Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Losartan*/pharmacology ; Losartan*/therapeutic use ; Rats, Inbred SHR* ; Cognitive Dysfunction*/drug therapy ; Cognitive Dysfunction*/etiology ; Cognitive Dysfunction*/metabolism ; Aging*/drug effects ; Oxidative Stress*/drug effects ; Hypertension*/drug therapy ; Hypertension*/metabolism ; Maze Learning*/drug effects ; Angiotensin II Type 1 Receptor Blockers*/pharmacology ; Angiotensin II Type 1 Receptor Blockers*/therapeutic use; Animals ; Rats ; Male ; Rats, Wistar ; Hippocampus/metabolism ; Hippocampus/drug effects ; Spatial Memory/drug effects ; Cyclic AMP Response Element-Binding Protein/metabolism ; Antihypertensive Agents/pharmacology ; Antihypertensive Agents/therapeutic use

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β 1-42 (Aβ 1-42 ) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ 1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

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N◦ BG-RRP-2.004-0002, "BiOrgaMCT" the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria

Keywords: Aβ1–42; CREB; aging; losartan; oxidative stress; rat

JMS50MPO89 (Losartan)
0 (Angiotensin II Type 1 Receptor Blockers)
0 (Cyclic AMP Response Element-Binding Protein)
0 (Antihypertensive Agents)

Date Created: 20240713 Date Completed: 20240713 Latest Revision: 20240718

20240718

PMC11242852

10.3390/ijms25137340

39000445