Seizures and Sodium Hydrogen Exchangers: Potential of Sodium Hydrogen Exchanger Inhibitors as Novel Anticonvulsants

Ali, Atif; Ahmad, Feroz; Dua, Yashomati; Pillai, K. K.; Vohora, Divya

doi:10.2174/187152708786441830

Cited by 15 publications

(12 citation statements)

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“…The diuretic drug amiloride and its analogs were the first NHE inhibitors to be developed (Masereel et al, 2003; Orlowski and Grinstein, 2004). NHE1 and NHE2 are the most sensitive to amiloride-mediated inhibition while NHE3, NHE4, and NHE7 are amiloride-resistant isoforms (Ali et al, 2008; Masereel et al, 2003). Additionally, amiloride inhibits voltage-gated Na + channels and the Na + /Ca 2+ exchangers (Schellenberg et al, 1983; Velly et al, 1988).…”

Section: Pharmacological Inhibitorsmentioning

confidence: 99%

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Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.

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Section: Pharmacological Inhibitorsmentioning

confidence: 99%

“…In vivo data have demonstrated the anticonvulsant efficacy of amiloride in the different animal models of seizure and epilepsy (Ali et al, 2008). Amiloride-treated mice show increased resistance to both electrical and chemical induced seizures (Ali et al, 2004).…”

Section: Pharmacological Inhibitorsmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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“…In line with this, NHE is assumed to favourably regulate neuronal excitability and post‐ictal recovery in different transgenic models (reviewed by Obara et al ., 2008). However, in contrast, several studies have obtained experimental findings indicating that inhibitors targeting NHE are of significant therapeutic value in epilepsy (reviewed by Ali et al ., 2008). In this context, the influence of H 3 receptor ligands on NHE and subsequent implications in epilepsy need to be assessed.…”

Section: Inhibition Of the Na+/h+ Exchangermentioning

confidence: 99%

Histamine H₃receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Bhowmik

Khanam

Vohora

2012

British J Pharmacology

106

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The central histaminergic actions are mediated by H1, H2, H3 and H4 receptors. The histamine H3 receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H3 receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go‐protein‐coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti‐epileptogenic drugs. So far, H3 receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H3 receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.

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“…The test groups received the testing compounds at the dose of 100 mg/kg IP before the PTZ administration. Animals devoid of clonic convulsions were considered to be protected and results were represented as percentage protection .…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents

Habib

Abdelfattah

Abadi

2015

Archiv der Pharmazie

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Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed.

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Seizures and Sodium Hydrogen Exchangers: Potential of Sodium Hydrogen Exchanger Inhibitors as Novel Anticonvulsants

Cited by 15 publications

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Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Histamine H₃receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents

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Seizures and Sodium Hydrogen Exchangers: Potential of Sodium Hydrogen Exchanger Inhibitors as Novel Anticonvulsants

Cited by 15 publications

References 0 publications

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Histamine H3receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents

Contact Info

Product

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Histamine H₃receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives