our publications
"Preclinical Development of the Na-K-2Cl Co-transporter-1 (NKCC1) Inhibitor ARN23746 for the Treatment of Neurodevelopmental Disorders"
ACS Pharmacol Transl Sci. 2023, 6(1):1-11
A. Savardi, M. Borgogno, M. De Vivo, L. Cancedda
"Pharmacological tools to target NKCC1 in brain disorders"
Trends in Pharmacological Sciences (Cell Press) 2021, 42, 12, 1009-1034
C. Portioli, M. J. Ruiz Munevar, M. De Vivo, L. Cancedda
"Cation-coupled chloride cotransporters: chemical insights and disease implications"
Trends in Chemistry (Cell Press), 2021, 3, 10, 832–849
M. Borgogno, A. Savardi, J. Manigrasso, A. Turci, C. Portioli, G. Ottonello, S. M. Bertozzi, A. Armirotti, A. Contestabile, L. Cancedda, M. De Vivo
"Design, synthesis, in vitro and in vivo characterization of selective NKCC1 inhibitors for the treatment of core symptoms in Down syndrome and other brain disorders”
Journal of Medicinal Chemistry 2021, 64, 14, 10203–10229
A. Savardi, M Borgogno, R. Narducci, G. La Sala, J. Ortega, M. Summa, A. Armirotti, R. Bertorelli, A. Contestabile, M. De Vivo, L Cancedda
"Discovery of a small molecule drug candidate for selective NKCC1 inhibition in brain disorders"
Chem (Cell Press) 2020, 6, 1–24
L. Riccardi, V. Genna, M. De Vivo
"Metal-ligand interactions in drug design"
Nature Reviews Chemistry, 2018, 2, 100–112
G. Deidda, M. Parrini, S. Naskar, I. F. Bozarth, A. Contestabile, L. Cancedda
"Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome”
Nature Medicine, 2015, 21, 318–326
scientific background and key publications
Below is a curated selection of key scientific publications related to NKCC1, the physiological and pathological imbalance between NKCC1 and KCC2, and the clinical development of bumetanide—an unselective NKCC1 inhibitor—as proof of concept for chloride modulation therapies in the central nervous system.
These studies highlight the central role of chloride homeostasis in regulating neuronal excitability, and demonstrate how NKCC1 hyperactivity and KCC2 downregulation contribute to altered GABAergic signaling across a wide range of neurological, neurodevelopmental, and psychiatric conditions.
Clinical and preclinical investigations of bumetanide have provided foundational evidence that targeting this pathway can have therapeutic impact in conditions such as epilepsy, autism spectrum disorder, Fragile X syndrome, Rett syndrome, neuropathic pain, and schizophrenia. Together, this body of work supports the rationale behind IAMA Therapeutics’ drug discovery platform and the development of selective NKCC1 inhibitors as a new generation of mechanism-based treatments for CNS disorders.Autism Spectrum Disorder
Tyzio R, Nardou R, Ferrari D C, et al.
Oxytocinmediated GABA inhibition
during delivery attenuates autism pathogenesis in rodent
offspring.
Science, 2014
Deidda G, Parrini M, Naskar S, et al.
Reversing excitatory GABA actions in
neurodevelopmental disorders: a novel therapeutic
strategy.
Front Cell Neurosci, 2015
Zhang HL, Li X, Xu Y, et al.
Inhibition of NKCC1 ameliorates anxiety and
autistic behaviours induced by maternal immune activation in mice.
Current
Issues in Molecular Biology, 2024
Lemonnier E, Degrez C, Phelip M, et al.
A randomised controlled trial of
bumetanide in the treatment of autism in children.
Transl Psychiatry, 2012
Bruining H, van Andel D, Oranje B, et al.
Bumetanide for core symptoms of
Autism Spectrum Disorder (BAMBI): a phaseII doubleblind
trial.
J Am Acad Child Adolesc Psychiatry, 2020
Fuentes J, de Nijeveld M, Bruining H, et al.
Bumetanide oral solution in
children and adolescents with ASD: two randomised phaseIII
trials.
Autism Research, 2023
Fragile X Syndrome
Banerjee A, Rikhye R V, BretonProvencher V, et al.
Impairment of GABAergic
inhibition in prefrontal cortex leads to workingmemory deficits in Fragile X
syndrome.
Neuron, 2016
Tang X, Drotar J, Li K, et al.
Regionspecific KCC2 rescue of GABA inhibition
improves behavioural deficits in Fragile X mice.
Molecular Psychiatry, 2019
Kourdougli N, Chamma I, Bui P, et al.
The NKCC1 inhibitor bumetanide
restores cortical feedforward inhibition and lessens sensory
hypersensitivity in early postnatal FXS mice.
Biological Psychiatry, 2025
Rett Syndrome
Duarte S T, Armstrong J, Roche A, et al.
Reduced expression of KCC2 in
neurons from patients with Rett syndrome.
Brain Research, 2013
Pozzi D, Rasile M, Corradini I, et al.
REST/NRSFmediated downregulation of
KCC2 contributes to GABAergic dysfunction in Rett syndrome.
Brain, 2013
Tang X, Zhang L, Chen Q, et al.
Pharmacological enhancement of KCC2
expression exerts therapeutic effects on human Rett neurons and Mecp2mutant
mice.
Science Translational Medicine, 2019
Epilepsy & Seizure Disorders
Developmental Epilepsy
Dzhala V I, Talos D M, Sdrulla D A, et al.
NKCC1 transporter facilitates
seizures in the developing brain.
Nature Medicine, 2005
Galanopoulou A S.
Sexually dimorphic expression of KCC2 and NKCC1 in rat
brain: implications for neonatal seizures.
Epilepsia, 2008
Nguyen T D, Chen Y, Zhou R, et al.
Astrocytic NKCC1 inhibits seizures by
buffering Cl⁻ at GABAergic synapses.
Epilepsia, 2023
DrugResistant Epilepsy
Puskarjov M, Kahle K T, Ruusuvuori E, et al.
Physiological effects of KCC2
deficiency and NKCC1 hyperactivity on seizure susceptibility.
Neuron, 2014
Barmashenko G, Hefft S, Aertsen A, Kirschstein T.
Reduced KCC2 expression
leads to enhanced neuronal excitability and seizure
activity.
Epilepsia, 2011
McMoneagle E, Kadam S D, Hegarty S V.
Neuronal KCC2 as a promising drug
target for epilepsy treatment.
Acta Pharmacologica Sinica, 2024
Status Epilepticus
Jarvis R, Ng S F, Cardarelli R A, et al.
Direct activation of KCC2 arrests
benzodiazepinerefractory status epilepticus and limits neuronal
injury.
Cell Reports Medicine, 2023
Neonatal Seizures
Pressler R M, Boylan G B, Neonatal
European Multicentre (NEMO) Group.
Bumetanide for the treatment of seizures
in newborn babies with hypoxicischaemic encephalopathy (phase I/II
dosefinding).
Lancet Neurology, 2015
Soul J S, Boston Bumetanide Trial Group.
A pilot randomised doubleblind
trial of bumetanide to treat neonatal seizures.
Annals of Neurology, 2021
Pain Disorders
Neuropathic Pain
Coull J A, Boudreau D, Bachand K, et al.
BDNF from microglia causes the
shift in neuronal anion gradient underlying neuropathic pain.
Nature, 2003
Pitcher G M, Beggs S, Woo R S, et al.
Spinal NKCC1 downregulation reverses
pathological pain in animal models.
Neuron, 2007
Li Y, Zhang P, Huang Y, et al.
Nociceptorlocalized KCC2 suppresses
brachialplexusavulsion neuropathic pain.
Nature Communications, 2025
Chronic / Inflammatory Pain
Hasbargen T, Ahmed M M, Miranpuri G, et al.
Role of NKCC1 in chronic pain
and spinalcord plasticity.
Journal of Neurotrauma, 2010
Kahle K T, Khanna A R, Alper S L, et al.
Therapeutic potential of targeting
cationchloride cotransporters in pain.
Nature Reviews Neurology, 2016
Keppel G, Rossi P, Bianchi M, et al.
Repurposing kenpaullone normalises
E_GABA via KCC2 upregulation and reverses mechanical
allodynia.
Nature Communications, 2021
Psychiatric Disorders
Schizophrenia
Hyde T M, Lipska B K, Ali T, et al.
Expression of GABArelated genes and
KCC2/NKCC1 in schizophrenia.
Biological Psychiatry, 2011
Rahmanzadeh R, Rahim F, Farrokhi E, et al.
Effect of bumetanide on
hallucinations of schizophrenic patients: a doubleblind randomised clinical
trial.
Schizophrenia Research, 2017
Takahashi N, Nagai T, Tateno T, et al.
NKCC1 inhibition normalises GABA
function and reverses social deficits in a schizophrenia
model.
Neuropsychopharmacology, 2020
Anxiety & Stress
Bosman L W, Takeuchi T, Hartmann J, et al.
Abnormal chloride transporter
expression in stressinduced anxiety.
Molecular Psychiatry, 2015
Sagi R, BenDavid Y, Avraham Y, et al.
Loss of ZnR/GPR39 increases
anxietylike behaviour and modulates KCC2 in the
amygdala.
Behavioural Brain Function, 2024
Memory / Emotion
Kreis A, Larsen E, Donato R, et al.
Conditional deletion of KCC2 impairs
synaptic plasticity and both spatial and nonspatial
memory.
Frontiers in Molecular Neuroscience, 2023
Neurodegeneration & CNS Trauma
Spinal Cord Injury
Gagnon M, Bergeron M J, Lavertu G, et al.
Chloride regulation and KCC2/NKCC1
expression after spinalcord injury.
Journal of Neuroscience, 2013
Boulenguez P, Liabeuf S, Bos R, et al.
Downregulation of KCC2 in motoneurons
after spinalcord injury leads to spasticity.
Nature Medicine, 2010
Pan YZ, Wang Z, Chen L, et al.
CLP290 plus bumetanide alleviates neuropathic
pain after SCI in rats.
CNS Neuroscience & Therapeutics, 2024
Traumatic Brain Injury
Dzhala V I, Kuchibhotla K V, Glykys J, et al.
Traumatic brain injuryinduced
NKCC1 expression disrupts inhibitory control.
Journal of Neuroscience, 2012
Tessier M, Simard F, SiroisRobin J, et al.
Bumetanide induces
microglia–interneuron contact and promotes neurogenesis after
TBI.
Brain, 2023
Alzheimer’s Disease
Ding Y, Ma X, Gu J, et al.
Imbalance of KCC2/NKCC1 contributes to cognitive
decline in Alzheimer’s models.
Molecular Brain, 2021
Ferando I, Younes K, Sha S, et al.
Restoring neuronal chloride extrusion
reverses cognitive decline in APP/PS1 mice.
Brain, 2023
Younes K, Stanford ADRC Group.
Bumetanide in patients with Alzheimer’s
disease (BumxAD): phase II safety and tolerability trial
(ongoing).
ClinicalTrials.gov, NCT06052163, started 2024
