,4-substituted piperazine derivatives. 1989 54

A series of new 3-hydroxy-6-hydroxymethyl-2-substituted 4H-pyran-4-one derivatives were synthesized as potential anticonvulsant compounds. Mannich compounds were prepared by the reaction of appropriate substituted piperazine derivatives with kojic acid and formaline. The structure of the synthesized compounds was confirmed using the elementary analysis results and spectroscopic techniques such as IR, 1H-NMR and ESI-MS. Anticonvulsant activities of the synthesized compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed according to procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 11) against MES seizures and 3-hydroxy-6-hydroxymethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4H-pyran-4-one (compound 7) against scMet seizures were determined to be the most active compounds at all doses without neurotoxicity.
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PMID:Synthesis and anticonvulsant activity of new kojic acid derivatives. 2018 23

The use of piperazine derivatives, colloquially named 'party pills', has been escalating in New Zealand and worldwide since their introduction in the 1990s. Benzylpiperazine (BZP) is often used alone, or can be combined with trifluoromethylphenylpiperazine (TFMPP). Taken together as an oral dose, they have been reported to produce effects similar to 3, 4-methylenedioxymethamphetamine (MDMA). While the pharmacokinetic data have recently been published, little research has been conducted on the subjective effects of these piperazines on humans. This paper outlines the subjective effects observed following oral doses of BZP (200 mg) and TFMPP (60 mg) alone, or in combination (100/30 mg) compared to placebo. Participants were asked to comment on the subjective effects of each drug using three subjective rating scales-the Addiction Center Research Inventory (ARCI), the Profile of Mood States (POMS), and the Visual Analog Scales (VAS)-before and approximately 120 min after a single dose. BZP showed significant dexamphetamine-like stimulant effects, inducing euphoria, sociability, and drug liking, whereas TFMPP induced fewer stimulant-like effects and increased anxiety, via its serotonergic effects. The combination of BZP and TFMPP induced similar subjective effects, along with well-characterized dexamphetamine- and MDMA-like effects. These subjective data allow for obvious comparisons to be made between party pill drugs and other commonly known stimulants. However, despite estimates of over 20 million doses sold in New Zealand alone and increasing seizures by the Drug Enforcement Administration in the USA, there are no published cases of dependence worldwide. The long-term effects of regular party pill use are also unknown, and create the potential for future research.
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PMID:Subjective effects in humans following administration of party pill drugs BZP and TFMPP alone and in combination. 2153 45

Although many piperazine derivatives exist, only a limited number have been studied, whereby they have been found to be generally stimulant in nature resulting from dopaminergic, noradrenergic, and predominantly serotoninergic effects in the brain. Reported toxic effects include agitation, anxiety, cardiac symptoms (e.g. tachycardia) and sometimes seizures. As for many drugs, they are primarily metabolized by cytochrome P450 with subsequent possible glucuronidation and/or sulfation. Their abuse has been relatively recently observed in the last decade with only a few identified in biological fluid (primarily 1-benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (3-TFMPP)) despite publications of a number of analytical methods. Even when detected, however, the toxicological significance of their presence is often difficult to ascertain as many cases involve other drugs as well as a wide and overlapping range of concentrations found in blood (both in life and after death). This paper reviews the current pharmacological and toxicological information for piperazine derivatives and also includes new ante-mortem and post-mortem blood data.
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PMID:Current awareness of piperazines: pharmacology and toxicology. 2174 14

The synthesis and anticonvulsant properties of new piperazine or morpholine acetamides derived from 2-(1,3-dioxoisoindolin-2-yl)-, 2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl-) and (3,5-dioxo-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)-acetic acid were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective in the MES screen. The most active was 2-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione (12) that revealed protection in the electrically induced seizures at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration in mice respectively. This molecule given orally in rats at a dose of 30 mg/kg was more potent than reference anticonvulsant--phenytoin.
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PMID:Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs. 2184 Jun 29

In the present study, a series of N(3)-substituted 2,4-imidazolidinediones and oxazolidinediones derivatives (1-16) were synthesized and tested for anticonvulsant activity using the maximal electroshock seizure test. Affinity towards receptor (5-HT<sub>1A/2A</sub>) was also studied. Their neurotoxicity was determined using the rotarod test. Structures of compounds were confirmed by spectroscopic methods. Compounds 1, 2, 5, 7, 9, and 10 exhibited significant anticonvulsant activity as compared to the standard drug phenytoin. Affinity toward receptor (5-HT<sub>1A/2A</sub>) was studied in vivo for compounds 1, 2, 5, 7, 9, and 10. Rectal body temperature, lower lip retractions and head twitch responses in Wistar rats/albino mice were determined for this purpose. The tested compounds showed affinity for 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors (agonists/antagonists and presynaptic/postsynaptic). Replacement of piperazine by aniline derivatives provides good outcomes in terms of affinity for 5-HT<sub>1A/2A</sub>.
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PMID:Design, synthesis, anticonvulsant screening and 5HT<sub>1A/2A</sub> receptor affinity of N(3)-substituted 2,4-imidazolidinediones and oxazolidinediones. 2246 69


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