Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus

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

Published: May 10, 2022

Language: Английский

---

Excitatory/inhibitory balance in epilepsies and neurodevelopmental disorders: Depolarizing γ‐aminobutyric acid as a common mechanism

Epilepsia, Journal Year: 2023, Volume and Issue: 64(8), P. 1975 - 1990

Published: May 17, 2023

Epilepsy is one of the most common neurological disorders. Although many factors contribute to epileptogenesis, seizure generation mostly linked hyperexcitability due alterations in excitatory/inhibitory (E/I) balance. The hypothesis that reduced inhibition, increased excitation, or both etiology epilepsy. Increasing evidence shows this view oversimplistic, and inhibition through depolarizing γ-aminobutyric acid (GABA) similarly contributes epileptogenisis. In early development, GABA signaling depolarizing, inducing outward Cl- currents high intracellular concentrations. During maturation, mechanisms action shift from hyperpolarizing, a critical event during brain development. Altered timing associated with neurodevelopmental disorders Here, we consider different ways altered E/I balance discuss could be denominator underlying epilepsies.

Language: Английский

---

Rearing is critical for forming spatial representations in pre-weanling rats

Behavioural Brain Research, Journal Year: 2023, Volume and Issue: 452, P. 114545 - 114545

Published: June 15, 2023

Language: Английский

---

Aperiodic brain activity and response to anesthesia vary in disorders of consciousness

NeuroImage, Journal Year: 2023, Volume and Issue: 275, P. 120154 - 120154

Published: May 19, 2023

In the human electroencephalogram (EEG), oscillatory power co-exist with non-oscillatory, aperiodic activity. Although EEG analysis has traditionally focused exclusively on power, recent investigations have shown that component can distinguish conscious wakefulness from sleep and anesthetic-induced unconsciousness. This study investigates of individuals in a disorder consciousness (DOC); how it changes response to exposure anesthesia; relates brain's information richness criticality. High-density was recorded 43 DOC, 16 these undergoing protocol propofol anesthesia. The defined by spectral slope density. Our results demonstrate is more informative about participants' level than component, especially for patients suffered stroke. Importantly, pharmacologically induced change 30 45 Hz positively correlated individual's pre-anesthetic consciousness. loss information-richness criticality associated component. During anesthesia, distinguished according their 3-month recovery status. been historically neglected; this research highlights necessity considering measure assessment DOC future seeks understand neurophysiological underpinnings

Language: Английский

---

Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit

European journal of medical research, Journal Year: 2024, Volume and Issue: 29(1)

Published: March 27, 2024

Abstract Parkinson's disease (PD) is a progressive neurodegenerative as result of the degeneration dopaminergic neurons in substantia nigra pars compacta (SNpc). The fundamental features PD are motor and non-motor symptoms. symptoms develop due to disruption neurotransmitters other such γ-aminobutyric acid (GABA). potential role GABA neuropathology concerning was not precisely discussed. Therefore, this review intended illustrate possible regarding pathway essential regulating inhibitory tone prevent excessive stimulation cerebral cortex. Degeneration linked with reducing GABAergic neurotransmission. Decreasing activity promotes mitochondrial dysfunction oxidative stress, which highly related neuropathology. Hence, restoring by agonists may attenuate progression dysregulation SNpc contributes developing Besides, also pathway, amelioration reduce In conclusion, deregulation might be intricate Improving novel, beneficial approach control

Language: Английский

---

Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(6), P. 3063 - 3094

Published: April 12, 2024

Language: Английский

---

Antisocial personality disorder:Failure to balance excitation/inhibition?

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110321 - 110321

Published: Jan. 1, 2025

Language: Английский

---

Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression

Neuroscience, Journal Year: 2025, Volume and Issue: 569, P. 161 - 183

Published: Feb. 7, 2025

Language: Английский

---

Pharmacological tools to target NKCC1 in brain disorders

Trends in Pharmacological Sciences, Journal Year: 2021, Volume and Issue: 42(12), P. 1009 - 1034

Published: Oct. 4, 2021

A growing number of studies indicate a defective ratio the chloride importer NKCC1 and exporter KCC2, consequent impaired Cl intracellular regulation, in several brain conditions, from neurodevelopmental to neurological neurodegenerative disorders.The FDA-approved diuretic bumetanide, nonselective inhibitor NKCC1, reverses core symptoms disorders rodent models and/or clinical trials patients.Bumetanide has low penetration, its repurposing brings collateral issues limitations due excessive diuresis caused by NKCC2 inhibition kidney.Recent drug discovery efforts have evaluated novel inhibitors modulators designed with diverse strategies avoid adverse effects bumetanide. The KCC2 are key regulators neuronal concentration. NKCC1/KCC2 expression is associated disorders. Preclinical/clinical shown that United States bumetanide potential therapeutic strategy preclinical/clinical multiple conditions. However, poor penetration causes unwanted inhibiting kidney. To overcome these issues, reported more brain-penetrating selective prodrugs, analogs, new molecular entities. Here, we review evidence for pharmacological as an effective manage We also discuss advantages benefits risks agents In neurons, sodium (Na+)–potassium (K+)–Cl– transporter isoform 1 (NKCC1, SLC12A2) K+–Cl– 2 (KCC2, SLC12A5) [1.Watanabe M. Fukuda A. Development regulation homeostasis central nervous system.Front. Cell. Neurosci. 2015; 9: 371Crossref PubMed Scopus (101) Google Scholar] concentration ([Cl–]i). system (CNS), functions Cl– importer, highly expressed immature neurons during early development [2.Kaila K. et al.Cation-chloride cotransporters development, plasticity disease.Nat. Rev. 2014; 15: 637-654Crossref (345) Scholar]. Conversely, relatively (resulting high ratio), increases postnatal period, mature ratio; Box 1). fine [Cl–]i essential including cell proliferation apoptosis, migration maturation [3.Peerboom C. Wierenga C.J. GABA shift: developmental perspective.Neurosci. Biobehav. 2021; 124: 179-192Crossref (1) Moreover, synaptic (see Glossary) maintaining proper excitatory/inhibitory balance, which fundamental Scholar].Box 1Chloride GABAAergic transmissionGamma-aminobutyric acid (GABA) main inhibitory neurotransmitter CNS regulates excitability. It exerts action binding different receptors, ionotropic GABAA receptor (GABAAR). GABAARs ligand-gated ion channels respond allowing permeability (and partially HCO3–) through membrane. Depending on gradient across membrane resting neuron, can flow GABAAR both directions. Therefore, regulating crucial functioning GABAergic signaling.The During neurodevelopment, present inside higher ratio. Thus, opening efflux outside cell. Consequently, activation results depolarization (Figure I, left). Depolarization leads voltage-gated calcium removal Mg2+ block NMDA causing further influx into [4.Schulte J.T. al.Chloride transporters polarity developmental, psychiatric conditions.Neurosci. 2018; 90: 260-271Crossref (44) This sequence events pivotal excitability second messengers participate migration, differentiation, synaptogenesis, physiological After maturation, adult lower levels this condition, increased conductance generates hyperpolarizing transmission center). Hyperpolarizing significant role neuronal-network function optimize processing sensorial information throughout life Scholar].However, demonstrated depolarizing range [5.Ben-Ari Y. antagonists attenuate many disorders.Trends 2017; 40: 536-554Abstract Full Text PDF (79) altered ratio, expression/function resulting right). alteration affects and, thus, contributes severity some characterized homeostasis.Three suitable restoring [Cl–]i, independent two dysregulated right): (i) inhibition/downregulation most widely used approach, described detail text; (ii) activation/upregulation promising, but less explored [134.Delpire E. Advances compounds targeting cation-chloride cotransporter physiology.Am. J. Physiol. Cell 320: C324-C340Crossref (0) Scholar]; (iii) upstream effectors was recently proposed, it briefly text. Gamma-aminobutyric signaling. homeostasis. Three often particular, large body literature reporting preclinical upregulation downregulation ratio) underlie neurodevelopmental, insult-induced neurological, (Box 1; see Outstanding questions). Restoring (an unselective inhibitor) first proof concept valuable target conditions (animal models) (patients) Scholar,6.Kharod S.C. al.Off-label use disorders: overview.Front. 2019; 13: 310Crossref (34) Bumetanide thick ascending loop (TAL) Henle diuretic, acts kidney NKCC2. Due potent effect, currently indicated only treat edema swelling congestive heart failure, acute pulmonary congestion, hepatic renal diseases [7.Sidhu G. Puckett Bumetanide. StatPearls, 2021Google Notably, via RNAi [e.g., schizophrenia [8.Kim H.R. al.Depolarizing current prefrontal cortex linked cognitive impairment mouse model relevant schizophrenia.Sci. Adv. 7eaba5032Crossref (2) Scholar], Huntington's disease (HD) [9.Hsu Y.T. al.Enhanced Na(+) -K(+) -2Cl(-) underlies motor dysfunction huntington's disease.Mov. Disord. 34: 845-857Crossref Down syndrome (DS) [10.Parrini al.Restoring anti-NKCC1 gene therapy rescues deficits syndrome.Mol. Ther. 29: 3072-3092Abstract Scholar]] glioma cells [11.Ma H. al.NKCC1 promotes EMT-like process GBM RhoA Rac1 signaling pathways.J. 234: 1630-1642Crossref (17) Scholar,12.Sun involvement epithelial-to-mesenchymal transition prognostic biomarker gliomas.PeerJ. 2020; 8e8787Crossref offered direct summarize demonstrating pathogenesis (Table 1), contextualizing indications being developed.Table 1Summary dysregulation studiesaAbbreviations: CBC, cerebellar cortex; CMECs, cerebral microvascular endothelial cells; CP, choroid plexus; CSF, cerebrospinal fluid; CTX, DRG, dorsal root ganglia; E, embryonic day; GW, gestational week; HP, hippocampus; iPSCs, induced pluripotent stem MN, neurons; P, Ph, phosphorylation; PBMCs, peripheral blood mononuclear Prot, protein; SC, spinal cord; SDH, horn; STNC, trigeminal nucleus caudalis; TG, ganglion; yr, years.DisordersNKCC1 upregulationKCC2 downregulationNKCC1 downregulationRefsh'S' refers references supplemental online.RodentHumanRodentHumanRodentHumanRodentHumanAutismProt, CTX- HP-CBC (P0–P60)Prot, CTX (17–45 yr)[17.Tyzio R. al.Oxytocin-mediated delivery attenuates autism offspring.Science. 343: 675-679Crossref (340) Scholar, 18.Li al.Reduced protein expressions cytomembrane GABAARbeta3 at stages rats exposed prenatally valproic acid.Brain Res. 1671: 33-42Crossref (9) 19.Savardi al.Discovery small molecule candidate disorders.Chem. 6: 2073-2096Abstract (11) Scholar,22.Eftekhari S. al.Response comment 'Oxytocin-mediated offspring'.Science. 346: 176Crossref Scholar][19.Savardi Scholar]Rett syndromeProt, (P20–P25)Prot-mRNA, CSF-iPSCs (2–22 yr)[20.Banerjee al.Jointly reduced excitation circuit-wide changes cortical Rett syndrome.Proc. Natl. Acad. Sci. U. 2016; 113: E7287-E7296Crossref Scholar][25.Hinz L. al.KCC2 post mortem tissue patients.Acta Neuropathol. Commun. 7: 196Crossref 26.Duarte S.T. al.Abnormal fluid cation patients syndrome.PLoS ONE. 2013; 8e68851Crossref (45) 27.Tang X. functional human derived 751-756Crossref (103) Scholar]Fragile X (P10)Prot, HP (P15, P30)[17.Tyzio Scholar,21.He Q. al.The switch delayed fragile mice.J. 446-450Crossref (123) Scholar]DiGeorge syndromeProt-mRNA, primary neurons[28.Amin al.Developmental excitatory-to-inhibitory GABA-polarity disrupted 22q11.2 deletion syndrome: therapeutics.Sci. Rep. 15752Crossref (22) Scholar]TSCProt-mRNA, tubers (15 GW–31 yr)[29.Talos D.M. al.Altered tuberous sclerosis type IIb dysplasia.Ann. Neurol. 2012; 71: 539-551Crossref (100) Scholar,30.Ruffolo al.Functional aspects preserved complex (TSC) epileptogenic lesions.Neurobiol. Dis. 95: 93-101Crossref (19) Scholar]Down CTX-HP (adult)Prot, (adult)[39.Deidda al.Reversing excitatory restores memory syndrome.Nat. Med. 21: 318-326Crossref (133) Scholar][39.Deidda Scholar]SchizophreniamRNA, (P30)mRNA, (adult)bDecreased level mRNA, 1–2a, NKCC1b alternative mRNAs together were PBMCs lateral schizophrenia, respectively [48,49].mRNA, (E18)mRNA-Prot, HP-CTX (adult)mRNA, (E18)[8.Kim Scholar,40.Larimore al.Dysbindin deficiency modifies neuron permeation transcripts developing hippocampus.Front. Genet. 8: 28Crossref (13) Scholar][45.Dean B. al.Gene profiling Brodmann's area 46 subjects schizophrenia.Aust. N. Z. Psychiatry. 2007; 41: 308-320Crossref 46.Hyde T.M. al.Expression molecules GAD1 schizophrenia.J. 2011; 31: 11088-11095Crossref (202) 47.Sullivan C.R. al.Decreased channel dorsolateral schizophrenia.PLoS 10e0123158Crossref (6) 48.Morita al.Characteristics brain: alternate transcripts, relationships 4929-4940Crossref (39) 49.Zhang T. GSK3beta, PICK1, NEFL, C4, synaptophysin first-episode patients.Asian Psychiatr. 55102520Crossref Scholar]FASDProt, (P45–P55)cKCC2 [41,42].[41.Everett J.C. al.Effects third trimester-equivalent ethanol exposure Cl(-) co-transporter expression, network activity, CA3 hippocampal region neonatal rats.Alcohol. 46: 595-601Crossref 42.Sanderson J.L. al.Modulation glutamatergic neocortex: vitro test hypothesis fetal alcohol spectrum disorder.Neuropharmacology. 2009; 56: 541-555Crossref (21) 43.Silvestre de Ferron al.Increase disturbances after perinatal exposure.Addict. Biol. 22: 1870-1882Crossref Scholar]Depressive-like behaviorsProt, (P14)Prot, (P35, P70)dKCC2 P40 maternal separation [50].mRNA, amygdala (adult)[50.Hu D. al.Bumetanide treatment separation-induced susceptibility stress.Sci. 11878Crossref 51.Furukawa al.Neonatal delays expression.Biochem. Biophys. 493: 1243-1249Crossref (24) 52.Yang combined brief etomidate anesthesia stress corticotropin-releasing hormone intake rats.Neurosci. Lett. 685: 83-89Crossref (5) 53.Goubert prevents trauma-induced depressive-like behavior.Front. Mol. 12: 12Crossref 54.Gazzo al.Overexpression sensory-affective sociability phenotype following separation.Brain Behav. Immun. 92: 193-202Crossref Scholar]FCD polymicrogyriaProt, (pediatric adult)mRNA, (P4)Prot-mRNA, (pediatric)mRNA, (P4)Prot, adult)[56.Shimizu-Okabe al.Changes cation-Cl- cotransporters, malformation freeze-lesion.Neurosci. 59: 288-295Crossref Scholar,57.Wang al.Accumulation focal ambient gradient, microgyrus formation polymicrogyria.Cereb. Cortex. 24: 1088-1101Crossref (18) Scholar][29.Talos [S1–S5]Dravet syndromemRNA, (1.4–61 yr)[61.Ruffolo al.A Dravet syndrome.Epilepsia. 2106-2117Crossref Scholar]Neonatal seizuresProt, epileptic hemisphere (P7)eKCC2 detected 24 h PTZ-induced seizures [S8].Prot, (P10)fNKCC1 significantly seizures; decreased 12 (both HP) (CTX) [S6].[S6–S8]TLEProt-mRNA, (adult)Prot-mRNA, (adult)gKCC2 pilocarpine-induced TLE mice humans [64].Prot, HP(adult)gKCC2 [64].Prot-mRNA, HP-PBMCs (adult)[62.Auer characterization derivatives epilepsy treatment.Neuropharmacology. 162107754Crossref (8) 63.Hampel P. al.Deletion Na-K-2Cl severe intrahippocampal kainate temporal lobe epilepsy.Neurobiol. 152105297Crossref 64.Karlocai M.R. potassium-chloride epilepsy.Brain Struct. Funct. 221: 3601-3615Crossref [S9–S18][64.Karlocai Scholar,66.Gharaylou preliminary study evaluating safety efficacy inhibitor, drug-resistant epilepsy.CNS Drugs. 33: 283-291Crossref [S19–S21]TBIProt-mRNA, HP-CP-CTX (adult)[68.Hui al.Inhibition Na(+)-K(+)-2Cl(-) Cotransporter-1 traumatic injury-induced apoptosis Erk signaling.Neurochem. Int. 94: 23-31Crossref 69.Zhang al.Astaxanthin alleviates modulating AQP4 injury mice.BMC 17: 60Crossref (28) 70.Wu al.Melatonin up-regulation K(+) -Cl(-) rats.J. Pineal 61: 241-250Crossref (43) 71.Wang F. post-traumatic seizure susceptibility.Brain 222: 1543-1556Crossref Scholar,73.Lizhnyak P.N. al.Traumatic proteome guides KCC2-targeted therapy.J. Neurotrauma. 36: 3092-3102Crossref [S22–S24]SCI, PNI, neuropathic painProt-mRNA-Ph, SC SDH-STNC-SC DRG-SC (adult)[76.Yan al.Pretreatment concurrently attenuated cord damage rats.Front. 6Crossref 77.Gao al.Suppression WNK1-SPAK/OSR1 bone cancer pain KCC2.J. Pain

Language: Английский

---

Prenatal influences on postnatal neuroplasticity: Integrating DOHaD and sensitive/critical period frameworks to understand biological embedding in early development

Infancy, Journal Year: 2024, Volume and Issue: unknown

Published: March 6, 2024

Abstract Early environments can have significant and lasting effects on brain, body, behavior across the lifecourse. Here, we address current research efforts to understand how experiences impact neurodevelopment with a new perspective integrating two well‐known conceptual frameworks – Developmental Origins of Health Disease (DOHaD) sensitive/critical period frameworks. Specifically, consider prenatal characterized in DOHaD model key neurobiological mechanisms periods for adapting learning from postnatal environment. We draw both animal human summarize state knowledge particular substance exposures (psychoactive substances heavy metals) nutritional profiles (protein‐energy malnutrition iron deficiency) each differentially brain circuits' excitation/GABAergic inhibition balance myelination. Finally, highlight directions that emerge this integrated framework, including testing alter timing identifying potential promotional/buffering periods. hope integrative framework considering influences neuroplasticity will stimulate early consequences our brains, behavior, health.

Language: Английский

---