Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type.

Aziz, A. A.; Leeming, R. J.; Blair, J.A.

doi:10.1136/jnnp.46.5.410

Cited by 34 publications

(14 citation statements)

References 13 publications

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“…However, cerebral tryptophan hydroxylase shows a poor affinity for oxygen 33 and therefore would be easily affected by ischemia. In contrast, tyrosine hydroxylase exhibits a higher affinity for oxygen, 8 which may explain the difference between the level of 5-HT and that of DA. Weinberger et al have demonstrated that the catecholamine nerve terminals utilizing NE and DA as transmitters are more susceptible to damage by cerebral ischemia than nerve terminals utilizing 5-HT.…”

Section: Cortex Deep Grey Brainstemmentioning

confidence: 74%

“…3 It has been suggested that concentration of BH4 in tissues may play a regulatory role in determining the rate of hydroxylase activity. 4 ' 5 Lack of BH4 leads to a severe mental and neurological retardation or malignant hyperphenylalaninemia, 6 and defective BH4 metabolism has been suggested in Parkinson's disease, 7 senile dementia 8 and dystonia. 9 Although BH4 plays such important roles in the brain, little is known about the effect of ischemia on BH4.…”

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confidence: 99%

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Effect of ischemia on hydroxylase cofactor (tetrahydrobiopterin) and monoamine neurotransmitters in rat brain.

Iijima¹,

Hara²,

Suga³

et al. 1986

Stroke

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SUMMARY Hydroxylase cofactor, monoamine neurotransmitters and their metabolites were measured in ischemic rat brain produced by four-vessel occlusion for 30 and 60 min periods. Slight reduction of hydroxylase cofactor activity was observed in the ischemic cortex after 60 min. Dopamine increased in the brainstem, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanlllic acid, increased throughout the brain. Decrease in norepinephrine was observed in the whole brain. Decrease in serotonin and increase in 5-hydroxyindoleacetic acid, a metabolite of serotonin, was observed in the ischemic cerebral cortex. The present study has revealed that there appears to be no significant relationship between hydroxylase cofactor activity and monoamine levels in the ischemk brain. Thus, the hydroxylase cofactor does not play a main role in regulating monoamine synthesis hi the acute phase of brain ischemia. Stroke Vol 17, No 3, 1986 TYROS1NE hydroxylase and tryptophan hydroxylase, the initial and rate-limiting enzymes in the biosynthesis of catecholamines and serotonin, require reduced pteridines as cofactors.1 -2 Tetrahydrobiopterin (BH4) is thought to be the natural cofactor.3 It has been suggested that concentration of BH4 in tissues may play a regulatory role in determining the rate of hydroxylase activity.4 ' 5 Lack of BH4 leads to a severe mental and neurological retardation or malignant hyperphenylalaninemia, 6 and defective BH4 metabolism has been suggested in Parkinson's disease, 7 senile dementia 8 and dystonia. 9 Although BH4 plays such important roles in the brain, little is known about the effect of ischemia on BH4.It has been suggested that various changes occur on monoamine neurotransmitters in the ischemic brain, which might be responsible for the brain dysfunction. There are, however, many discrepancies among findings presented by previous workers because they used experimental animals of different species or various ischemic periods, or because the distribution of ischemia was not reliably reproducible. At present, however, the rat model of four-vessel occlusion, which has recently been developed by Pulsinelli et al, 10 yields a bilateral forebrain ischemia with a relatively high reproducibility. During four-vessel occlusion, blood flow was severely reduced, to less than 3% of control values, in neocortex, striatum and hippocampus, and blood flow to the brainstem was reduced to 26%."In the present study, we have measured hydroxylase cofactor activity and concentrations of dopamine (DA), norepinephrine (NE), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the brains of rats subjected to four-vessel occlusion, in order to evaluate the effect of ischemia on monoamine neurotransmitters and hydroxylase cofactor, 1985; accepted September 30, 1985. and to assess the role of cofactor in ischemic changes of neurotransmitters. MethodsMale Wistar rats weighing 250-300 gm were subjected to four-vessel occlusion as described by Pul...

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Section: Cortex Deep Grey Brainstemmentioning

confidence: 74%

mentioning

confidence: 99%

Effect of ischemia on hydroxylase cofactor (tetrahydrobiopterin) and monoamine neurotransmitters in rat brain.

Iijima¹,

Hara²,

Suga³

et al. 1986

Stroke

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“…AD patients exhibit disturbed brain metabolism of tetrahydrobiopterin, an essential cofactor for NOS [12, 53], and lower steady levels of NO in the plasma [54], thereby suggesting the contribution of low bioavailability of NO in reduced cerebral blood flow under those neurodegenerative conditions. In support, de la Torre and colleagues previously reported (using rat model of permanent BCCAO) that vascular NO derived from eNOS plays a critical role in spatial cognitive function by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow [8], in turn suggesting that the restoration of NO bioavailability or NO-mediated vascular function may be beneficial for alleviating cognitive decline associated with conditions of chronic cerebral hypoperfusion.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of S-Nitrosoglutathione (GSNO) Against Cognitive Impairment in Rat Model of Chronic Cerebral Hypoperfusion

Won

Kim

Annamalai

et al. 2013

JAD

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Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of Aβ and vascular inflammatory markers. GSNO treatment (50 μg/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the Aβ levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NFκB and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial Aβ uptake. Additionally, GSNO treatment inhibited the β-secretase activity in primary rat neuron cell culture, thus reducing secretion of Aβ, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease.

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“…The mRNA and protein levels of the enzyme argininosuccinate synthetase, the rate limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine (the physiological substrates of NOS), are significantly higher in glial cells of AD brain [68,69]. Metabolism of tetrahydrobiopterin (BH 4 ), an essential cofactor for NOS, is disturbed in AD patients [70,71], which will lead to the "uncoupling" of NOS favoring the production of superoxide anion and hydrogen peroxide [72]. Large and small mutipolar and pyramidal neurons demonstrate increased nNOS levels over the entire chronic AD evolution [72,73].…”

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confidence: 99%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

160

156

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Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process. KeywordsAlzheimer disease; hypoperfusion; mitochondria; nitric oxide; nitric oxide synthase; oxidative stress; vascular abnormalitiesCorrespondence to: George Perry, Ph.D., College of Sciences, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, Texas 78249-0661 USA, , george.perry@utsa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . Therefore, perivascular Aβ deposits may be a risk factor for reduced regional CBF [7]. Ultrastructural studies on blood vessels associated with Aβ deposits have shown their intermittent association with membrane abnormalities of smooth muscle cells [5]. Indeed, in AD cases with a clinical history of cerebral bleeding, the muscle layer is sometimes completely replaced by Aβ deposits, suggesting that the vascular system may be an initiator for the development of diseas...

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Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type.

Cited by 34 publications

References 13 publications

Effect of ischemia on hydroxylase cofactor (tetrahydrobiopterin) and monoamine neurotransmitters in rat brain.

Effect of ischemia on hydroxylase cofactor (tetrahydrobiopterin) and monoamine neurotransmitters in rat brain.

Protective Role of S-Nitrosoglutathione (GSNO) Against Cognitive Impairment in Rat Model of Chronic Cerebral Hypoperfusion

Vascular oxidative stress in Alzheimer disease

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