Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals – A randomized double- blind pre-clinical study

Ahmed, Heba A.; Ishrat, Tauheed; Pillai, Bindu; Bunting, Kristopher M.; Patel, Ashni; Vazdarjanova, Almira; Waller, Jennifer L.; Arbab, Ali S.; Ergul, Adviye; Fagan, Susan C.

doi:10.1016/j.bbr.2017.12.007

Cited by 35 publications

(28 citation statements)

References 47 publications

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“…Even though Ang II can bind two different receptors, ACE upregulation specifically leads to increased AT1R activation. Hyperactivation of AT1R signaling and upregulation of ACE expression is well known for its role in vasoconstriction but within the brain, specifically exacerbates cognitive impairment [ 19 ], cell death [ 20 , 21 ] and inflammation [ 18 ].…”

Section: Central Renin Angiotensin Systemmentioning

confidence: 99%

“…MrgDs are less studied but they are also GPCRs and are located on neurons [ 23 , 24 ]. AT2Rs, MasRs, MrgDs and ACE2 are known for their roles in vasodilation, but within the brain they specifically enhance cognition, cell survival and have both antioxidant and anti-inflammatory properties [ 18 , 19 , 25 , 26 , 27 ] ( Figure 3 ). The AT2R, MasR and MrgD pathways in interdependent.…”

Section: Central Renin Angiotensin Systemmentioning

confidence: 99%

“…AT2R activation facilitates cognition, cell survival and has both antioxidant properties and anti-inflammatory properties [ 18 , 19 , 25 , 26 , 27 ]. Cell surface AT2R can lead to the activation of pathways such as Src Homology Region 2 Domain-Containing Phosphatase-1 (SHP–1), serine-threonine phosphatase (PP2A) and Peroxisome Proliferator-activated Receptors (PPARγ) to promote cell survival and counteract the AT1R activation [ 46 , 47 , 48 ].…”

Section: Angiotensin Receptor Functions Within Each Cell Typementioning

confidence: 99%

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Within the Brain: The Renin Angiotensin System

Jackson

Eldahshan

Fagan

et al. 2018

IJMS

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248

187

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For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial.

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Section: Central Renin Angiotensin Systemmentioning

confidence: 99%

Section: Central Renin Angiotensin Systemmentioning

confidence: 99%

Section: Angiotensin Receptor Functions Within Each Cell Typementioning

confidence: 99%

See 1 more Smart Citation

Within the Brain: The Renin Angiotensin System

Jackson

Eldahshan

Fagan

et al. 2018

IJMS

Self Cite

248

187

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“…High levels of Ang II are found to increase oxidative stress and promote neuroinflammation while ARBs prevent many risk factors for AD and protect neurons (Saavedra, 2016;Liu et al, 2015). Activation of AT1R by Ang II due to increased expression of ACE is known to play important role in vasoconstriction in the brain and impairs cognition (Ahmed et al, 2018. ), cell death and inflammation .…”

Section: Introductionmentioning

confidence: 99%

Role of brain renin angiotensin system in neurodegeneration: An update

Abiodun¹,

Ola²

2020

Saudi Journal of Biological Sciences

104

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a b s t r a c tRenin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1-7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1-7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain.

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“…The Morris water maze was used to assess animals' spatial learning and memory through a combination of training and probe trials [22]. In brief, training trial animals were allowed to learn the location of the hidden escape platform submerged 2 cm below the surface of the water (25 ± 2 °C) in a circular water tank (132 cm diameter and 60 cm height), divided into four virtual quadrants.…”

Section: Water Maze Testmentioning

confidence: 99%

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals – A randomized double- blind pre-clinical study

Cited by 35 publications

References 47 publications

Within the Brain: The Renin Angiotensin System

Within the Brain: The Renin Angiotensin System

Role of brain renin angiotensin system in neurodegeneration: An update

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

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