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

Polis, Baruh; Samson, Abraham O.

doi:10.4236/aad.2018.74009

“…ARG2 activation is a leading factor of atherosclerotic vascular disease development [52], and diabetic renal injury [53]. Accordingly, arginase inhibition has been suggested to be a promising therapeutic strategy [20,54,55].…”

Section: Discussionmentioning

confidence: 99%

“…However, the decline in substrate bioavailability and/or activation of arginase leads to a substantial shift of the balance toward ornithine synthesis ( Figure 1b). It seems that arginase activation is a conserved evolutionary reaction to various stimuli [20].…”

Section: Introductionmentioning

confidence: 99%

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

Gilinsky

¹

,

Polityko

²

,

Al

³

et al. 2019

Preprint

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Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, to superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis.Recent preclinical investigations point to arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with non-proteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed.We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolites levels were amplified in normotonic but not in hypertensive rats following the treatment.The data indicate that L-norvaline is a potential antihypertensive agent, and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon the BP regulation.

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“…Brain arginine deprivation, due to arginase over-activation, has been suggested as a cause of AD [12]. Consequently, arginine supplementation [13] and/or arginase inhibition have been proposed to halt AD development [14], and have been successfully tested in AD mice [15]. Of note, non-proteinogenic unbranched-chain amino acid norvaline was shown to amplify the NO levels and reduce urea production and it has been used successfully to treat artificial metabolic syndrome in rats.…”

mentioning

confidence: 99%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Srikanth

²

,

Gurevich

³

et al. 2020

IJMS

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Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

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“…These authors demonstrated that NOS1 repression decreases neuronal differentiation, and vice versa, NOS1 upregulation promotes it.The semi-essential amino acid, arginine, is a mutual substrate for both NOS and arginase. Brain arginine deprivation, due to arginase over-activation, has been suggested as a cause of AD [12].Consequently, arginine supplementation [13] and/or arginase inhibition have been proposed to halt AD development [14], and have been successfully tested in AD mice [15]. Previously, we showed that arginase inhibition with norvaline upsurges the hippocampal levels of NOS3 [16], and NOS1[17] in AD model mice.Additionally, our advanced proteomics assay revealed that chronic treatment of 3×Tg mice with norvaline led to the activation of several critical for adult neurogenesis biological processes [15].One of the most significant pathways detected was the neuregulin (NRG) pathway.…”

mentioning

confidence: 99%

“…Consequently, arginine supplementation [13] and/or arginase inhibition have been proposed to halt AD development [14], and have been successfully tested in AD mice [15]. Previously, we showed that arginase inhibition with norvaline upsurges the hippocampal levels of NOS3 [16], and NOS1…”

mentioning

confidence: 99%

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Polis

¹

,

Gurevich

²

,

Bloch

³

et al. 2019

Preprint

Self Cite

1

0

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Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer's disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis.Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administer an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and apply an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy.Remarkably, we evidence a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline shows no significant effect upon the progenitor cell number and constitution. We demonstrate that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identify a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.However, the existence of human adult neurogenesis has been a subject of intense scientific debate, until recently. Tobin et al. (2019) evidenced hippocampal neurogenesis persisting throughout life in the brains of centenarians and even of Alzheimer's disease (AD) patients [2]. Convincingly, they demonstrated that the density of NPCs, neuroblasts, and immature neurons significantly decreases in cases of mild cognitive impairment and in clinical AD as compared to healthy controls. In addition, various animal models of AD are characterized by diminished adult neurogenesis. In particular, triple-transgenic mice (3×Tg) show an age-dependent neurogenesis insufficiency that is detectable in the hippocampus starting at four months of age [3]. Of note, the decline of neurogenesis in this AD model precedes the manifestation of classical hallmarks of AD pathology, such as deposition of amyloid plaques and neurofibrillary tangles in the brain, as well as memory impairment. Remarkably, as a form of neuroplasticity, adult neurogenesis has been shown to modulate vulnerability to degenerative processes and influence the course of AD [4]. Moreover, various supporting adult neurogenesis treatment strategies have demonstrated their competence to counteract the pathological behavioral outcomes in murine AD models [5]. Nevertheless, the mechanisms that regulate NPC proliferation, ...

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

Cited by 22 publications

References 110 publications

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

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