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Abstract <p>Rationale. The central renin-angiotensin system (cRAS) is a neuromodulator system that has been associated with neuropsychiatric disorders. Mainly through angiotensin II type 1 (AT1) receptor activation, cRAS increases dopamine release in striatum, and modulates glutamate release and brain cytokine levels.</p> Objectives <p>Considering that schizophrenia pathophysiology involves both neurotransmission and cytokine unbalance, we verified whether AT1 receptor blockade would have beneficial effects on a mouse model of schizophrenia.</p> Methods <p>Phencyclidine, an NMDA receptor antagonist, was used to model schizophrenia in C57BL/6 male and female mice, while AT1 receptor antagonism was achieved by telmisartan administration. From postnatal day (PN) 60 to 70, mice received daily injections of telmisartan (0.25 or 1&#xa0;mg/kg, i.p.) or saline, followed by phencyclidine (2.5&#xa0;mg/kg, PN60-69; 10&#xa0;mg/kg on PN70, s.c.) or saline. Mice were submitted to behavioral tests (PN63-70) and the frontal cerebral cortex and hippocampus were harvested.</p> Results <p>Telmisartan lower dose reversed phencyclidine-evoked reduced levels of interleukin-6 and interleukin-10, as well as AT1 receptor downregulation in the frontal cortex. Its higher dose mitigated hyperactivity (schizophrenia-like positive symptomatology). Deleterious effects were also identified. Both telmisartan doses, when combined with phencyclidine, impaired spatial working memory, and caused prepulse inhibition deficits (an endophenotype of schizophrenia) at one prepulse intensity used, being most unfavorable at the lower dose.</p> Conclusions <p>Despite evidence of beneficial effects, the telmisartan-mediated impairments observed in the phencyclidine model bring concerns as to the use of this AT1 receptor antagonist as a potential therapeutic agent in schizophrenia.</p>

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Telmisartan mitigates behavioral and cytokine level alterations but impairs spatial working memory in a phencyclidine-induced mouse model of schizophrenia

  • 期刊论文

  • 发表日期：

    2025年5月23日

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  • Ana Carolina Dutra-Tavares,
  • Julyana Gomes Maia,
  • Thainá Pereira de Souza,
  • Claudio Carneiro Filgueiras,
  • Anderson Ribeiro-Carvalho,
  • Alex Christian Manhães,
  • Yael Abreu-Villaça

摘要

Abstract

Rationale. The central renin-angiotensin system (cRAS) is a neuromodulator system that has been associated with neuropsychiatric disorders. Mainly through angiotensin II type 1 (AT1) receptor activation, cRAS increases dopamine release in striatum, and modulates glutamate release and brain cytokine levels.

Objectives

Considering that schizophrenia pathophysiology involves both neurotransmission and cytokine unbalance, we verified whether AT1 receptor blockade would have beneficial effects on a mouse model of schizophrenia.

Methods

Phencyclidine, an NMDA receptor antagonist, was used to model schizophrenia in C57BL/6 male and female mice, while AT1 receptor antagonism was achieved by telmisartan administration. From postnatal day (PN) 60 to 70, mice received daily injections of telmisartan (0.25 or 1 mg/kg, i.p.) or saline, followed by phencyclidine (2.5 mg/kg, PN60-69; 10 mg/kg on PN70, s.c.) or saline. Mice were submitted to behavioral tests (PN63-70) and the frontal cerebral cortex and hippocampus were harvested.

Results

Telmisartan lower dose reversed phencyclidine-evoked reduced levels of interleukin-6 and interleukin-10, as well as AT1 receptor downregulation in the frontal cortex. Its higher dose mitigated hyperactivity (schizophrenia-like positive symptomatology). Deleterious effects were also identified. Both telmisartan doses, when combined with phencyclidine, impaired spatial working memory, and caused prepulse inhibition deficits (an endophenotype of schizophrenia) at one prepulse intensity used, being most unfavorable at the lower dose.

Conclusions

Despite evidence of beneficial effects, the telmisartan-mediated impairments observed in the phencyclidine model bring concerns as to the use of this AT1 receptor antagonist as a potential therapeutic agent in schizophrenia.