Telmisartana, um bloqueador do receptor AT1, pode mitigar alterações comportamentais associadas à esquizofrenia?

Abstract

Schizophrenia (SCHZ) is a psychiatric disorder that affects approximately 1% of the world population. This disorder is constituted by the combination of 3 types of symptoms: positive, negative and cognitive. Although antipsychotics treat this disorder, they are not effective in controlling negative and cognitive symptoms, in addition to cause significant adverse effects. Considering these data, many studies point out the brain Renin-Angiotensin System (RAS) as a promising therapeutic target. The brain RAS has angiotensin II as its main bioactive peptide and its most abundantly expressed receptor in the brain is type 1 (AT1), through which it exerts effects on neurobiological systems and processes involved in the pathophysiology of SCHZ, such as the dopaminergic and glutamatergic and the neuroinflammatory response. Thus, the present work investigated the effects of AT1 blockade through the administration of telmisartan (TEL), on behavioral changes associated with SCHZ induced by a pharmacological model obtained through the administration of phencyclidine (PCP), an NMDA receptor antagonist. For this, we used C57BL/6 male and female mice. From postnatal days (PN) 60 to 70, mice received a daily injections of TEL (0.25 or 1mg/Kg, ip), or saline and, after 30 minutes, received an injection of PCP (2.5mg/kg, PN60-69; 10mg/kg in PN70) or saline. The formed experimental groups were: CT, PCP, PCP-Tel0.25 and PCP-Tel1. From PN63 to PN70, 10 minutes after the last injection, the animals were submitted to behavioral tests: Open Field to verify the expression of locomotor hyperactivity associated with positive symptoms and habituation, an indicator of non-associative memory (PN63-65); Object Recognition, which evaluates declarative memory (PN66); T-maze, a task capable of analyzing working memory (PN67); Passive Avoidance, which analyzes memory and learning through fear conditioning (PN68-69); and finally, Pre-Pulse Inhibition (PPI), a measure of the sensorimotor filter (PN70), all of which are impaired in patients with SCHZ. The 3 phencyclidine-exposed groups showed hyperactivity when compared to the CT group on the 3-day CA test. However, the repeated administration of telmisartan reduced locomotor activity, so that on the 3rd day, the PCP-Tel1 group was significantly different from the PCP group. The CT and PCP-Tel1 groups showed a progressive reduction in locomotor activity throughout the test days, which indicates habituation to the arena. Thus, repeated administration of telmisartan is able to mitigate phencyclidine-induced hyperactivity and reverse memory/non-associative learning impairment. No cognitive impairment was identified in the Object Recognition and Passive Avoidance tests. In the T-maze the PCP-Tel0.25 and PCP-Tel1 groups showed impairment in working memory when compared to CT and PCP groups. In PPI, both doses of telmisartan failed to reverse PCP-induced cognitive impairment. Together, our data indicate that the effects of telmisartan on SCHZ-like behavioral changes vary depending on the cognitive domain analyzed. Thus, further studies are needed to understand the participation of the RAS and the dose-response curve of telmisartan in SCHZ.