Patelurology2/Metabolic syndrome, hypertension, dementia, drug therapy, interactions, side effects, pathophysiology
Formation of Beta Amyloid
Aβ is formed after sequential cleavage of the amyloid precursor protein, a transmembraneglycoprotein of undetermined function. APP can be processed by α-, β- and γ-secretases; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39-43 amino acid residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleavage in the trans-Golgi network.[1] The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.[2]
Study indicates that intrasynaptic oAβ42, but not oAβ40, acutely inhibits transmission at the squid giant synapse. This inhibition is molecularly tied to a cascade of events involving CK2 activation and the rapid clathrin-independent endocytosis pathway. The reduction of FAT induced by oAβ42 showed in the accompanying article, in combination with our results showing a dramatic acute inhibition of synaptic transmission after intrasynaptic injection of oAβ42, represent novel findings concerning AD synaptic failure now clearly associated with a reduction of synaptic vesicle pools and transmitter release.
Effective therapeutic intervention in progressive neurological disorders depends on a clear understanding of the molecular mechanisms associated with the disease in question. In this manuscript we have shown that dysregulation of CK2 by oAβ is capable of inhibiting the vital neuronal process of FAT. Therefore, we propose that pharmacological regulation of CK2 activity represents a promising target for therapeutic intervention in AD, particularly when combined with treatments that help manage GSK3 activity as well.Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta
ACE Inhibitors
Examples=
ACE inhibitors can be divided into three groups based on their molecular structure:
Sulfhydryl-containing agents
Captopril (trade name Capoten), the first ACE inhibitor
Fosinopril (Monopril) is the only member of this group
Naturally occurring
Casokinins and lactokinins are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.[3] The tripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probioticLactobacillus helveticus have been shown to have ACE-inhibiting and antihypertensive functions.[4]
Further, functionally can be grouped according to ability to cross Blood Brain Barrier- implication currently being studied for ability to affect dementia.
List:
BBB Crossing ACE
Lisinopril
Perindropril
Ramipril
Trandolapril
Captopril
Fosinopril
BBB Non Crossing ACE
Benzapril
Enalapril
Moexipril
Imidapril
Other Antihypertensives, and even all ACE Inhibitors, possibly indirectly via RAAS feedback some of the effects on dementia and related complex - Construct: deemntia and BP dynamics and possibly incorporating known circadian rythm affecting Beta amyloid.
Choosing an ACE Inhibitor
Several ACE inhibitors are on the market. Here is a list
of some by generic name followed by brand name(s).
Dynamics & Flux Between Amyloid β fragments Beta amyloid & Blood Pressure & Autonomous System- Dementia as a Case Study
Brain has ACE enzyme which takes part in local RAAS and converts Aβ42 ( plaquogenic ) to Aβ40( more soluble and removal ) forms of Beta amyloid ; latter is prdominentally a function of N domain portion on the ACE enzyme; Inhibition of ACE with ACE Inhibitors, especially Blood Brain Barrier crossing and with preferentially select N terminal activity would cause accumulation of Aβ42 which is plaquogenic causing progression of dementia; preferential C domain active BBB crossing ACE would linkely have less of this latter effect.
Whether plaque is dementic environment or the downstream small fragment generated by the action of ACE are inflammatory and hence dementic an environment, is the question!
Mass spectral fragmentation reactions of angiotensin-converting enzyme (ACE) inhibitors: n interesting dissociation process (rearrangement) unique to one of the compounds, lisinopril, has been investigated using isotopic labeling experiments and exact mass measurements. The general nature of the process has been probed through both the positive and negative ion analyses of fourteen related compounds exhibiting structural homolog
Wondering : ACE ARBS BP Statins : Interactions and complexities
Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events. ACE inhibitors augment endothelium-dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3-6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.
BBB Crossing Statins and effecton brain, RAAS ACE ARBS Dementia
Most of the ACE inhibitors on the market today are non-selective towards the two active sites of ACE because their binding to the enzyme is based mostly on the strong interaction between the zinc atom in the enzyme and the strong chelating group on the inhibitor. The resolution of the 3D structure of germinal ACE, which has only one active site that corresponds with C-domain of the somatic ACE, offers a structural framework for structure-based design approach. Although N- and C-domain have comparable rates in vitro of ACE hydrolyzing, it seems like that in vivo the C-domain is mainly responsible for regulating blood pressure. This indicates that C-domain selective inhibitors could have similar profile to that of a current non-selective inhibitors. Angiotensin I is mainly hydrolyzed by the C-domain in vivo but bradykinin is hydrolyzed by both active sites. Thus, by developing a C-domain selective inhibitor would permit some degradation of bradykinin by the N-domain and this degradation could be enough to prevent accumulation of excess bradykinin which has been observed during attacks of angioedema. C-domain selective inhibition could possibly result in specialized control of blood pressure with less vasodilator-related adverse effects. N-domain selective inhibitors on the other hand give the possibility of opening up novel therapeutic areas. Apparently, the N-domain doesn’t have a big role in controlling blood pressure but it seems to be the principal metabolizing enzyme for AcSDKP, a natural haemoregulatory hormone.
The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N- and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in high- salt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N- and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors.
Structure of angiotensin I-converting enzyme. The inhibitor complex does provide insights into the network of hydrogen-bonding and ionic interactions in the active site as well as the mechanism of ACE substrate hydrolysis. The three-dimensional structure of ACE now paves the way for the rational design of a new generation of domain-selective ACE inhibitors.
Potency For C domain L > E > C Lisinopril, Enalprilat, Captopril
Potency For N domain C > E > L
Aß42-40 converting inhibition is solely in N domain where Captopril is the strongest N: C>E>L
ACE Inhibiting activity is solely in C domain where.........Lisionopril is the strongest C: L>E>C
Aβ42-to-Aβ40-converting activity is solely found in the N-domain of ACE and the angiotensin-converting activity is found predominantly in the C-domain of ACE. The N-linked glycosylation is essential for both Aβ42-to-Aβ40- and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domain-specific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin-converting C-domain, without inhibiting the Aβ42-to-Aβ40-converting activity of ACE or increasing neurotoxic Aβ42.
Centrally Active ACE Inhibitors May Help Prevent Dementia -coming soon -! can? non central ACE & possibly other Non ACE antihypertensives, be more preventive? Why recent study finds otherwise? FACTORS IN CONSTRUCT. ACE Degrades/converts Amyloid Aβ42 ( fibrillogenic, plaque forming ! ) to favorable Aβ40 more soluble possibly 'removable' amyloid & Central acting (BBB crossing) ACE Inhibitors thus likely to increase dementia; anti-inflammatory effects of ACE Inhibitors likely to decrease dementia, Acute effect of ACE on Ach likely to increase short term acuity confusing the picture for evaluation
The following Construct development in progress and involve all these and more points in hypothesis development.
Centrally acting ACE Inhibitors have acute Ach effects helping in mental acuity short term during which measurement may be biased and the long term effect of amyloid Aβ42 accumulation may be masked in testing; favorable anti-inflammatory effect not withstanding, long term more Aβ42 is deposited or not converted to more soluble, disposable or removable Aβ40. Vascular Aβ42 vs Aβ40 to be considered and could be important along with the favorable anti-inflammatory effect.
Acute, Chronic and Chronic with short term non use ( washed off ) use of ACE considering short term acuity enhancing effects of Ach.
Difference between Aβ42 ? more in nerves and ? Aβ40 more in vessel
Aβ42 vs Aβ40
Pleomorphism and genetics of ACE
RAAS -Systemic vs Local and interactions and cross influence
ALL above to be considered in both below: along with congruency of the two studies with each other and restrospective congruency with prior knowledge base of studies and general understanding of the science.
Currently reported study in Archives of Intl Med July 09-BBB crossing ACE reduce Dementia needs explanation.... Standby
Current AII AT1 Inhibitors -Sartan--retrospective VA study expl and corroboration standby......
Results From the Cardiovascular Health Study: While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.]
Alzheimer's-beta amyloid, tau protein,-- Drug Rember, Methylene Blue
Alzheimer's researchers are divided on whether the disease is caused by 'beta amyloid' (a peptide found in Alzheimer brains) or by 'tau protein' (normally used for cellular scaffolding, but can aggregate out of control and destroy neurons). Today in Chicago a new drug has been announced that stops tau aggregation and appears to have halted Alzheimer's-related decline in 300 clinical trial patients. The drug is known as 'rember.
Angiotensin Receptor Blockers lower progression of Alzheimer's Disease- ! explanation coming and Construct intergration in progress
SHORT Explanation for this: mech related to above ACE AND ACE Inhibitors and BP dynamcs. Standby for full expl......
http://www.physorg.com/print136426165.html
Angiotensin receptor blockers are lower incidence, progression of Alzheimer's disease
July 28th, 2008 in Medicine & Health / Diseases
Researchers at Boston University School of Medicine (BUSM) have, for the first time, found that angiotensin receptor blockers (ARBs)—a particular class of anti-hypertensive medicines—are associated with a striking decrease in the occurrence and progression of dementia. Data from this study will be presented this weekend (July 27) at the 2008 International Conference on Alzheimer's disease in Chicago.
Using data from the Decision Support System Database of the U.S. Department of Health System Veterans Affairs (with information on more than 5 million people), researchers looked at records from patients using ARBs, and compared them with subjects who had a similar health status, but were taking different medications. They found patients taking ARBs had about a 35-40 percent lower chance of getting Alzheimer's disease or dementia.
The researchers also examined patients who were already suffering from Alzheimer's disease or dementia, and found those subjects had up to a 45 percent lower chance of developing delirium, being admitted to nursing homes or dying. Patients who appeared to benefit particularly well from use of ARBs were those who had experienced strokes before or during the course of their illness.
According to the researchers these results suggest that ARBs might protect against developing Alzheimer's disease and dementia. "For those who already have dementia, use of ARBs might delay deterioration of brain function and help keep patients out of nursing homes," said lead presenter Benjamin Wolozin, MD, PhD, a professor of pharmacology at BUSM. "The study is particularly interesting because we compared the effects of ARBs to other medications used for treating blood pressure or cardiovascular disease. This suggests that ARBs are more effective than other blood pressure and cardiovascular medications for preventing Alzheimer's disease or dementia," he added.
Although the researchers are unsure why ARBs might be so beneficial, they believe one possibility suggested by prior studies on animal models is that ARBs help prevent nerve cell injury from blood vessel damage or help promote nerve cell recovery after blood vessel damage. Damage to blood vessels is thought to reduce brain capacity and promote dementia, so reducing this damage might prevent the occurrence or progression of dementia.
Source: Boston University
ACE-I vs angiotensin II receptor antagonists vs Vasopeptidase inhibitor (VPI)
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In typesetting technical literature, it is a commonly made mistake to use the German letter ß as a replacement for the β. The two letters resemble each other superficially, but they are unrelated. This substitution looks extremely unprofessional to the eyes of German or Greek readers.
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References
^Hartmann T, Bieger SC, Brühl B; et al. (1997). "Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides". Nat. Med. 3 (9): 1016–20. doi:10.1038/nm0997-1016. PMID9288729. ((cite journal)): Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^Yin YI, Bassit B, Zhu L, Yang X, Wang C, Li YM (2007). "γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio: Implications for Alzheimer's disease". J. Biol. Chem. 282 (32): 23639–44. doi:10.1074/jbc.M704601200. PMID17556361.((cite journal)): CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Dive, V.; et al. (2004), "Review: Phosphinic peptides as zinc metalloproteinase inhibitors.", Cellular and Molecular Life Science, 61: 2010–2019 ((citation)): Explicit use of et al. in: |author= (help) Phosphinic peptides as zinc metalloproteinase inhibitors
^ Gerogiadis, D.; Guniasse, P.; Cotton, J.; Yiotakis, A.; Dive, V. (2004), "Structural Determinants of RXPA380, a Potent and Highly Selective Inhibitor of the Angiotensin-Converting Enzyme C-domain.", Biochemistry, 43: 8048–8054, doi:10.1021/bi049504q