Low-dose candesartan prevents schizophrenia-like behavioral alterations in a neurodevelopmental two-hit model of schizophrenia

Vasconcelos, Germana Silva; Júnior, Manuel Alves dos Santos; Monte, Aline Santos; Silva, Francisco Eliclécio Rodrigues da; Lima, Camila Nayane de Carvalho; Neto, Abelardo Barbosa Moreira Lima; Medeiros, Ingridy da Silva; Teixeira, Antônio Lúcio; Lucena, David Freitas de; Vasconcelos, Silvânia Maria Mendes; Macêdo, Danielle Silveira

doi:10.1016/j.pnpbp.2021.110348

Cited by 11 publications

(8 citation statements)

References 78 publications

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“…Low doses of candesartan prevented SZ-like behavior in female and male mice. But only males induced with the two-hits had an increase in pro-inflammatory cytokines in the hippocampus that could be significantly reduced to control levels with the peri-pubertal administration of candesartan [101]. These results add novel evidence for differential sex contribution in SZ neurobiology, with different pathways possibly contributing to BBB susceptibility.…”

Section: Introductionmentioning

confidence: 68%

“…Overlaying SZ-associated genes with the transcriptomic profile of different cellular components of the NVU at distinct neurodevelopmental stages could shed lights on particular cells, cellular states, and molecular pathways being altered during SZ etiology. Additionally, the sex of the patients should also be taken into account when evaluating BBB performance, due to potential sex interactions with brain barrier integrity and permeability in SZ [91 ▪ ,93 ▪ ,96 ▪ ,101].…”

Section: Discussionmentioning

confidence: 99%

“…Increased serum AGT was reported in SZ (111 SZ and 109 controls) [100]. Vasconcelos et al (2021), studied the effectofperi-pubertaladministrationofanAT1R blocker, candesartan, in a two-hit mice model of SZ that combines a neonatal immune challenge with stressors during puberty. Low doses of candesartan prevented SZ-like behavior in female and male mice.…”

Section: Evidence From Mice Modelsmentioning

confidence: 99%

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Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

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Purpose of reviewThe vascular hypothesis of schizophrenia (SZ) postulates that brain endothelial dysfunction contributes to brain pathophysiology. This review discusses recent evidence for and against this hypothesis, including data related to blood–brain barrier (BBB), brain endothelium, and brain blood supply, to provide a critical weighed update.Recent findingsDifferent studies report a consistent proportion of SZ patients showing increased BBB permeability, reflected by higher levels of albumin in the cerebral spinal fluid. Of note, this was not a result of antipsychotic medication. The high inflammatory profile observed in some SZ patients is strongly associated with increased BBB permeability to circulating immune cells, and with more severe cognitive deficiencies. Also, sex was found to interact with BBB integrity and permeability in SZ. The strongest independent genetic association with SZ has been identified in FZD1, a hypoxia-response gene that is 600-fold higher expressed in early development endothelium as compared to adult brain endothelium. Regarding brain blood supply, there is evidence to suggest alterations in proper brain perfusion in SZ. Nonetheless, ex-vivo experiments suggested that widely used antipsychotics favor vasoconstriction; thus, alterations in cerebral perfusion might be related to the patients′ medication.SummaryIn some patients with SZ, a vulnerable brain endothelium may be interacting with environmental stressors, such as inflammation or hypoxia, converging into a more severe SZ symptomatology. Gene expression and performance of human brain endothelium could vary along with development and the establishment of the BBB; therefore, we encourage to investigate its possible contribution to SZ considering this dynamic context.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Evidence From Mice Modelsmentioning

confidence: 99%

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Brain vasculature disturbance in schizophrenia

Puvogel

Palma

Sommer

2022

Current Opinion in Psychiatry

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“…It prevented behavioural alterations with a mechanism that appeared to be independent of AT1R activation and presumably consistent with a direct antioxidant effect of the molecule. 268 , 269 …”

Section: Renin-angiotensin System Modulatorsmentioning

confidence: 99%

Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects

Carnovale

Perrotta

Baldelli

et al. 2022

Cardiovascular Research

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A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette’s syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.

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“… Note : References: AbdAlla et al (2013); Ahmad (1996); Anderson (2010); Andrade (2020); Barnes et al (1992); Boal et al (2016); Borsook and Sava (2009); Carnovale et al, 2022; Chrissobolis et al (2020); Currie et al (1990); Diniz et al (2018); Hu and Lin (2021); Ivanova and Tchekalarova (2019); Jo et al (2022); Khoury et al (2012); Min et al (2014); Nocito et al (2020); Saavedra (2012); Saavedra (2021); Thakur et al (2015); Thomas et al (2021); Torika et al (2016); Urmila et al (2021); Vasconcelos et al (2021); Wang et al (2016). …”

Section: The Physiological Roles and Therapeutic Potential Of Ace And...mentioning

confidence: 99%

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

Santiago

Parra

Nani

et al. 2023

Journal of Neurochemistry

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The renin‐angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin‐I‐converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti‐inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness.

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Low-dose candesartan prevents schizophrenia-like behavioral alterations in a neurodevelopmental two-hit model of schizophrenia

Cited by 11 publications

References 78 publications

Brain vasculature disturbance in schizophrenia

Brain vasculature disturbance in schizophrenia

Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

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