Intracerebroventricular administration of L-arginine improves spatial memory acquisition in triple transgenic mice via reduction of oxidative stress and apoptosis

Fonar, Gennadiy; Polis, Baruh; Meirson, Tomer; Maltsev, Alexander V.; Elliott, Evan; Samson, Abraham O.

doi:10.1515/tnsci-2018-0009

Cited by 25 publications

(15 citation statements)

References 44 publications

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“…Arginine was shown to mitigate hydrogen peroxide-induced apoptosis and protect against Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) -induced toxicity in cultured PC-12 cells (97). The amino acid supplementation improves cognitive function in demented elderly (98).…”

Section: A Contribution Of the Urea Cycle And Polyamine Metabolic Patmentioning

confidence: 99%

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Polis

Samson

2019

Alzheimer’s Disease

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Alzheimer' s disease (AD) is an irredeemable chronic neurodegenerative disorder and the predominant cause of dementia. The disease progression is associated with the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, yet clinical dementia is the end and culminating stage of the enduring pathology. Recent evidence suggests that AD is characterized by distinctive abnormalities apparent on systemic, histological, macromolecular, and biochemical levels. Besides the well-described characteristic profuse neurofibrillary tangles, dystrophic neurites, and Aβ deposits, the AD pathology includes substantial neuronal loss, inflammation, extensive DNA damage, considerable mitochondrial malfunction, impaired energy metabolism, and chronic oxidative stress. Moreover, severe metabolic dysfunction leading to oxidative stress is a possible cause and hallmark of AD that is apparent decades before the disease manifestation. State-of-the-art metabolomics studies have proved that arginine and branched-chain amino acids metabolism disturbances accompany AD and contribute to its pathogenesis. Repetitive failures to find an efficient anti-amyloid or anti-Tau treatment, which would face the challenges of the complex AD pathology, led to the hypothesis that hyperphosphorylated Tau and deposited

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Section: A Contribution Of the Urea Cycle And Polyamine Metabolic Patmentioning

confidence: 99%

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Polis

Samson

2019

Alzheimer’s Disease

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“…The theory has found an experimental approval. Fonar et al bypassed the BBB by chronic intraventricular administration of the amino acid in mice (Fonar et al 2018). The treatment improved significantly spatial memory acquisition in 3xTg-AD mice via a reduction of oxidative stress and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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“…The reverse was also shown: deprivation of L-arginine induces oxidative stress-mediated apoptosis [33]. The antiapoptotic and neuroprotective properties of the amino acid were confirmed in cultured PC-12 cells [34], in motor neurons with excitotoxic injury, and in a transgenic amyotrophic lateral sclerosis mouse model [35].…”

Section: L-arginine Metabolism and Alzheimer's Diseasementioning

confidence: 87%

“…This makes systemic administration inadequate to show all of its possible neurotrophic properties. In order to overcome this limitation, Fonar et al (2017) bypassed the BBB via chronic intraventricular administration of the amino acid in a mouse model of AD [34]. The animals treated with L-arginine showed significantly improved spatial memory acquisition.…”

Section: L-arginine Metabolism and Alzheimer's Diseasementioning

confidence: 99%

Arginase as a Potential Target in the Treatment of Alzheimer’s Disease

Polis¹,

Samson²

2018

AAD

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Alzheimer's disease (AD) is a slowly progressive, neurodegenerative disorder with an insidious onset that is characterized by severe decline in memory, thinking and reasoning skills. Advanced age is a prominent risk factor for AD and other metabolic diseases, such as type II diabetes and atherosclerosis. Their causal mechanisms are multifaceted and not fully understood. The precise pathophysiology of AD remains a mystery despite decades of intensive investigation. Thus far, there is no truly successful AD therapy. Arginase is the central enzyme of the urea cycle. Recent studies have identified arginase function in the brain and associated this enzyme with the development of neurodegenerative diseases. Upregulation of arginase has been shown to contribute to endothelial dysfunction, ischemia-reperfusion, atherosclerosis, diabetes, and neurodegeneration. Other state-of-the-art discoveries of the precise molecular machinery of neurodegeneration have provided new directions for the rational development of innovative therapeutic strategies in the treatment of common neurodegenerative diseases. In this context, the regulation of arginase activity appears to be a universal approach in interfering with the pathogenesis of AD and providing relief for it and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target. Arginase inhibition has been shown to reverse amyloid-driven neuronal dysfunction and microgliosis and prevent the development of other AD symptoms in rodent models of AD. Consequently, the methodology represents a promising direction for clinical development.

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Intracerebroventricular administration of L-arginine improves spatial memory acquisition in triple transgenic mice via reduction of oxidative stress and apoptosis

Cited by 25 publications

References 44 publications

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Arginase as a Potential Target in the Treatment of Alzheimer’s Disease

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