Preliminary study of analgesic effect of bumetanide on neuropathic pain in patients with spinal cord injury

Zarepour, Leila; Gharaylou, Zeinab; Hadjighassem, Mahmoudreza; Shafaghi, Lida; Majedi, Hossein; Behzad, Ebrahim; Hosseindoost, Saereh; Ramezani, Fatemeh; Nasirinezhad, Farinaz

doi:10.1016/j.jocn.2020.10.010

Cited by 14 publications

(17 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1 H NMR (400 MHz, DMSO-d 6 ): δ 12.63 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.77 (t, J = 5.5 Hz, 1H), 3.38−3.32 (m, 2H), 3.26 (q, J = 6.5 Hz, 2H), 3.22 (s, 3H), 2.65 (s, 6H), 1.65−1.51 (m, 4H). 13 3-(-N,N-Dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic Acid (31). Compound 31 was synthesized according to the general procedure 6 using intermediate 50b (50 mg, 0.20 mmol) and amine 53b (53.1 mg, 0.40 mmol) in dry 1,4-dioxane (0.7 mL).…”

Section: Journal Ofmentioning

confidence: 99%

“…Several studies have indeed indicated that bumetanide rescues [Cl – ] i and behavioral deficits in the Ts65Dn mouse model of DS, as well as in mouse models of a number of other brain disorders. , Most notably, bumetanide treatment has shown positive outcomes also in humans during several clinical trials and case studies of neurodevelopmental disorders (autism, − Fragile X, Asperger syndrome, 15q11.2 duplication, schizophrenia, , and tuberous sclerosis complex , ), neurodegenerative disorders (Parkinson disease), and also neurological disorders (epilepsy − and neuropathic pain). Nevertheless, the strong diuretic effect of bumetanide severely endangers drug compliance, while also leading to hypokalaemia and general ionic imbalance, ototoxicity in young individuals, and potential kidney damage upon chronic treatments. − As such, bumetanide and its close analogues and prodrugs − have severe limitations and downsides when considered as a clinical option to treat brain disorders.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome

et al. 2021

View full text Add to dashboard Cite

Intracellular chloride concentration [Cl – ] i is defective in several neurological disorders. In neurons, [Cl – ] i is mainly regulated by the action of the Na + –K + –Cl – importer NKCC1 and the K + –Cl – exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead with in vivo efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.

show abstract

Section: Journal Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Dysfunctions of GABAergic transmission at the level of dorsal microcircuits impair the mechanisms of presynaptic inhibition, resulting in neuropathic pain states [ 72 ]. Neuropathic pain is one of the most frequent complications in paraplegics, with an incidence of 53% [ 73 ], and is often treated with GABAergic drugs [ 74 , 75 ].…”

Section: Presynaptic Gabaergic Inhibition and Neuropathic Painmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

“…Interestingly, NKCC1 downregulation in PBMCs was also reported in schizophrenic subjects [49]. Moreover, KCC2 downregulation was observed in PBMCs from patients with SCI and was normalized after bumetanide treatment [89]. Furthermore, reduced levels of KCC2 protein were reported in CSF from Rett syndrome subjects [26].…”

Section: Box 2 Biomarkers For Neurological Disordersmentioning

confidence: 89%

“…Nevertheless, NKCC1 activation is required to regenerate injured peripheral nerves in the SCI and PNI models [74,88], which complicates possible therapeutic interventions. Downregulation of KCC2 in PBMCs (Box 2) was observed in patients with SCI, and bumetanide normalized KCC2 levels and reduced pain intensity [89] (Tables 1 and 3).…”

Section: Insult-induced Neurological Disordersmentioning

confidence: 94%

Pharmacological tools to target NKCC1 in brain disorders

Savardi

Borgogno

Vivo

et al. 2021

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

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...

show abstract

Preliminary study of analgesic effect of bumetanide on neuropathic pain in patients with spinal cord injury

Cited by 14 publications

References 47 publications

Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome

Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome

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

Pharmacological tools to target NKCC1 in brain disorders

Contact Info

Product

Resources

About