Effect of sacubitril/valsartan on cognitive impairment in colchicine‐induced Alzheimer's model in rats

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine-induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 μg/5 μl/bilaterally), Group III: colchicine (15 μg/5 μl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 μg/5 μl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, β-amyloid (1-40 and 1-42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor-alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine-induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in β-amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/ valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine-induced AD rat model. Hence, special caution should be taken following long-term intake of ARNI on cognitive functions.

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

“…Experimental study NEP inhibitors trigger AD-like diseases in mice Hüttenrauch et al 44 Experimental study LCZ696 increased Aβ concentration in the CSF but not in the brain Bavishi et al 43 Experimental study LCZ696 accelerates AD progression in animals Vodovar et al 47 Experimental study Long-term effects of NEP inhibitors promote AD and late-onset axonal polyneuropathy Auer-Grumbach et al 41 Experimental study LCZ696 increases AD risk compared with valsartan alone in rats El-din Hussein et al 48 Experimental study LCZ696 accelerates colchicine-induced cognitive impairment in rats Hammadi El-din Hussein et al 50 Preclinical studies LCZ696 has a neuroprotective effect by inhibiting homocysteine-induced BBB injury…”

“…Valsartan can decrease the risk of AD development as it selectively blocks AT 1 R as RAS inhibitors have been associated with the reduction of brain damage in different experimental and clinical models of neurodegenerative diseases 49 . In addition, LCZ696 extravagant colchicine‐induced cognitive impairment in rats by increasing Aβ accumulation, oxidative stress and inflammation compared to valsartan alone 50 . Hence, LCZ696 triggers a deleterious effect on cognitive impairment in the colchicine‐induced AD rat model.…”

“… 49 In addition, LCZ696 extravagant colchicine‐induced cognitive impairment in rats by increasing Aβ accumulation, oxidative stress and inflammation compared to valsartan alone. 50 Hence, LCZ696 triggers a deleterious effect on cognitive impairment in the colchicine‐induced AD rat model. Henceforth, special caution should be taken following long‐term intake of LCZ696 on cognitive functions.…”

Anti-Hyperuricemic, Anti-Arthritic, Hemolytic Activity and Therapeutic Safety of Glycoconjugated Triazole-Phthalimides

“…Still, regarding this class of drugs, we can highlight corticosteroids and colchicine. Corticosteroids can cause weight gain, generating metabolic problems and fluid retention, compromising hemodynamic, cardiovascular, and renal functions [ 19 ], while colchicine can cause gastrointestinal complications and a reduction in circulating neutrophils, and high doses can cause aplastic anemia by inhibiting erythroid precursor mitosis and increase the risk of developing Alzheimer’s disease [ 20 ]. The most widespread hyperuricemia inhibitors are the xanthine oxidase inhibitorallopurinol and the uricosuric agent probenecid, which inhibit the reabsorption of urates at the level of the proximal convoluted tubule, and seeks to bring the serum uric acid level below 6 mg/dL (357 µmol/L).…”

Electrochemical Determination of the Drug Colchicine in Pharmaceutical and Βiological Samples Using a 3D-Printed Device

“…It has been demonstrated that a low concentration of Colc (1.2 mg per day) causes a reduction in pain and gout symptoms, whereas a high dose of Colc (4.8 mg over 6 h) can cause common side effects, such as gastrointestinal upset including nausea, diarrhea, vomiting, low blood cell count, and rhabdomyolysis, as well as bone marrow damage, anemia, and hair loss. Colc causes oxidative stress in animals, leading to cognitive impairment, and its therapeutic use has been linked to sporadic Alzheimer’s disease in humans [ 8 , 9 , 10 ].…”