Bidirectional Regulation of GABAA Reversal Potential in the Adult Brain: Physiological and Pathological Implications DOI Creative Commons
Haram Kim, Marco Martina

Life, Journal Year: 2024, Volume and Issue: 14(1), P. 143 - 143

Published: Jan. 19, 2024

In physiological conditions, the intracellular chloride concentration is much lower than extracellular. As GABAA channels are permeable to anions, reversal potential of very close that Cl−, which most abundant free anion in intra- and extracellular spaces. Intracellular regulated by activity ratio NKCC1 KCC2, two chloride-cation cotransporters import export respectively. Due closeness between value resting membrane neurons, small changes have a major functional impact, makes uniquely flexible signaling system. neurons adult brain, slightly more negative potential, hyperpolarizing. Alterations common feature numerous conditions as they consequence an imbalance NKCC1-KCC2 ratio. (including Alzheimer’s disease, schizophrenia, Down’s syndrome), becomes depolarizing, causes network desynchronization behavioral impairment. other (neonatal inflammation neuropathic pain), however, hypernegative, affects behavior through potent circuit deactivation.

Language: Английский

New epilepsy therapies in development DOI
Pavel Klein, Rafal M. Kaminski, Matthias J. Koepp

et al.

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 682 - 708

Published: July 22, 2024

Language: Английский

Citations

27
Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus DOI
Richard J. Burman, Richard Rosch, Jo M. Wilmshurst

et al.

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 18(7), P. 428 - 441

Published: May 10, 2022

Language: Английский

Citations

61
Dogs as a Natural Animal Model of Epilepsy DOI Creative Commons
Wolfgang Löscher

Frontiers in Veterinary Science, Journal Year: 2022, Volume and Issue: 9

Published: June 22, 2022

Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In species, epilepsy complex brain characterized by enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as humans, status epilepticus one the more emergencies with not single but group disorders broad array clinical signs, age onset, underlying causes. Brain imaging suggests that limbic system, including hippocampus cingulate gyrus, often affected canine epilepsy, which could explain high incidence comorbid behavioral problems such anxiety cognitive alterations. Resistance antiseizure medications significant problem human so can be used study mechanisms drug resistance develop novel therapeutic strategies benefit species. Importantly, are large enough accommodate intracranial EEG responsive neurostimulation devices designed for humans. Studies have reported ictal interictal events remarkably similar those occurring Continuous (24/7) recordings select >1 year provided rich dataset unprecedented length studying seizure periodicities developing new methods forecasting. The data presented this review substantiate excellent several facets research. techniques inducing seizures laboratory discussed related advances. development vagus nerve stimulation therapy drug-resistant people was based on series studies induced Dogs naturally or provide large-animal models bridge gap between rodents therapies. because dog only preclinical species medicine also potential patient pet, research serves veterinary medicine.

Language: Английский

Citations

40
Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus DOI Creative Commons
Cameron Sadegh, Huixin Xu, Jason Sutin

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(10), P. 1591 - 1608.e4

Published: March 8, 2023

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding this variably progressive condition has hampered the development new therapies beyond serial neurosurgical interventions. Here, we show key role for bidirectional Na-K-Cl cotransporter, NKCC1, in choroid plexus (ChP) mitigate PHH. Mimicking IVH with blood led increased CSF [K+] and triggered cytosolic calcium activity ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly persistently clearance capacity. These data demonstrate trans-choroidal, NKCC1-dependent mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed ventriculomegaly. Excessive fluctuations correlated permanent shunting outcome humans hemorrhagic stroke, suggesting targeted gene therapy as potential treatment intracranial hemorrhage.

Language: Английский

Citations

39
New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development DOI Creative Commons
Emilio Perucca, H. Steve White, Meir Bialer

et al.

CNS Drugs, Journal Year: 2023, Volume and Issue: 37(9), P. 781 - 795

Published: Aug. 21, 2023

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption GABAergic transmission contributes to pathogenesis some seizure disorders. Although many currently available antiseizure medications do act at least part by potentiating transmission, there is opportunity for further research aimed developing more innovative GABA-targeting therapies. present article summarises evidence on number such treatments clinical development. These can be broadly divided into three groups. first group consists positive allosteric modulators GABAA receptors includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed epilepsy as potential rescue inhalation treatment prolonged repetitive seizures), α2/3/5 subtype-selective agents darigabat ENX-101, orally active neurosteroids ETX155 LPCN 2101. A second comprises two drugs non-neurological indications, which could include bumetanide, diuretic agent that has undergone trials phenobarbital-resistant neonatal seizures rationale development this indication under debate, ivermectin, antiparasitic drug investigated randomised double-blind trial focal epilepsy. last series highly therapies, namely interneurons (NRTX-001) delivered via stereotactic cerebral implantation mesial temporal lobe epilepsy, antisense oligonucleotide (STK-001) upregulating NaV1.1 currents restoring function interneurons, tested patients with Dravet syndrome, adenoviral vector-based gene therapy (ETX-101) scheduled investigation syndrome. Another agent, subcutaneously administered neuroactive peptide (NRP2945) reportedly upregulates expression receptor α β subunits investigated, Lennox–Gastaut syndrome other epilepsies proposed indications. diversity current pipeline underscores strong interest GABA system target new To date, limited data are these investigational studies required assess their value addressing unmet needs management.

Language: Английский

Citations

25
Fundamental Neurochemistry Review: GABAA receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy DOI Open Access
Alexander Bryson, Christopher A. Reid, Steven Petrou

et al.

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(1), P. 6 - 28

Published: Jan. 22, 2023

Abstract Epilepsy is a common neurological disorder associated with alterations of excitation‐inhibition balance within brain neuronal networks. GABA A receptor neurotransmission the most prevalent form inhibitory and strongly implicated in both pathophysiology treatment epilepsy, serving as primary target for antiseizure medications over century. It now established that exerts multifaceted influence through an array subtypes extends far beyond simply negating excitatory activity. As role circuits elaborated, this will enable development precision therapies correct network dysfunction underlying epileptic pathology. image

Language: Английский

Citations

22
Expression patterns of NKCC1 in neurons and non-neuronal cells during cortico-hippocampal development DOI Creative Commons
Samu Kurki, Pavel Uvarov, Alexey S. Pospelov

et al.

Cerebral Cortex, Journal Year: 2022, Volume and Issue: 33(10), P. 5906 - 5923

Published: Dec. 27, 2022

Abstract The Na-K-2Cl cotransporter NKCC1 is widely expressed in cells within and outside the brain. However, our understanding of its roles brain functions throughout development, as well neuropsychiatric neurological disorders, has been severely hindered by lack reliable data on developmental (sub)cellular expression patterns. We provide here first properly controlled analysis protein various cell types mouse using custom-made antibodies an knock-out validated immunohistochemical procedure, with parallel based advanced mRNA approaches. are at remarkably high levels oligodendrocytes. In immature neurons, was located somata, whereas adult only could be clearly detected. immunoreactivity also seen microglia, astrocytes, developing pericytes, progenitor dentate gyrus. Finally, a differential splice variants observed, NKCC1a predominating non-neuronal NKCC1b neurons. Taken together, cellular basis for enable identification major limitations promises development neuron-targeting NKCC1-blockers.

Language: Английский

Citations

32
Mechanisms of cerebrospinal fluid and brain interstitial fluid production DOI Creative Commons
Jianming Xiang, Ya Hua, Guohua Xi

et al.

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 183, P. 106159 - 106159

Published: May 19, 2023

Fluid homeostasis is fundamental for brain function with cerebral edema and hydrocephalus both being major neurological conditions. movement from blood into one crucial element in fluid homeostasis. Traditionally it has been thought to occur primarily at the choroid plexus (CP) as cerebrospinal (CSF) secretion due polarized distribution of ion transporters CP epithelium. However, there are currently controversies importance secretion, just how transport occurs that epithelium versus other sites, well direction flow ventricles. The purpose this review evaluate evidence on CSF vasculature differs tissues, e.g., blood-brain barrier may drive flow. It also addresses recent promising data two potential targets modulating Na

Language: Английский

Citations

18
The NKCC1 inhibitor bumetanide restores cortical feedforward inhibition and lessens sensory hypersensitivity in early postnatal fragile X mice. DOI
Nazim Kourdougli,

Toshihiro Nomura,

M. Wu

et al.

Biological Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

Citations

6
GABAergic circuits drive focal seizures DOI Creative Commons
Elena Dossi, Gilles Huberfeld

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 180, P. 106102 - 106102

Published: March 26, 2023

Epilepsy is based on abnormal neuronal activities that have historically been suggested to arise from an excess of excitation and a defect inhibition, or in other words excessive glutamatergic drive not balanced by GABAergic activity. More recent data however indicate signaling defective at focal seizure onset may even be actively involved generation providing excitatory inputs. Recordings interneurons revealed they are active initiation their selective time-controlled activation using optogenetics triggers seizures more general context increased excitability. Moreover, appears mandatory many models. The main pro-ictogenic effect the depolarizing action GABAA conductance which occur when activity causes Cl- accumulation neurons. This process combine with background dysregulation Cl-, well described epileptic tissues. equilibrium maintained (Na+)/K+/Cl- co-transporters, can therefore favor effects GABA. In addition, these co-transporters further contribute this as mediate K+ outflow together extrusion, responsible for extracellular space subsequent increase local role obvious but its complex dynamics balance between flux polarity excitability still remain established, especially tissues where receptors ion regulators disrupted rather plays 2 faces Janus role.

Language: Английский

Citations

14