关键词:
Angiotensin II
ARB
Telmisartan
Stress
PPAR-gamma
GW9662
BDNF
PPAR-GAMMA AGONIST
FOCAL CEREBRAL-ISCHEMIA
PREFRONTAL CORTEX
COGNITIVE DECLINE
HYPERTENSIVE-RATS
ANTAGONIST
IMPROVES
ACTIVATION
SYSTEM
HIPPOCAMPUS
摘要:
Physical and psychological aspects of chronic stress continue to be a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. By the results of our previous work it has been demonstrated that telmisartan (TLM), an angiotensin type 1 receptor (AT(1)) blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor gamma (PPAR gamma), alleviates stress-induced cognitive decline. Understanding of mechanistic background of this phenomenon is hampered by both dual binding sites of TLM and limited data on the consequences of central AT(1) blockade and PPAR gamma activation. Therefore, a critical need exists for progress in the characterization of this target for pro-cognitive drug discovery. An unusual ability of novel ARBs to exert various PPAR gamma binding activities is commonly being viewed as predominant over angiotensin blockade in terms of neuroprotection. Here we aimed to verify this hypothesis using an animal model of chronic psychological stress (Wistar rats restrained 2.5 h daily for 21 days) with simultaneous oral administration of TLM (1 mg/kg), GW9662 - PPAR gamma receptor antagonist (0.5 mg/kg), or both in combination, followed by a battery of behavioral tests (open field, elevated plus maze, inhibitory avoidance - IA, object recognition - OR), quantitative determination of serum corticosterone (CORT) and evaluation of brain-derived neurotrophic factor (BDNF) gene expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Stressed animals displayed decreased recall of the IA behavior (p < 0.001), decreased OR (p < 0.001), substantial CORT increase (p < 0.001) and significantly downregulated expression of BDNF in the mPFC (p < 0.001), which were attenuated in rats receiving TLM and TLM + GW9662. These data indicate that procognitive effect of ARBs in stressed subjects do not result from PPAR-gamma activation, but AT(1), blockade and subsequent hypothalamus-pituitary-adrenal axis dea