Comparative efficacy of liposome-entrapped amiloride and free amiloride in animal models of seizures and serum potassium in mice

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

doi:10.1016/j.euroneuro.2006.05.003

Cited by 21 publications

(13 citation statements)

References 9 publications

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“…Amiloride is an aromatic drug that can diffuse across membranes and accumulate within cells (Kleyman and Cragoe, 1988), allowing it to cross the blood-brain barrier at sufficient doses. Seizure studies in mice suggest that amiloride crosses the blood-brain barrier when administered at 0.65 mg/kg i.v., causing anticonvulsant actions by acting on CNS targets (Ali et al, 2007). Similarly, other studies suggest that amiloride crosses the blood-brain and blood-spinal cord barriers, exerting neuroprotective effects when administered systemically at 10 mg/kg i.p.…”

Section: Amiloride Improves Locomotor Recoverymentioning

confidence: 99%

“…This could be achieved by using liposome-encapsulated amiloride, with liposomes that are designed to avoid the kidneys using an approach similar to the reversible masking method described by Shi and associates (2010). It has already been shown that systemically administered liposomeencapsulated amiloride does not increase serum potassium levels, in contrast to systemically administered free amiloride (Ali et al, 2007).…”

Section: Fig 2 (A)mentioning

confidence: 99%

“…Additionally, amiloride can cross the blood-brain barrier and has proven beneficial in the treatment of several neuropathological conditions including brain ischemia (Xiong et al, 2004), multiple sclerosis (Friese et al, 2007;Vergo et al, 2011), seizures (Ali et al, 2004(Ali et al, , 2005(Ali et al, , 2007N'Gouemo, 2008), Parkinson's disease (Arias et al, 2008), gliomas (Sipos et al, 2000), and in an in vitro model of spinal cord dorsal column compression injury (Agrawal and Fehlings, 1996). However, the therapeutic potential of amiloride has not been tested in a clinically relevant animal model of contusion spinal cord injury (SCI).…”

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confidence: 99%

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Amiloride Improves Locomotor Recovery after Spinal Cord Injury

Durham-Lee

Mokkapati²,

Johnson³

et al. 2011

Journal of Neurotrauma

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Amiloride is a drug approved by the United States Food and Drug Administration, which has shown neuroprotective effects in different neuropathological conditions, including brain injury or brain ischemia, but has not been tested in spinal cord injury (SCI). We tested amiloride's therapeutic potential in a clinically relevant rat model of contusion SCI inflicted at the thoracic segment T10. Rats receiving daily administration of amiloride from 24 h to 35 days after SCI exhibited a significant improvement in hindlimb locomotor ability at 21, 28, and 35 days after injury, when compared to vehicle-treated SCI rats. Rats receiving amiloride treatment also exhibited a significant increase in myelin oligodendrocyte glycoprotein (MOG) levels 35 days after SCI at the site of injury (T10) when compared to vehicle-treated controls, which indicated a partial reverse in the decrease of MOG observed with injury. Our data indicate that higher levels of MOG correlate with improved locomotor recovery after SCI, and that this may explain the beneficial effects of amiloride after SCI. Given that amiloride treatment after SCI caused a significant preservation of myelin levels, and improved locomotor recovery, it should be considered as a possible therapeutic intervention after SCI.

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Section: Amiloride Improves Locomotor Recoverymentioning

confidence: 99%

Section: Fig 2 (A)mentioning

confidence: 99%

mentioning

confidence: 99%

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Amiloride Improves Locomotor Recovery after Spinal Cord Injury

Durham-Lee

Mokkapati²,

Johnson³

et al. 2011

Journal of Neurotrauma

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“…At present, no selective ASIC antagonists are available to test the role of ASICs as anticonvulsant targets; however, the potassium-sparing diuretic amiloride does act as an ASIC antagonist and it appears to have anticonvulsant properties. 280 The peripheral cardiotoxicity of amiloride caused by its hyperkalemic action can be reduced by a liposome encapsulation. Status epilepticus has been shown to cause downregulation of ASIC mRNA (types 2b and 1a) in the hippocampus, raising the possibility that resistance to ASIC antagonists could occur under some circumstances.…”

Section: Acid-sensing Ion Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…These experiments showed that amiloride can increase the seizure threshold, prolong the latent period of kindling, decrease the incidence of seizures, improve emotion and memory, and alleviate behavioral impairment [104][105][106][107]. In addition, when the drug was delivered in a liposomeentrapped manner, its anticonvulsant effect was enhanced [108].…”

Section: Amiloridementioning

confidence: 99%

Exploring novel AEDs from drugs used for treatment of non-epileptic disorders

Zheng

Wang

2016

Expert Review of Neurotherapeutics

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Epilepsy is a chronic neurological disease. Although many anti-epileptic drugs (AEDs) have been developed for clinical use, they have no effect on 20-30% of patients and do not generally prevent epileptogenesis. Because of the long development cycle for new AEDs and the high cost, increasing efforts are being made to find anti-epileptic effects among drugs that are already listed for the treatment of other diseases and repurpose them as potential anti-epileptic treatments. Here, we review the progress that has been made in this field as a result of animal and clinical trials of drugs such as rapamycin, everolimus, losartan, celecoxib, bumetanide and other non-epileptic drugs. These drugs can prevent the epileptogenesis, reduce the epileptic pathological changes, and even be used to treat intractable epilepsy. Their mechanisms of action are completely different from those of existing AEDs, prompting researchers to change their perspectives in the search for new AEDs. ARTICLE HISTORY

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Comparative efficacy of liposome-entrapped amiloride and free amiloride in animal models of seizures and serum potassium in mice

Cited by 21 publications

References 9 publications

Amiloride Improves Locomotor Recovery after Spinal Cord Injury

Amiloride Improves Locomotor Recovery after Spinal Cord Injury

Molecular Targets for Antiepileptic Drug Development

Exploring novel AEDs from drugs used for treatment of non-epileptic disorders

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