Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia*

Akhondzadeh, Shahin; Mojtahedzadeh, V.; Mir-Sepassi, Gholam Reza; Moin, Mostafa; Amini-Nooshabadi, H.; Kamalipour, Abbas

doi:10.1046/j.1365-2710.2002.00445.x

Cited by 13 publications

(5 citation statements)

References 26 publications

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“…Several potassium ion channels, which have been postulated to have a role in the pathophysiolgy of schizophrenia (Wolfart et al, 2001;Akhondzadeh et al, 2002;Tomita et al, 2003), did show significant changes in the hippocampus of subjects with schizophrenia. Some as shown in Table 4, some of these genes encode voltage-gated channels (eg KCNAB1,2 and KCNG2) that showed significant downregulations.…”

Section: Potassium Ion Channelsmentioning

confidence: 95%

Amygdalocortical Circuitry in Schizophrenia: From Circuits to Molecules

Beneš

2009

Neuropsychopharmacol

173

151

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Schizophrenia is a disorder in which disturbances in the integration of emotion with cognition plays a central role and probably involves several different regions, including the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the hippocampal formation, and basolateral amygdala (BLA). Recent brain imaging studies have reported changes in volume, whereas postmortem studies point to dysfunction of the GABA and glutamate systems in these regions. Microarray-based profiles indicate that complex changes in the expression of genes associated with synaptic transmission and ion channels are involved in GABA cell dysfunction in schizophrenics. Molecular abnormalities vary considerably on the basis of sector and layer, suggesting that the unique connectivity of intrinsic and extrinsic afferents may critical in regulating the activity of genes in specific subpopulations of GABA cells. Projections of the BLA may be of particular importance to the induction of abnormal circuitry in schizophrenia, as their ingrowth during late adolescence and early adulthood may help to 'trigger' the onset of illness in susceptible individuals. A preponderance of cellular and molecular abnormalities has been found in the stratum oriens (SO) of sectors CA3/2 in which BLA afferents provide a robust innervation. These observations have lead to the development of a rodent model for the study of abnormal circuitry in this disorder. For example, single-cell recordings in hippocampal slices exposed to increased activation from the BLA have shown decreases in GABA currents in pyramidal neurons in SO of CA3/2, but not CA1, and support the validity of this model. Overall, the postmortem studies of neural circuitry abnormalities in schizophrenia are beginning to implicate specific cellular, molecular, and electrophysiological mechanism in specific subtypes of cortical neurons defined by their afferent and efferent connectivity within key corticolimbic regions.

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Section: Potassium Ion Channelsmentioning

confidence: 95%

Amygdalocortical Circuitry in Schizophrenia: From Circuits to Molecules

Beneš

2009

Neuropsychopharmacol

173

151

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“…49 Some studies have observed that potassium channel activators have antipsychotic effects. [50][51][52] It is also suggested that the current antipsychotic drugs could mediate part of their therapeutic actions by affecting potassium channels because genetic variation in Kv11.1 (KCNH2) modulates antipsychotic treatment response in patients with schizophrenia. 53 Additionally, it has been shown that the amount of Kv3.1 channels is reduced in patients with untreated schizophrenia and normalized with antipsychotic drugs.…”

Section: Discussionmentioning

confidence: 99%

AMIGO-Kv2.1 Potassium Channel Complex is Associated With Schizophrenia-Related Phenotypes

Peltola

Kuja-Panula

Liuhanen

et al. 2015

SCHBUL

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The enormous variability in electrical properties of neurons is largely affected by a multitude of potassium channel subunits. Kv2.1 is a widely expressed voltage-dependent potassium channel and an important regulator of neuronal excitability. The Kv2.1 auxiliary subunit AMIGO constitutes an integral part of the Kv2.1 channel complex in brain and regulates the activity of the channel. AMIGO and Kv2.1 localize to the distinct somatodendritic clusters at the neuronal plasma membrane. Here we have created and characterized a mouse line lacking the AMIGO gene. Absence of AMIGO clearly reduced the amount of the Kv2.1 channel protein in mouse brain and altered the electrophysiological properties of neurons. These changes were accompanied by behavioral and pharmacological abnormalities reminiscent of those identified in schizophrenia. Concomitantly, we have detected an association of a rare, population-specific polymorphism of KV2.1 (KCNB1) with human schizophrenia in a genetic isolate enriched with schizophrenia. Our study demonstrates the involvement of AMIGO-Kv2.1 channel complex in schizophrenia-related behavioral domains in mice and identifies KV2.1 (KCNB1) as a strong susceptibility gene for schizophrenia spectrum disorders in humans.

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“…An initial study of the ampakine CX516, documented some cognitive improvement [ 111 ]; however, a larger trial ( N = 105, 4 weeks) showed no improvement in cognition [ 112 ]. Small studies with piracetam and diazoxide, other AMPA-R modulators, have showed beneficial effect for positive symptoms [ 113 , 114 ] but further support with larger studies is missing.…”

Section: Pharmacological Studiesmentioning

confidence: 99%

Glutamatergic dysfunction in Schizophrenia

Kruse

Bustillo

2022

Transl Psychiatry

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The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.

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Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia*

Abstract: The results of this study present a novel application for potassium channel openers/activators in the neuropsychiatric disorders and diazoxide may be an effective adjuvant agent in the management of schizophrenia.

Cited by 13 publications

References 26 publications

Amygdalocortical Circuitry in Schizophrenia: From Circuits to Molecules

Amygdalocortical Circuitry in Schizophrenia: From Circuits to Molecules

AMIGO-Kv2.1 Potassium Channel Complex is Associated With Schizophrenia-Related Phenotypes

Glutamatergic dysfunction in Schizophrenia

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