Efficacy and Safety of Bumetanide in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Clinical Trial

Mehrabi, Soraya; Sedighi, Mohsen; Ashtiani, Bahram Haghi; Afrakhteh, Motahareh; Shahriari, Elahe; Habibi, Seyed Amirhassan; Pourhamzeh, Mahsa; Susanabadi, Alireza; Soleimani, Mansoureh; Joghataei, Mohammad Taghi

doi:10.21203/rs.3.rs-265649/v1

Cited by 1 publication

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“…In agreement with preclinical data, NKCC1 upregulation was detected in patients with HD [9], and bumetanide ameliorated motor symptoms in ten patients with PD [103,104]. Interestingly, bumetanide also reduced ALS symptoms in a clinical trial [105] (Table 3). A Phase II trial is currently assessing the efficacy of bumetanide in PD (Table 3).…”

Section: Neurodegenerative Disorderssupporting

confidence: 80%

Pharmacological tools to target NKCC1 in brain disorders

Savardi

Borgogno

Vivo

et al. 2021

Trends in Pharmacological Sciences

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The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders. Neuronal Cl homeostasis: role in brain function and disordersIn neurons, the sodium (Na + )-potassium (K + )-Cltransporter isoform 1 (NKCC1, SLC12A2) and the K + -Cltransporter isoform 2 (KCC2, SLC12A5) [1] are key regulators of intracellular chloride concentration ([Cl -] i ). In the central nervous system (CNS), NKCC1 functions as a Climporter, and is highly expressed in immature neurons during early development [2]. Conversely, KCC2 expression is relatively low in early development (resulting in a high NKCC1/KCC2 ratio), increases during the postnatal period, and is more highly expressed in mature neurons (resulting in a low NKCC1/KCC2 ratio; Box 1). The fine regulation of [Cl -] i by NKCC1 and KCC2 is essential for brain development, including cell proliferation and apoptosis, and neuronal migration and maturation [3]. Moreover, NKCC1 and KCC2 are key for neuronal synaptic plasticity (see Glossary) and for maintaining a proper excitatory/inhibitory balance, which is fundamental for brain functions [3].A defective NKCC1/KCC2 expression ratio is often associated with several neurological and psychiatric disorders [4]. In particular, a large and growing body of literature reporting preclinical and clinical studies has shown that upregulation of NKCC1 and/or downregulation of KCC2 (resulting in an increased NKCC1/KCC2 ratio) underlie neurodevelopmental, insult-induced neurological, and neurodegenerative disorders [4] (Box 1; see Outstanding questions). Restoring neuronal [Cl -] i by inhibiting NKCC1 with bumetanide (an unselective NKCC1 inhibitor) was the first proof of concept for NKCC1 as a valuable target for several neurological conditions in preclinical (animal models) and clinical studies (patients) [5,6] (see Outstanding questions). Bumetanide is an FDAapproved thick ascending loop (TAL) of Henle diuretic, which acts by inhibiting the kidney transporter NKCC2. Due to its potent diuretic effect, bumetanide is currently indicated only to treat edema and swelling caused by congestive heart failure, acute pulmonary congestion, and hepatic an...

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Section: Neurodegenerative Disorderssupporting

confidence: 80%