Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction

Rajagopal, Lakshmi; Soni, D. K.; Meltzer, Herbert Y.

doi:10.1016/j.bbr.2018.05.005

Cited by 21 publications

(17 citation statements)

References 132 publications

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“…In a dopamine transporter knockout mouse model of schizophrenia, acute treatment with PREGS was able to rescue behavioral anomalies through the NMDA receptor‐mediated AKT/GSK3β signaling pathway (Wong et al, ). The current body of evidence supports further research with PREGS as a cognitive enhancer, as well as for treating negative symptoms in schizophrenia and related disorders (Rajagopal et al, ). The role of the identified risk variant in SLC51A in schizophrenia should be explored further.…”

Section: Discussionsupporting

confidence: 62%

“…After delivery to their target sites, they act as endogenous neurotransmitters or modulators on γ‐aminobutyric acid (GABA), particularly type A (GABA A ), N‐methyl‐aspartate (NMDA) glutamate, serotonin (5‐HT3), and alpha‐1 receptors (Akwa, Ladurelle, Covey, & Baulieu, ; Smith, Gibbs, & Farb, ; Tuem & Atey, ; Whittaker, Gibbs, & Farb, ). PREGS may also act as a negative allosteric modulator of the AMPA, kainate, and glycine receptors, potassium channels, and voltage‐gated sodium channels; it may also inhibit voltage‐gated calcium channels and interact with nicotinic cholinergic receptors and sigma receptors (Rajagopal, Soni, & Meltzer, ). In this way, they exert potent effects on neuronal excitability and neurotransmitter receptor function.…”

Section: Discussionmentioning

confidence: 99%

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Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

Malt

Frengen

Wangensteen

et al. 2019

Molec Gen & Gen Med

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Background Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. Methods In‐depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first‐degree relatives. Risk variants were identified through bioinformatic analysis. Results One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. Conclusion 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow‐up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

Malt

Frengen

Wangensteen

et al. 2019

Molec Gen & Gen Med

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“…Hormones and related steroidal structures derived from cholesterol are known to have a role in brain function. Observed in this study pregnenolone sulfate is a known neuro-steroid species 60 , 61 reported to influence cognition in rodent models 62 and patient studies, perhaps through its role in modulating gamma-aminobutyric acid subunit A (GABAA) and N-methyl d -aspartate (NMDA) receptors 61 . The other hormone we annotated—pregnanediol, a metabolite of pregnenolone, was previously reported to be lower in the urine of older men 62 , however, this has not been linked to AD.…”

Section: Discussionmentioning

confidence: 80%

Urinary metabolic phenotyping for Alzheimer’s disease

Kurbatova

Garg

Whiley

et al. 2020

Sci Rep

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Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer’s Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer’s Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer’s Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer’s Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer’s pathology in previous studies.

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“…Growing evidence also suggests that low doses of GABA A R antagonists show therapeutic potentials in a particular type of neurodevelopmental disorders such as in Down syndrome [ 18 ] and the antipsychotic efficacy [ 51 , 60 ]. Of note, negative allosteric modulators selectively targeting α5-subunit-containing GABA A Rs consistently exhibit substantial pharmacological effects to restore cognitive deficits [ 2 , 3 , 30 , 40 , 53 , 61 ], promote functional recovery after stroke [ 8 ], or exert the anti-depressant action [ 72 ].…”

Section: Introductionmentioning

confidence: 99%

Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity

Fan

Zhu

et al. 2018

EBioMedicine

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An imbalance between neuronal excitation and inhibition represents a core feature in multiple neuropsychiatry disorders, necessitating the development of novel strategies to calibrate the excitatory–inhibitory balance of therapeutics. Here we identify a natural compound quercetin that reduces prefrontal cortical GABAergic transmission and alleviates the hyperactivity induced by glutamatergic N-methyl-d-aspartate receptor antagonist MK-801. Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. Notably, systemic and prefrontal-specific delivery of quercetin reduced basal locomotor activity in addition to alleviated the MK-801-induced hyperactivity. The effects of quercetin were not exclusively dependent on α5-subunit-containing A type GABA receptors (GABAARs), as viral-mediated, region-specific genetic knockdown of the α5-subunit in prefrontal cortex improved the MK-801-evoked psychotic symptom but reserved the pharmacological responsivity to quercetin. Both interventions together completely normalized the locomotor activity. Together, quercetin as a negative allosteric GABAAR modulator exerted antipsychotic activity, facilitating further therapeutic development for the excitatory–inhibitory imbalance disorders.

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Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction

Cited by 21 publications

References 132 publications

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

Urinary metabolic phenotyping for Alzheimer’s disease

Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity

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