Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats

Carreño, Fernando; Helfer, Victória Etges; Staudt, Keli Jaqueline; Paese, Karina; Meyer, Fabíola Schons; Herrmann, Ana Paula; Guterres, Sílvia Stanisçuaski; Rates, Stela Maris Kuze; Costa, Teresa Dalla

doi:10.1016/j.schres.2020.01.007

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…In a first of its kind research, Carreño et al demonstrated a reversal in PPI disruption induced by prenatal poly I:C challenge utilising quetiapine lipid nanocarriers, a novel drug delivery system in both male and female Wistar rats. The lipid nanocarriers facilitated an increase in quetiapine delivery to brain particularly the hippocampus interstitium accounting for the therapeutic response [48].…”

Section: Gestational and Perinatal Modelsmentioning

confidence: 99%

Animal models for the evaluation of antipsychotic agents

Ayyar

Ravinder

2022

Fundamemntal Clinical Pharma

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Schizophrenia, the most serious among psychoses, has negative symptoms such as anhedonia, avolition and apathy, and cognitive defects in addition to positive symptoms such as hallucinations and delusions characterising all psychotic disorders. Traditional antipsychotics had dopamine D 2 receptor antagonism as their principal mechanism of action, with disabling extrapyramidal symptoms as corollary. Newer atypical agents with diverse receptor actions introduced to circumvent this issue, nevertheless, had varied side effects such as agranulocytosis, insulin resistance, seizures, and cardiac events. Also, symptoms in cognitive and negative domains do not respond well even to newer agents creating an unmet need. Designing a valid animal model with translational relevance for a complex disease such as schizophrenia is a tedious process. Induction or suppression of certain animal behaviours by test compounds (behavioural models) and antagonising effects induced by compounds with psychotic potential (pharmacological models) are the conventional models used. One among the major disadvantages with conventional models is that these paradigms are induced acutely and relate to aberration of a single neurotransmitter system, which is in sharp contrast to the chronic nature and interplay of multiple neurotransmitter systems in psychotic diseases. However, with progress in elucidation of disease mechanisms, novel models are generated utilising developmental, genetic, and environmental factors (neurodevelopmental models) to effectively reflect the human disease pathogenesis and clinical manifestations, but with paucity of studies assessing the impact of drugs on them. This review presents an overview of schizophrenia hypotheses, requisites of a valid animal model, available animal models with their advantages and disadvantages.

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Section: Gestational and Perinatal Modelsmentioning

confidence: 99%

Animal models for the evaluation of antipsychotic agents

Ayyar

Ravinder

2022

Fundamemntal Clinical Pharma

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“…The favourable action of this drug has also been described in animal models of schizophrenia-like alterations. In rats after basolateral amygdala lesions generated using quinolinic acid [13], as well as in a rodent model based on prenatal exposure to polyinosinic-polycytidylic acid [14], quetiapine normalized deficits in prepulse inhibition of sensorimotor gating. A similar phenomenon was reported for rat offspring subjected to lipopolysaccharide (LPS) in the prenatal period [15].…”

Section: Introductionmentioning

confidence: 99%

Insights into the Potential Impact of Quetiapine on the Microglial Trajectory and Inflammatory Response in Organotypic Cortical Cultures Derived from Rat Offspring

et al. 2023

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Atypical antipsychotics currently constitute the first-line medication for schizophrenia, with quetiapine being one of the most commonly prescribed representatives of the group. Along with its specific affinity for multiple receptors, this compound exerts other biological characteristics, among which anti-inflammatory effects are strongly suggested. Simultaneously, published data indicated that inflammation and microglial activation could be diminished by stimulation of the CD200 receptor (CD200R), which takes place by binding to its ligand (CD200) or soluble CD200 fusion protein (CD200Fc). Therefore, in the present study, we sought to evaluate whether quetiapine could affect certain aspects of microglial activity, including the CD200-CD200R and CX3CL1-CX3CR1 axes, which are involved in the regulation of neuron–microglia interactions, as well as the expression of selected markers of the pro- and anti-inflammatory profile of microglia (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β). Concurrently, we examined the impact of quetiapine and CD200Fc on the IL-6 and IL-10 protein levels. The abovementioned aspects were investigated in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those subjected to maternal immune activation (MIA OCCs), which is a widely implemented approach to explore schizophrenia-like disturbances in animals. The experiments were performed under basal conditions and after additional exposure to the bacterial endotoxin lipopolysaccharide (LPS), according to the “two-hit” hypothesis of schizophrenia. The results of our research revealed differences between control and MIA OCCs under basal conditions and in response to treatment with LPS in terms of lactate dehydrogenase and nitric oxide release as well as Cd200r, Il-1β, Il-6 and Cd206 expression. The additional stimulation with the bacterial endotoxin resulted in a notable change in the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Quetiapine diminished the influence of LPS on Il-1β, Il-6, Cebpb and Arg1 expression in control OCCs as well as on IL-6 and IL-10 levels in MIA OCCs. Moreover, CD200Fc reduced the impact of the bacterial endotoxin on IL-6 production in MIA OCCs. Thus, our results demonstrated that quetiapine, as well as the stimulation of CD200R by CD200Fc, beneficially affected LPS-induced neuroimmunological changes, including microglia-related activation.

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“…Previously, we demonstrated that SPR did not respond to the FQ formulation, in the dose investigated, on the PPI test 21 . Although the neurological pathway that governs PPI response and changes in DA levels in the mPFC might not be correlated, one can infer that alterations in other neurotransmitter receptors as a result of SCZ can be expected.…”

Section: Discussionmentioning

confidence: 79%

“…20 Previously, we demonstrated that SPR did not respond to the FQ formulation, in the dose investigated, on the PPI test. 21 Although the neurological pathway that governs PPI response and changes in DA levels in the mPFC might not be correlated, one can infer that alterations in other neurotransmitter receptors as a result of SCZ can be expected. The PK/PD model considers that DA baseline levels in the rats before QTP administration and the DA baseline estimated for naïve rats and SPR were significantly different, confirming that SCZ alters DA pathways 2,3 In the selected model, the DA precursor is synthesized in a rate described by K in (0.313 ng/mL • h).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats

Dias,

Carreño,

Helfer

et al. 2024

CPT Pharmacom & Syst Pharma

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Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration–effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

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Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats

Cited by 9 publications

References 28 publications

Animal models for the evaluation of antipsychotic agents

Animal models for the evaluation of antipsychotic agents

Insights into the Potential Impact of Quetiapine on the Microglial Trajectory and Inflammatory Response in Organotypic Cortical Cultures Derived from Rat Offspring

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats

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