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)

Because brain inositides are enriched in the 1-stearoyl-2-arachidonoyl species, they form a likely source for the tetraenoic free fatty acids (FFA) and diacylglycerols (DG) that are accumulated during seizures. To study inositide turnover during bicuculline-induced seizures, rats were injected intraventricularly and bilaterally with 10-20 microCi 32P, mechanically ventilated and sacrificed by 6.5 KW head-focused microwave irradiation. Seizure activity was recorded by electroencephalography. Bicuculline-induced seizure activity resulted in: a) almost 50% increase in 32P labeling of phosphatidic acid (PA); phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP2) also increased (24% and 36%, respectively); b) no change in other lipids; and c) water-soluble phosphodiesteratic degradation products, analyzed by high voltage paper electrophoresis, increased 24% in the amount of radiotracer recovered as inositol 1,4-bisphosphate (IP2) and by 44% in the amount recovered as inositol 1,4,5-trisphosphate (IP3). These data indicate that during experimental status epilepticus the cerebral inositide cycle is accelerated: PIP2----(IP3----IP2----IP----I) + DG----PA----PI----PIP----PIP2.
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PMID:Enhanced inositide turnover in brain during bicuculline-induced status epilepticus. 301 Oct

Eight patients (7 men and 1 woman, mean age 43.1 +/- 8.9 years) with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) underwent treatment with demeclocycline in an effort to normalize serum sodium levels and thereby protect the PIP patients against complications including hyponatremic seizures and coma. There tended to be an improvement (p = .080) in early morning serum sodium following treatment with demeclocycline (baseline 132.6 +/- SD 3.3 and treatment serum sodium 134.8 +/- SD 3.3 mEq/1). At the same time, there was an increase (p = .043) in urinary specific gravity following treatment with demeclocycline (baseline 1.0047 +/- SD .0029 and treatment urinary specific gravity 1.0063 +/- SD .0026). Clinical indications for and potential mechanisms of action of demeclocycline treatment in the PIP syndrome are discussed.
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PMID:The use of demeclocycline in the treatment of patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). 313 88

Six patients [5 men and 1 woman, mean age 37.3 +/- 8.2 (SD) years] with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) underwent a sequence of treatments in an effort to normalize basal serum sodium levels and thereby protect the patients against complications, including hyponatremic seizures and coma. The morning baseline group mean basal serum sodium value was 132.5 +/- 3.8 meq/liter. Over a 20-month period, the sequence of treatments was salt-added diet, lithium and phenytoin, and lithium alone. Each treatment program yielded morning group mean basal serum sodium determinations superior to baseline values, except for the program of lithium alone, which could not be tolerated. The combination of lithium and phenytoin provided a morning group mean basal serum sodium level of 140.6 +/- 3.2 meq/liter, which was superior (p less than 0.01) to all other treatment modalities. Early morning hyposthenuria persisted throughout the 20-month period of observation.
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PMID:Treatment of psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) using lithium and phenytoin. 333 51

We describe four patients with left temporal lobe epilepsy who developed psychosis, intermittent polydipsia and hyponatremia (PIP-syndrome) while being treated with carbamazepine. These cases illustrate the close links between dysfunction of the limbic system causing epileptic seizures and psychosis on the one hand and dysregulation in hypothalamic centers manifestating in polydipsia and osmodysregulation on the other.
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PMID:Carbamazepine and PIP-syndrome in temporal lobe epilepsy. 899 88

Lithium inhibits the enzyme inositol monophosphatase and thus obstructs the enzymatic degradation of inositol triphosphate (IP3) to inositol in the phosphate-phosphoinositide (PIP) cycle. This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithium's therapeutic and prophylactic effect in affective disorders. Inositol is also available to the cell by uptake from the intercellular matrix, and therefore it is possible that compounds that block the uptake may have lithium-like effects. To test this hypothesis, the present study evaluates the effects of two inositol uptake inhibitors, the carbohydrate L-fucose and the cyclodepsipeptide nordidemnin, in a behavioral model of pilocarpine-induced seizures known to be enhanced by lithium. We tested the possibility that L-fucose produces lithium-like effects, or that L-fucose or nordidemnin augment lithium's behavioral effects. Results indicate that acute ICV treatment with L-fucose did not by itself have a lithium-like effect in the behavioral model, but significantly augmented lithium's effect when combined with lithium treatment. Nordidemnin treatment showed similar effects. The results suggest that when inositol monophosphatase is inhibited by lithium, further restriction of cellular inositol availability may result in an augmentation of lithium's behavioral effects. It is possible that such manipulations may be applicable in the treatment of patients with affective disorders, especially patients who are poor responders to lithium monotherapy.
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PMID:Augmentation of lithium's behavioral effect by inositol uptake inhibitors. 958 58

Local anesthetics, commonly used for treating cardiac arrhythmias, pain, and seizures, are best known for their inhibitory effects on voltage-gated Na(+) channels. Cardiovascular and central nervous system toxicity are unwanted side-effects from local anesthetics that cannot be attributed to the inhibition of only Na(+) channels. Here, we report that extracellular application of the membrane-permeant local anesthetic bupivacaine selectively inhibited G protein-gated inwardly rectifying K(+) channels (GIRK:Kir3) but not other families of inwardly rectifying K(+) channels (ROMK:Kir1 and IRK:Kir2). Bupivacaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directly via coexpressed G protein G(beta)gamma subunits. Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive G proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels containing the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP(2)) domain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP(2) were inhibited by ethanol, like IRK1 channels. We propose that membrane-permeant local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP(2) with the channel, which is essential for G(beta)gamma and ethanol activation of GIRK channels.
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PMID:Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels. 1135 68

Levetiracetam (LEV) is an effective antiepileptic drug (AED) with distinct mechanism from the conventional AEDs. The major physiological function of ROMK1 channels is to maintain the resting membrane potential (RMP). In this study, we investigated the mechanisms underling LEV on ROMK1 channels. Xenopus oocytes were injected with mRNA to express the wild-type or mutant ROMK1 channels. Giant inside-out patch clamp recordings were performed to study the effect of LEV on these channels. LEV increased the activity of ROMK1 channels in a concentration-dependent manner and enhanced both wild-type and pH(i) gating residue mutant (K80M) channels over a range of pH(i) values. LEV activated the mutated channels at PIP(2)-binding sites (R188Q, R217A and K218A) and PKC-phosphorylation sites channels (S4A, S183A, T191A, T193A, S201A and T234A). However, this drug failed to enhance the channel activity in the presence of PKA inhibitors and did not activate the mutants of PKA-phosphorylation sites on C-terminal (S219A, S313A) and the constructed mutants (S219D and S313D) that mimic the negative charge carried by a phosphate group bound to a serine. Our results demonstrated PKA-mediated phosphorylation is a novel mechanism for LEV activating ROMK1 channels. These findings show that LEV activates ROMK1 channels independently from pH(i) and not via a PIP(2)- or PKC-dependent pathway. The effects of LEV may come from the PKA-induced conformational change but not charge-charge interaction in ROMK1 channels. Enhancing the activity of ROMK1 channels may be an important molecular mechanism for the antiepileptic effects of LEV in restoring neuronal RMP to prevent seizure spreading.
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PMID:PKA-mediated phosphorylation is a novel mechanism for levetiracetam, an antiepileptic drug, activating ROMK1 channels. 1854 45

Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [PtdInsP (also known as PIP) and PtdInsP(2) (also known as PIP(2))] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds (nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.
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PMID:The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium. 2187 11

The M-current formed by tetramerization of Kv7.2 and Kv7.3 subunits is a neuronal voltage-gated K(+) conductance that controls resting membrane potential and cell excitability. In Xenopus laevis oocytes, an increase in Kv7.2/3 function by the serum- and glucocorticoid-regulated kinase 1 (SGK1) has been reported previously (Schuetz et al., 2008). We now show that the neuronal isoform of this kinase (SGK1.1), with distinct subcellular localization and modulation, upregulates the Kv7.2/3 current in Xenopus oocytes and mammalian human embryonic kidney HEK293 cells. In contrast to the ubiquitously expressed SGK1, the neuronal isoform SGK1.1 interacts with phosphoinositide-phosphatidylinositol 4,5-bisphosphate (PIP(2)) and is distinctly localized to the plasma membrane (Arteaga et al., 2008). An SGK1.1 mutant with disrupted PIP(2) binding sites produced no effect on Kv7.2/3 current amplitude. SGK1.1 failed to modify the voltage dependence of activation and did not change activation or deactivation kinetics of Kv7.2/3 channels. These results suggest that the kinase increases channel membrane abundance, which was confirmed with flow cytometry assays. To evaluate the effect of the kinase in neuronal excitability, we generated a transgenic mouse (Tg.sgk) expressing a constitutively active form of SGK1.1 (S515D). Superior cervical ganglion (SCG) neurons isolated from Tg.sgk mice showed a significant increase in M-current levels, paralleled by reduced excitability and more negative resting potentials. SGK1.1 effect on M-current in Tg.sgk-SCG neurons was counteracted by muscarinic receptor activation. Transgenic mice with increased SGK1.1 activity also showed diminished sensitivity to kainic acid-induced seizures. Altogether, our results unveil a novel role of SGK1.1 as a physiological regulator of the M-current and neuronal excitability.
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PMID:The neuronal serum- and glucocorticoid-regulated kinase 1.1 reduces neuronal excitability and protects against seizures through upregulation of the M-current. 2339 95

In patients with epilepsy, coexisting psychoses, either interictal (IIP) or postictal (PIP), are associated with serious disturbance in psychosocial function and well-being, and often require the care of a specialist. Unfortunately, evidence-based treatment systems for psychosis in patients with epilepsy have not yet been established. This article aims to propose concise and practical treatment procedures for IIP and PIP based on currently available data and international consensus statements, and primarily targeting nonpsychiatrist epileptologists who are often the first to be involved in the management of these complex patients. Accurate and early diagnosis of IIP and PIP and their staging in terms of acuity and severity form the essential first step in management. It is important to suspect the presence of psychosis whenever patients manifest unusual behavior. Knowledge of psychopathology and both individual and epilepsy-related vulnerabilities relevant to IIP and PIP facilitate early diagnosis. Treatment for IIP involves (1) obtaining consent to psychiatric treatment from the patient, whenever possible, (2) optimization of antiepileptic drugs, and (3) initiation of antipsychotic pharmacotherapy in line with symptom severity and severity of behavioral and functional disturbance. Basic psychosocial interventions will help reinforce adherence to treatment and should be made available. Due consideration must be given to patients' ability to provide informed consent to treatment in the short term, with the issue being revisited regularly over time. Given the often prolonged and recurrent nature of IIP, treatment frequently needs to be long-term. Treatment of PIP consists of two aspects, that is, acute protective measures and preventive procedures in repetitive episodes. Protective measures prioritize the management of risk in the early stages, and may involve sedation with or without the use of antipsychotic drugs, and the judicious application of local mental health legislation if appropriate. As for preventative procedures, optimizing seizure control by adjusting antiepileptic drugs or by surgical treatment is necessary.
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PMID:Basic treatment principles for psychotic disorders in patients with epilepsy. 2345 63


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