Nitric Oxide Synthase Activity Is Elevated in Brain Microvessels in Alzheimer′s Disease

Dorheim, M A; Tracey, W. Ross; Pollock, Jennifer S.; Grammas, Paula

doi:10.1006/bbrc.1994.2716

Cited by 211 publications

(140 citation statements)

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“…Several studies have shown that ßA stimulates microglial and astrocytic NO production probably throughout the activation of inflammatory mechanisms by means of an iNOS-mediated release (18,34,35). Moreover, similar mechanisms, iNOS activation and consequent NO high levels of induction, seem to be operative in brain microvessels isolated from AD patients which are amyloid burdened (36).…”

Section: Discussionmentioning

confidence: 96%

Involvement of the receptor for advanced glycation-end products (RAGE) in β-amyloid-induced toxic effects in rat cerebromicrovascular endothelial cells cultured in vitro

Baiguera

Fioravanzo²,

Grandi³

et al. 2009

Int J Mol Med

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Abstract. To ascertain whether the potential biological effects of ß amyloid (ßA) on the endothelium are partly mediated by the receptor for advanced glycation-end products (RAGE), we performed a series of experiments which analyzed the effects of the ßA peptide on in vitro cerebromicrovascular endothelial cells (CECs). Our results suggest that RAGE is directly responsible for ßA actions on CECs, such as its toxic effect on cell survival, viability and angiogenic capability. We observed that a 6-h incubation period exposing CECs to ßA increased the extracellular levels of nitrite. Furthermore, the presence of a nitric oxide synthase inhibitor, L-NAME, was able to enhance CEC survival and viability. Immunocytochemical analyses demonstrated that the peptide induced expression of the inducible form of NOS, iNOS, typically synthesized in response to immune/inflammatory stimuli. Upon blocking the interaction of ßA and RAGE, we observed significantly decreased levels of NO and suppression of iNOS immunoreactivity. In conclusion, our data suggest the involvement of RAGE, at least partly, in mediating the effects of ßA on CECs. In particular, the decrease of in vitro cell viability and functionality and nitrosative stress activation was inhibited by blocking ßA (1-42) -RAGE interaction.

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Section: Discussionmentioning

confidence: 96%

Involvement of the receptor for advanced glycation-end products (RAGE) in β-amyloid-induced toxic effects in rat cerebromicrovascular endothelial cells cultured in vitro

Baiguera

Fioravanzo²,

Grandi³

et al. 2009

Int J Mol Med

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show abstract

“…Dorheim et al (1994) reported that the elevated level of BNO may result from the activation of nitric oxide synthase (NOS) which was also elevated in the brain of patients with AD, indicating that BNO may play a role in neuronal cell injury in this disease.…”

Section: Biochemical Studymentioning

confidence: 99%

POTENTIAL ROLE OF Jasonia montanta AND Jasonia candicans AGAINST ALZHEIMER'S DISEASE: ASSESSMENT OF OXIDATIVE STRESS AND GENE EXPRESSION CHANGES IN AD-INDUCED RATS

Linjawi

Ahmed

Khalil

et al. 2011

Egyptian Journal of Genetics and Cytology

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“…Macrophage cells generate NO as an immune defense system to destroy microorganisms and pathogens. 5,6 The overproduction of NO, especially by nNOS (in brain) is implicated in various disease states such as neurodegeneration, oxidative stress, stroke, migraine and chronic headache, Parkinson, 7 Alzheimer, 8 and Huntington diseases, 9 tissue damage, hypotensive crises during septic shock, arthritis, and various kinds of inflammatory diseases. 10,11 It also reacts with other free radicals to create specific molecular modifications.…”

Section: Introductionmentioning

confidence: 99%

De Novo Design of Potent and Selective Neuronal Nitric Oxide Synthase (nNOS) Inhibitors by a Fragment-Based Approach

Yelekçi

Ortmen

2015

J PHARM CHEM

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Nitric oxide, a gaseous free radical molecule (NO) behaves, as a secondary messenger in various tissues. It is responsible for different physiological functions and pathological symptoms. Mammals contain three different nitric oxide synthase (NOS) isoforms: neuronal NOS (nNOS: in the brain, in peripheral nervous system and muscle tissues), inducible NOS (iNOS: in macrophage cells), endothelial NOS (eNOS: in endothelial cells). Under certain pathological conditions and/or after certain ages excessive NO produced in brain causes tissue damage and oxidative stress. It also reacts with other free radicals to create specific molecular modifications. The excessive production of NO, especially by nNOS (in brain) is implicated in various disease states such as neurodegeneration, stroke, migraine and Parkinson's, Alzheimer's, and Huntington's diseases. The active sites of three NOS isoforms show great similarity; therefore, designing of selective nNOS inhibitors is not an easy task. The computational results carried out with all of the docking tools clearly demonstrate that the selected scaffold is a potential candidate for further modifications and optimization for designing selective and potent nNOS inhibitors. Subtle differences in the conformations of amino acid sequences (e.g. ASP597 in nNOS) of the three isoforms in the active site region were the determining factors for the selectivity and the potency of the compounds. In this study several hundred compounds were screened in silico using the ZINCv12 lead library for prioritization of lead candidates. De novo design method was used rationally for the modifications of selected scaffold within a target--binding site in order to enhance its binding affinity and selectivity to nNOS enzyme. The potency and the selectivity of nNOS isoform were achieved by introducing 1--methyl amino group at the forth position of the imidazole moiety of the best inhibitor. The positively charged 1--methyl amino group makes three hydrogen bonds with the two--propionate groups of the heme cofactor, which does not occur in eNOS and iNOS. Removing of 1--methyl amino group from scaffold totally abolished both potency and selectivity for nNOS. Newly designed inhibitor 7 shows nNOS inhibition 23 and 17 fold better than both eNOS and iNOS, respectively.

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Nitric Oxide Synthase Activity Is Elevated in Brain Microvessels in Alzheimer′s Disease

Cited by 211 publications

References 0 publications

Involvement of the receptor for advanced glycation-end products (RAGE) in β-amyloid-induced toxic effects in rat cerebromicrovascular endothelial cells cultured in vitro

Involvement of the receptor for advanced glycation-end products (RAGE) in β-amyloid-induced toxic effects in rat cerebromicrovascular endothelial cells cultured in vitro

POTENTIAL ROLE OF Jasonia montanta AND Jasonia candicans AGAINST ALZHEIMER'S DISEASE: ASSESSMENT OF OXIDATIVE STRESS AND GENE EXPRESSION CHANGES IN AD-INDUCED RATS

De Novo Design of Potent and Selective Neuronal Nitric Oxide Synthase (nNOS) Inhibitors by a Fragment-Based Approach

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