Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice

Hampel, Philip; Römermann, Kerstin; Gailus, Björn; Johne, Marie; Gericke, Birthe; Kaczmarek, Edith; Löscher, Wolfgang

doi:10.1016/j.neuropharm.2021.108449

Cited by 8 publications

(8 citation statements)

References 67 publications

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“…The strength of postsynaptic inhibition, related to Clhomeostasis, is hampered in several pathophysiological conditions [55] such as seizure, epilepsy, stroke, and ischemic injury [33,56] and proprioception disorders [57]. Indeed, impaired excitation/inhibition balance due to changed NKCC1 or KCC2 expression was also related to chronic stress [58], brain or peripheral injury [47,59], and locomotor activity after spinal cord injury [60,61] or developmental changes [62][63][64].…”

Section: Neuronal Chloride Homeostasis In the Spinal Cord Is Regulated By Two Transportersmentioning

confidence: 99%

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

et al. 2021

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Correct operation of neuronal networks depends on the interplay between synaptic excitation and inhibition processes leading to a dynamic state termed balanced network. In the spinal cord, balanced network activity is fundamental for the expression of locomotor patterns necessary for rhythmic activation of limb extensor and flexor muscles. After spinal cord lesion, paralysis ensues often followed by spasticity. These conditions imply that, below the damaged site, the state of balanced networks has been disrupted and that restoration might be attempted by modulating the excitability of sublesional spinal neurons. Because of the widespread expression of inhibitory GABAergic neurons in the spinal cord, their role in the early and late phases of spinal cord injury deserves full attention. Thus, an early surge in extracellular GABA might be involved in the onset of spinal shock while a relative deficit of GABAergic mechanisms may be a contributor to spasticity. We discuss the role of GABA A receptors at synaptic and extrasynaptic level to modulate network excitability and to offer a pharmacological target for symptom control. In particular, it is proposed that activation of GABA A receptors with synthetic GABA agonists may downregulate motoneuron hyperexcitability (due to enhanced persistent ionic currents) and, therefore, diminish spasticity. This approach might constitute a complementary strategy to regulate network excitability after injury so that reconstruction of damaged spinal networks with new materials or cell transplants might proceed more successfully.

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Section: Neuronal Chloride Homeostasis In the Spinal Cord Is Regulated By Two Transportersmentioning

confidence: 99%

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

et al. 2021

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“…In another series of experiments, we investigated various other loop diuretics previously not known to inhibit NKCC1. We found that (1) azosemide is a more potent inhibitor of human NKCC1 than bumetanide and various other loop diuretics 23 ; (2) both azosemide and its close analog torasemide increase the antiseizure potency of phenobarbital in a mouse model 24 ; but (3) neither azosemide nor torasemide reaches higher relative brain levels than bumetanide 25 . The latter finding is due to all three loop diuretics being actively transported out of the brain, which reduces their brain‐to‐plasma ratio 10,25 …”

Section: Bumetanide and Its Derivativesmentioning

confidence: 88%

“…The pharmacokinetics of the bumetanide derivatives described above have been assessed only in rodents 15,17,25 …”

Section: Bumetanide and Its Derivativesmentioning

confidence: 99%

“…We found that (1) azosemide is a more potent inhibitor of human NKCC1 than bumetanide and various other loop diuretics 23 ; (2) both azosemide and its close analog torasemide increase the antiseizure potency of phenobarbital in a mouse model 24 ; but (3) neither azosemide nor torasemide reaches higher relative brain levels than bumetanide. 25 The latter finding is due to all three loop diuretics being actively transported out of the brain, which reduces their brain-to-plasma ratio. 10,25 The groups of Thomas Erker in Vienna, Austria, and Laura Cancedda in Genoa, Italy, reported several other potentially interesting bumetanide derivatives, 14,26 but it remains to be established whether these compounds exhibit advantages versus bumetanide in the treatment of brain disorders.…”

Section: Activity Profile In Animal Models Of Seizures and Epilepsymentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI):II. Drugs in more advanced clinical development

et al. 2022

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The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22–25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK‐001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin‐dependent kinase‐like 5 deficiency disorder in patients 2 years of age and older.

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“…However, much has been learned by studying the sclerosed hippocampi in preclinical models of TLE, which have shown similar pathophysiology like mossy fiber sprouting in the dorsal hippocampi [119]. Attempts to increase PB efficacy in a pilocarpine-induced epilepsy adult rodent model showed that the NKCC1 inhibitors BTN, azosemide, or torasemide did not improve PB efficacy [120], suggesting that NKCC1 antagonism is not a promising avenue for rescuing refractory epilepsies.…”

Section: Refractory Tle Seizuresmentioning

confidence: 99%

Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures

Kipnis

Kadam

2021

Aging and disease

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Epilepsy is associated with a multitude of acquired or genetic neurological disorders characterized by a predisposition to spontaneous recurrent seizures. An estimated 15 million patients worldwide have ongoing seizures despite optimal management and are classified as having refractory epilepsy. Early-life seizures like those caused by perinatal hypoxic ischemic encephalopathy (HIE) remain a clinical challenge because although transient, they are difficult to treat and associated with poor neurological outcomes. Pediatric epilepsy syndromes are consistently associated with intellectual disability and neurocognitive comorbidities. HIE and arterial ischemic stroke are the most common causes of seizures in term neonates and account for 7.5-20% of neonatal seizures. Standard first-line treatments such as phenobarbital (PB) and phenytoin fail to curb seizures in ~50% of neonates. In the long-term, HIE can result in hippocampal sclerosis and temporal lobe epilepsy (TLE), which is the most common adult epilepsy, ~30% of which is associated with refractory seizures. For patients with refractory TLE seizures, a viable option is the surgical resection of the epileptic foci. Novel insights gained from investigating the developmental role of Clcotransporter function have helped to elucidate some of the mechanisms underlying the emergence of refractory seizures in both HIE and TLE. KCC2 as the chief Clextruder in neurons is critical for enabling strong hyperpolarizing synaptic inhibition in the brain and has been implicated in the pathophysiology underlying both conditions. More recently, KCC2 function has become a novel therapeutic target to combat refractory seizures.

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Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice

Cited by 8 publications

References 67 publications

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI):II. Drugs in more advanced clinical development

Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures

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