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Tempol and perindopril protect against lipopolysaccharide-induced cognition impairment and amyloidogenesis by modulating brain-derived neurotropic factor, neuroinflammation and oxido-nitrosative stress

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Abstract

We aim to evaluate the protective role of the central angiotensin-converting enzyme (ACE) inhibitor perindopril, compared with the standard reactive oxygen species (ROS) scavenger tempol, against lipopolysaccharide (LPS)-induced cognition impairment and amyloidogenesis in a simulation to Alzheimer’s disease (AD). Mice were allocated into a control group, an LPS control group (0.8 mg/kg, i.p., once), a tempol (100 mg/kg/day, p.o., 7 days) treatment group, and two perindopril (0.5 and 1 mg/kg/day, p.o., 7 days) treatment groups. A behavioral study was conducted to evaluate spatial and nonspatial memory in mice, followed by a biochemical study involving assessment of brain levels of Aβ and BDNF as Alzheimer and neuroplasticity markers; tumor necrosis factor-alpha (TNF-α), nitric oxide end-products (NOx), neuronal nitric oxide synthase (nNOS), and inducible nitric oxide synthase (iNOS) as inflammatory markers; and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione reduced (GSH), and nitrotyrosine (NT) as oxido-nitrosative stress markers. Finally, histopathological examination of cerebral cortex, hippocampus, and cerebellum sections was performed using both routine and special staining. Tempol and perindopril improved spatial and nonspatial memory in mice without affecting locomotor activity; decreased brain Aβ deposition and BDNF depletion; decreased brain TNF-α, NOx, nNOS, iNOS, MDA, and NT levels; and increased brain SOD and GSH contents, parallel to confirmatory histopathological findings. Tempol and perindopril may be promising agents against AD progression via suppression of Aβ deposition and BDNF decline, suppression of TNF-α production, support of brain antioxidant status, and amelioration of oxido-nitrosative stress and NT production.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Beni Suef Governorate, Egypt

    Mohammed Ragab Abdel-Aziz Ali, Amira Morad Hussein Abo-Youssef & Basim Anwar Shehata Messiha

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo University Rd, Oula, Giza Governorate, Egypt

    Mahmoud Mohamed Khattab

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  1. Mohammed Ragab Abdel-Aziz Ali
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  2. Amira Morad Hussein Abo-Youssef
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  3. Basim Anwar Shehata Messiha
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  4. Mahmoud Mohamed Khattab
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Correspondence to Basim Anwar Shehata Messiha.

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Highlights

• Administration of LPS to mice in a single i.p. dose causes AD simulation.

• Tempol and perindopril may be protected against experimental AD progression.

• Both agents act through inhibition of Aβ deposition and BDNF decline.

• Both agents also suppress brain TNF-α production and oxido-nitrosative stress.

About the current study

We are interested in investigating beneficial effects of drugs interfering with the renin-angiotensin system on noncardiovascular disorders, including respiratory, musculoskeletal, immunological, and CNS disorders. I have just coauthored a manuscript in the European Journal of Pharmacology concerning the effect of angiotensin-converting enzyme inhibition by ramipril on experimental rheumatoid arthritis (doi:10.1016/j.ejphar.2015.08.026), another one in Pharmacological Reports concerning the role of angiotensin receptor blockade by telmisartan on the progression of bronchial asthma (doi:10.1016/j.pharep.2015.02.010), and a third one in Saudi Pharmaceutical Journal concerning the hepatoprotective role of ACE inhibition by lisinopril (doi:10.1016/j.jsps.2015.04.004).

In the present investigation, we evaluated the protective effect of perindopril, a centrally acting angiotensin-converting enzyme inhibitor, compared with tempol, a well-known superoxide scavenger, on LPS-induced cognition impairment and amyloidogenesis in mice in a simulation to Alzheimer disease. We focused on mechanisms not studied before regarding the effect of tempol or perindopril on this model, including particularly the role of brain-derived neurotropic factor, nitrotyrosine production, and cerebellar amyloidogenesis.

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Ali, M.R.AA., Abo-Youssef, A.M.H., Messiha, B.A.S. et al. Tempol and perindopril protect against lipopolysaccharide-induced cognition impairment and amyloidogenesis by modulating brain-derived neurotropic factor, neuroinflammation and oxido-nitrosative stress. Naunyn-Schmiedeberg's Arch Pharmacol 389, 637–656 (2016). https://doi.org/10.1007/s00210-016-1234-6

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  • DOI: https://doi.org/10.1007/s00210-016-1234-6

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