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I have been preaching for years that oxidation not amyloid nor tau tangles are the cause of Alzheimer's disease. The research team working on ANAVEX agree.
ANAVEX 2-73 has been shown to provide protection from oxidative stress, which damages and destroys neurons and is believed to be a primary cause of Alzheimer's disease. Research in recent years indicates that oxidative stress is a precursor to amyloid-beta plaques and tau (Neuro-Fibrillary Tangles or NFT) and, as such, is the appropriate therapeutic target. ANAVEX 2-73 is not focused on reducing or dissolving amyloid-beta protein, unlike drug candidates from other biopharmaceutical companies that have recently produced disappointing clinical results.
ANAVEX 2-73 is currently undergoing a Phase 2a trial in Alzheimer’s patients after completing a Phase 1 study with a clean data profile. In earlier preclinical studies, ANAVEX 2-73 showed potential to halt and/or reverse Alzheimer’s disease.
http://www.microcapdaily.com/riding-the-anavex-life-sciences-corp-otcmktsavxl-express/112567/
“This is the first time the investigational drug ANAVEX 2-73 has been administered to Alzheimer’s patients. In addition to the positive EEG/ERP P300 biomarker signal, the feedback we’ve had so far is that patients and care providers have noticed both cognitive and functional improvement, increased alertness, improvement in activities of daily living, greater organization and a requirement for less prompting,” said study’s principal investigator Dr. Stephen Macfarlane, FRANZCP, Associate Professor and Director of Aged Psychiatry at The Alfred Hospital. “Subsequent to the positive initial feedback, we are applying to expand the extension period from 26 weeks to 52 weeks at the request of the participants.”
http://www.alzheimersweekly.com/2015/08/anavex-2-73-shows-positive-cognitive.html
I don't think this is the Holy Grail for the treatment of Alzheimer's disease but it is getting close as ANAVEX seems to inhibit oxidative stress via NMDA receptor (like Namenda but much better). Combine it with a more direct or more powerful peroxynitrite scavenger such as eugenol in various essential oils, ferulic acid in ginseng, or cannabinoids in medicinal marijuana and the answer to treating Alzheimer's disease is clearly in sight.
http://www.anavex.com/?post_type=news&p=1369
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Wait a minute, this NMDA Receptor is proving to be a central factor in the disease. I have not spent much time researching it. What are the NMDA Receptor's connections to sugar intake, insulin resistance, obesity, metabolic syndrome and diabetes? Well, here's something, leptin (the hormone that tells you you're full and is produced by fat cells) interacts with the NMDA Receptor! What does this mean? What about insulin? Insulin is known to block leptin which leads obease people to overeat because their leptin is being blocked by overproduction of insulin. Look at this article:
Leptin Enhances NMDA Receptor Function and Modulates Hippocampal Synaptic Plasticity
Click
Here
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Serenoa when you are not here, I become complacent in my research. No one asks as many important questions as well as you do.
In Alzheimer's disease, there are two pathways that initially lead to the overactivation of NMDA receptors--one is receptor tyrosine kinases (including the insulin receptor) and the other is g protein-coupled receptors (or direct g protein activation).
http://www.jneurosci.org/content/22/22/9679.full.pdf
Sugar in the brain increases myo-inositol levels and increases the activation of platelet derived growth factor receptor which is another receptor tyrosine kinase.
http://diabetes.diabetesjournals.org/content/45/4/507.short
The result of this pathway is the production of peroxynitrites which nitrates the insulin receptor substrate such that less glucose can get into the rest of the body and ends up in the brain, where the whole process begins all over again.
http://www.ncbi.nlm.nih.gov/pubmed/21110800
http://www.ncbi.nlm.nih.gov/pubmed/15240096
On a separate part, the activation of NMDA receptors contributes to synaptic plasticity but its overactivation leads to the production of peroxynitrites. Leptin can do both.
http://www.ncbi.nlm.nih.gov/pubmed/23207144
But leptin usually appears to be low in some people with Alzheimer's disease perhaps due to the prevalence of insulin resistance.
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The key to treating Alzheimer's disease in its middle to later stages is likely this: inhibit NMDA receptors and scavenge peroxynitrites. The overactivation of NMDA receptors leads to the production of peroxynitrites which leads to the further activation of NMDA receptors (except at very high levels where it can lead to NMDA hypofunction--Alzheimer's disease with hallucinations).
Here is one suggestive piece:
Given the potential therapeutic benefit of cannabis as well as the increased use of medical marijuana in the general population, these findings highlight the need for a stronger scientific understanding of cannabis or its components in indications such as neuropathic pain and neurological diseases. Understanding cannabinoid receptor modulation will help reduce the potentially negative influence of cannabis. It will also assist with the development of drugs to treat psychosis possibly caused by cannabis. The data published in IJNP indicates that the sigma-1 receptor acts as a stability system for the interaction of the cannabinoid receptor 1 (CB1) and the glutamate N-methyl-D-aspartate (NMDA) receptor. The calcium-sensitive sigma-1 receptor appears to function as a safety switch, releasing NMDA receptors (NMDAR) from the influence of cannabinoid receptors and avoiding glutamate hypofunction, a condition commonly found in schizophrenia. “This study could encourage the exploration of marijuana components in combination with sigma-1 receptor drug candidates in order to understand the potential therapeutic benefit for neurodegenerative diseases, including Alzheimer’s, schizophrenia and neuropathic pain,” said Dr. Chuanhai Cao, Assistant Professor at the University of South Florida (USF) Health Byrd Alzheimer’s Institute. Dr. Cao and colleagues recently published a report showing that a compound in marijuana has potential applications in Alzheimer’s treatment. “With Anavex drug candidates targeting the sigma-1 receptor, and with the mechanism of action being further validated, we are even more encouraged to advance our studies with additional neurodegenerative diseases,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. “The Company is intrigued to realize the direct link to the body’s endocannabinoid system and to proceed with potential studies with our sigma-1 drugs candidates and cannabinoids.” http://www.anavex.com/?post_type=news&p=1369
I am not particularly concerned about the potential negative effects of THC (cannabinoids) on cognition and behavior in most Alzheimer's patients because the receptor its activates (a g protein-coupled receptor) are mostly oxidated and disabled early on in the disease. What is of interest is that THC is a peroxynitrite scavenger. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892413/
http://www.ncbi.nlm.nih.gov/pubmed/25024327
Eugenol in various essential oils and ferulic acid (in ginseng and rice bran oil, for instance) are perhaps even better peroxynitrite scavengers and inhibitors of NMDA receptors. http://www.ncbi.nlm.nih.gov/pubmed/9147382
http://www.ncbi.nlm.nih.gov/pubmed/16257184
Find the right combination or combination of NMDA receptor antagonists and peroxynitrite scavengers and you likely find the proper treatment for Alzheimer's disease.
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I found this really good article on the dual nature of NMDA receptors.
NMDA receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca2+ influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington’s. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render them vulnerable to secondary trauma. Thus, responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death both in response to both hyper- and hypoactivity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837198/
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You are too kind Lane. It is your research that has lead me to so much new information!
It will take me some time to get through all that you have posted here. Very interesting stuff. Thanks.
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Yes! You have given me a great lead, the connection between peroxynitrites and the insulin receptor substrate 1 (IRS1). I have found more evidence implicating IRS1 in brain insulin resistance. And tyrosine phosphorylation is also a great connection. Please review this article and tell me more about these connections to IRS1. THis is critical stuff. Thanks!
Demonstrated brain insulin resistance in
Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1
dysregulation, and cognitive declinehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314463/
In the cerebellar cortex and HF of both the AD and N cases, insulin induced activation of IRβ (pY1150/1151 and pY960) and IRS-1 (total pY and pY612) as well as IRβ binding of IRS-1 and IRS-1 binding of PI3K p85α (Figures and
and Supplemental Tables 2 and 3). In AD cases, however, the percent
increase in these insulin responses above baseline levels was less than
in N cases at all levels of the insulin signaling pathway studied
(Figure and Tables and ). Except for activation of IRβ pY960
in the cerebellar cortex, the reduced responsiveness to 1 nM insulin in
both structures was modest at the level of the IR, but moderate to
strong with respect to IRS-1 and its interactions with PI3K p85α (Figure
and Tables and ).
While there were marked reductions in IRS-1 activation and binding of
IRβ and PI3K p85α in response to 1 nM insulin in AD, there were no such
reductions in IRS-2 responses to that dose of insulin (Tables and ).
In the same samples that showed insulin resistance in AD, IGF-1
resistance was discovered in the IGF-1R→IRS-2→PI3K pathway. Responses to
1 and 10 nM IGF-1 were reduced at all tested levels of that pathway
(Figures –) and were nearly always greater in the HF than the cerebellar cortex (Tables and ).
In other respects, however, IGF-1 resistance clearly differed from
insulin resistance. First, stimulus-induced receptor activation, as
shown by IGF-1Rβ pY1135/1136 and IGF-1Rβ pY1131 levels, was strongly reduced and was not significantly ameliorated at 10 nM IGF-1, even in the cerebellar cortex (Tables and ).
Second, while the AD cases showed marked reductions in 1 nM
IGF-1–induced activation of IRS-2 and of IRS-2 binding to IGF-1Rβ and
PI3K p85α, they showed no such corresponding effects of IGF-1 on IRS-1
(Tables and ).
The increase in total basal levels of IRS-2 in both brain areas studied
was thus probably associated with resistance to IGF-1, not insulin.
Since we lacked clues to the proximal causes of brain IGF-1 resistance,
we did not pursue that phenomenon further. Instead, we next focused on
the many clues to the potential proximal causes of brain insulin
resistance.
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Thank you for the compliment, Serenoa. We have helped each other.
I can shed a bit of light on this article. The peroxynitrite-mediated nitration of the insulin receptor substrate-1 probably plays a key role in type-2 diabetes because it prevents the activation of the phosphatiylinositol 3-kinase/Akt pathway that leads to glucose uptake into cells.
http://www.ncbi.nlm.nih.gov/pubmed/21110800
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011021/
The insulin like-growth factor receptors is also nitrated via peroxynitrites and this reduces the stimulus from insulin-like growth factor.
www.sciencedirect.com/science/.../S1063458404001396
Whether either, both, or neither of these pathways reduces glucose in the brain is still open to question (there is some debate about whether insulin is needed for glucose uptake in brain cells).
http://diabetes.diabetesjournals.org/content/51/12/3384.full
Another possibility is that peroxynitrites directly damage glucose transporters in the brain.
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One ironic aspect of Alzheimer's disease is that the receptors that initially lead to the formation of peroxynitrites and Alzheimer's disease (receptor tyrosine kinases and g protein-coupled receptors) are inactivated by oxidation and nitration during the course of the disease. This should stop the disease, but instead peroxynitrites continue to be produced via NMDA receptors. Here are some nice pairings of ginseng with these later processes.
Korean Red Ginseng Extract Inhibits Excitotoxic and Aβ-induced Apoptotic Cell Death in the Cultured Neurons
Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red GinsengJae-Hyeok Heo,1 Soon-Tae Lee,2,3 Min Jung Oh,2,3 Hyun-Jung Park,2,3 Ji-Young Shim,2,3 Kon Chu,2,3 and Manho Kim2,3,*A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/
Evaluation of the Peroxynitrite Scavenging Activity of Heat-Processed Ginseng
http://online.liebertpub.com/doi/abs/10.1089/jmf.2007.0646
Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.
Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.
Abstract
OBJECTIVES:
Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).
METHODS:
Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.
RESULTS:
The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.
DISCUSSION:
These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.
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Yes, insulin resistance stops the beneficial PI3k/Akt pathway. That is what clued me in to the importance of insulin in this disease a while back. One reason I recognized it is because of all your posts Lane on the benefits of that pathway for cell survival. Then I found out that Leukine also activates that pathway.
Anyway, in the link below is some great info on the connection between the insulin receptor and ROS. This makes sense to me. eNOS and the production of NO via the PI3k/Akt pathway is good. NO only becomes destructive when ROS (like superoxide) are present to convert it to peroxynitrite. The NO essentially deactivates ROS but also creates some more potent bad guys in the process. This is the simple explanation of the Jekel/Hyde nature of NO. Here's the quote:
"When generated in excess, ROS impairs insulin signaling by impairing insulin-stimulated activation of Akt and eNOS [70, 71] and limiting NO bioavailability [72]. Typically, the production of NO occurs in a sequence of tightly coupled reactions involving eNOS, tetrahydrobiopterin (BH4), and several other co-factors [73]. ROS limits BH4 availability, resulting in eNOS uncoupling and superoxide production [73].
Additionally, ROS may interact directly with NO to form the powerful
oxidant peroxynitrite (ONOO-), which may contribute to further
uncoupling of eNOS. In other words, excess oxidative stress diverts NO
to inactivate free radicals, thereby limiting the amount of NO available
for vasoregulatory processes"
So what is producing the ROS in the first place? And, how are they causing insulin resistance?
"Lipotoxicity (dyslipidemia) contributes to endothelial
insulin resistance by impairing the PI3K/Akt/eNOS branch of the insulin
signaling pathway while augmenting the MAPK/ET-1 branch [6].
Elevated free fatty acids (FFAs) and lipid metabolites
(diacylglycerols, ceramides, acyl coenzyme As) activate protein kinase C
(PKC), IkB kinase β (IKKB), and nuclear factor-ĸB (NF-ĸB), which serine
phosphorylate IRS-1 [23, 74, 75].
Unlike tyrosine phosphorylation, which activates IRS-1, serine
phosphorylation deactivates IRS-1 and effectively blunts
insulin-stimulated production of NO. Glucotoxicity activates the hexosamine biosynthetic pathway, promoting the production of O-linked β-N-acetylglucosamine (O-GlcNAc). Insulin signaling is impaired when O-linked glycosylation obstructs key phosphorylation sites on IRS-1 and eNOS [70, 76].
AGEs generated as a result of hyperglycemia activate PKC, which
inhibits activation of PI-3K/Akt via serine phosphorylation of IRS-1/2 [77], as well as NF-ĸB, which increases the expression of ET-1 [78]. AGEs also accelerate the degradation of eNOS mRNA [79]." Really want to get your input on this perspective Lane. Here's the link:
http://www.intechopen.com/books/type-2-diabetes/insulin-resistance-and-endothelial-dysfunction-macro-and-microangiopathy
Insulin Resistance and Endothelial Dysfunction: Macro and Microangiopathy
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The first quote on the Jekyll and Hyde nature of nitric oxide is golden. I never have seen it explained so well.
In regards to the article, I knew that tyrosine nitration inhibited the tyrosine phosphorylation of the insulin receptor substrate but was not aware that serine phosphorylation inhibited the tyrosine phosphorylation of the insulin receptor substrate as well. Both result from the overactivation of protein kinase C via g protein-coupled receptors and/or receptor tyrosine kinases.
Advanced glycation end products act through a g protein-coupled receptor (receptor for advanced glycation end products). Glucose itself increases myo-inositol levels in the brain leading to higher levels of phosphatidylinositol 4,5 biphosphate which can end up producing more protein kinase C via phospholipase C.
http://www.biocarta.com/pathfiles/h_plcpathway.asp
Glucose may also activate platelet derived growth factor receptors which are a receptor tyrosine kinase. So there are multiple connections between high levels of glucose and the increased risk for Alzheimer's disease.
The article also provides an explanation of how free fatty acids might contribute to Alzheimer's disease (via increases in protein kinase C).
Glucose is not the only factor creating oxidative stress that can lead to Alzheimer's disease but it is a very important one.
Thank you very much for the article.
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There are two pathways stimulated by the activation of g protein-coupled receptors and receptor tyrosine kinases in the brain. The one is neuroprotective: the phosphatidylinositol 3-kinase/Akt pathway. This pathway leads to increased blood flow (higher levels of nitric oxide), maintenance of the critical antioxidant glutathione, and the regeneration of neurons in the hippocampus. The other pathway is neurodestructive: protein kinase C, p38 MAPK, and peroxynitrites. This pathway depletes nitric oxide, depletes glutathione, prevents the regeneration of neurons, and kills neurons. So something like insulin that works through a receptor tyrosine kinase may be good at low to moderate levels but destructive at higher levels.
http://www.ncbi.nlm.nih.gov/pubmed/15477536
This goes for a lot of other things as well: cell phones, smoking, exercise, industrial solvents, etc. Almost all the studies showing that these lower the risk of Alzheimer's disease were at low levels (moderate levels for exercise). High levels of any of these likely increase the risk of Alzheimer's disease, substantially in some cases.
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A few more:
The damage of human brain vascular endothelial cells (HBVECs) is the key pathogenesis of diabetes-associated cerebral vascular complications. The aim of this study was to elucidate the effects of glutathione (GSH) on free fatty acids (FFAs)-induced HBVECs apoptosis, oxidative stress, and the involved possible signaling pathway...
GSH may prevent FFAs-induced HBVECs damage, oxidative stress, and apoptosis through activating the Akt pathway.
Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.AbstractThe mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.
The key to preventing and treating Alzheimer's disease in its earliest stages is to limit the production of peroxynitrites via g protein-coupled receptors and/or receptor tyrosine kinases. The key to treating it later is to scavenge peroxynitrites and to prevent the overactivation of NMDA receptors.
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Tyrosine nitration is one of the keys to Alzheimer's disease. Unfortunately, tyrosine nitration inhibits the neuroprotective phosphatidylinositol 3-kinase while it overactivates the src kinase leading to neurodegeneration.
Hyperoxia-induced peroxynitrite caused endothelial cell apoptosis as indicated by expression of cleaved caspase-3 and PARP leading to vaso-obliteration. These effects were associated with significant tyrosine nitration of the p85 subunit of PI 3-kinase, decreased Akt activation, and enhanced p38 MAPK activation.
http://www.ncbi.nlm.nih.gov/pubmed/10845713
Src family kinases (SFKs) play critical roles in the regulation of many
cellular functions by growth factors, G-protein-coupled receptors and
ligand-gated ion channels. Recent data have shown that SFKs serve as a
convergent point of multiple signaling pathways regulating N-methyl-Daspartate
(NMDA) receptors in the central nervous system.
http://www.eurosiva.org/archive/vienna/abstracts/speakers/sureda.htm
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Thank you for looking at that Lane, and for the additional info. It will take me some time to study all this further, but I feel that our two perspectives on this disease have really converged with this information.
I like that these ideas about root causes of neurodegeneration lend themselves to prevention and holistic treatments. It's empowering. I feel that we must separate the lifestyle causes from the unavoidable causes (like genetics or infection) of disease. I used to think that pharmaceuticals were the solution for all, but now I see the incredible folly in trying to correct lifestyle causes of disease with drugs. It hurts me to see how people abuse themselves and their children daily with the western diet and lifestyle. And, they don't know it, and they don't believe you if you tell them, or they don't want to believe you. Hey, I was the same way before I started researching this stuff.
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Please be aware that the initial Anavex 2-73 data came from 12 patients, that this data was not published in peer-reviewed medical literature, and that the phase IIa study is still recruiting.
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A wise summation and perspective, Serenoa. I have been leaning in the same direction for awhile but researching Alzheimer's disease has pushed me to the same conclusion more rapidly.
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All factually correct, Marta. I will just add the results of the very preliminary study.
ANAVEX 2-73 showed in 83 percent (10/12) of patients positive cognitive effects during PART A of the study, which consists of a 36-day on-off-on not-yet-optimized dosing regimen to assess bioavailability. At day 36, the amplitude of the cognitive EEG/ERP biomarker P300 increased 38 percent from baseline. Published data suggests that a 38 percent increase is approximately 4 times higher than donepezil (Aricept®), the current standard of care, in the same timeframe. Preliminary measured Mini Mental State Examination (MMSE) and Cogstate scale changes are consistent with the observed trend of the cognitive EEG/ERP effect. The safety profile of ANAVEX 2-73 during Phase 2a appears consistent with the Phase 1 data; additional clinical data of the trial will be presented at future medical meetings. http://www.anavex.com/?post_type=news&p=1491
When mechanisms match results albeit very preliminary results the chances for success in larger scale trials hold considerable promise. Nothing, however, is ever guaranteed until results from those larger trials come in.
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The exact mechanism by which ANAVEX--a tetrahydrofuran derivative and a sigma-1 receptor agonists--might help treat Alzheimer's disease has been a puzzle. Many of its actions would seem to increase the risk for Alzheimer's disease and not help in the treatment of the disease. But here is probably the key.
Sigma-1 and N-Methyl- D -Aspartate
Receptors: A Partnership with Beneficial
Outcomes
Abstract
Sigma-1 receptors (σ-1R) are interorganelle signaling molecules,
which have been implicated in synaptic plasticity, primarily
by enhancing the function of N-methyl- D -aspartate
receptors (NMDARs). On the other hand, excessive influx of
calcium via activated NMDAR can cause excitotoxicity. Yet,
despite their NMDAR-enhancing role, multiple lines of evidence
suggest that σ-1Rs are involved in neuroprotection.
The mechanism underlying these intriguing opposing effects
is not known. Recent studies now suggest the possibility
that σ-1Rs could exert neuroprotective effects via targeted
disruption of protein-protein interactions between
NMDARs and their associated intracellular signaling machinery,
specifically the neuronal nitric oxide synthase (nNOS).
This targeted disruption of protein-protein interactions between
NMDARs and nNOS results in lower levels of nitric oxide
generation, thus having a neuroprotective effect. Here,
we briefly summarize aspects of σ-1R-mediated enhancement
of NMDAR function and possible neuroprotection. Indepth
mechanistic understanding of σ-1R modulation of NMDAR function, which preserves Ca 2+ homoeostasis while
limiting excitotoxicity would provide valuable information
for designing novel as well as improving prevailing therapeutic
strategies.
https://www.karger.com/Article/Pdf/376549
Normally the activation of the NMDA receptor would be detrimental for someone with Alzheimer's disease, but ANAVEX may inhibit not only neuronal nitric oxide but also the formation of peroxynitrites and this would be beneficial. At the very least, ANAVEX should slow down the progression of Alzheimer's disease and at best it may partially reverse the disease. Combine it with a peroxynitrite scavenger and that partial reversal could be rather significant.
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This explains the potential benefit of ANAVEX in regards to reducing the production of neuronal nitric oxide:
As summarised above, glutamate and glutamate receptors are engaged in cognition and behaviour control. However, an excessive amount of glutamate and over-activation of glutamate receptors leads to neuronal cell injury. Thus, the same processes which are essential and critical for normal neuronal functioning, in excess lead to excitotoxic cell death. This phenomenon is termed glutamate-related excitotoxicity and was first used by John Olney in 1970 [ 16, 21].
The mechanisms of excitotoxicity arise from many factors. In pathological conditions, an excessive Ca2+ influx into the neuron promotes various processes resulting in dendritic and/or synaptic damage and cell necrosis or apoptosis. This is the consequence of Ca2+ mitochondrial overload, causing oxygen free radical formation, caspase activation, and intracellular protein degradation. This calcium overload also causes Ca-dependent activation of neuronal NOS which in turn causes overproduction of toxic peroxynitrite ion (ONOO-). An important element of excitotoxicity is the stimulation of mitogen-activated protein kinase p38 (MAPK p3  which activates transcription factors affecting neuronal apoptosis [ 13, 17].
http://www.phmd.pl/fulltxthtml.php?ICID=946637
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Lane do you know if the new drug is working? Do we have any feedback from care givers or family? Thanks for the updates.
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Welcome here, dsmithey. From the very small, initial trial it is difficult to determine how well ANAVEX is working. 10 and of 12 patients improved on a measure that seems to closely correspond to cognition. And the reports from caregivers were positive. Most wanted their loved one to continue with the drug.
So far the drug seems to work better than Aricept and likely works better than Namenda. A larger study is now in the works.
http://www.anavex.com/wp-content/uploads/2015-07-22_Poster_AVXL_Phase_2a_AAIC_July_2015.pdf
I don't think ANAVEX will reverse the damage already done to the brain by Alzheimer's disease, but it may significantly slow down the progression of the disease.
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ANAVEX is a tetrahydrofuran derivative. Here is some curious suggestions that tetrahydrofuran increases the antioxidant capacity of certain phenols such as ferulic acid found in panax ginseng and coconut oil.
The effect of solvent extraction on antioxidant properties of apricot fruitIn tetrahydrofuran direct extractions, the total antioxidant capacity and total phenols were higher than values obtained with aqueous ethanol...
http://link.springer.com/article/10.2478%2Fs11535-010-0113-2
http://www.academia.edu/5199236/SYNTHESIS_OF_FERULIC_ACID_DERIVATEIVES
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I am trying to parse through the data that ANAVEX presented today at the Clinical Trials for Alzheimer Disease conference in Barcelona. The results look relatively good: a 1.5 improvement in MMSE [mini-mental state exam] scores after five weeks, improvement in 5 out of 6 measures of cognitive state tasks (two of which were significant improvements), and a 3.21 improvement in a test designed to measure activities of daily living (11 out of 14 patients improved in this regard--although the number of participants was too small for the results to be significant).
These results are not too different from those reported in the clinical trial on Korean red ginseng.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/
When using certain antioxidants to treat Alzheimer's disease, there is a window in which there appears to be a partial reversal of the disease and then it levels off so that there is no further decline. This is far from optimal but at least better than the current situation.
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Joined: 12/12/2011
Posts: 5179
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I am slightly uneasy about posting this because the doctor quoted in the story over-promised on another Alzheimer's drug (Pbt2). On the other hand, this is one of the few drugs specifically designed to reduce oxidation in Alzheimer's disease, and I think that this is the key to treating the disease (whether it be with CBD oil, aromatherapy, or panax ginseng).
PATIENTS have woken up from some of the most devastating impacts of Alzheimer’s disease, regaining the ability to play sport, paint and enjoy time with family, after a world-first drug trial in Melbourne.
The remarkable results have fuelled hopes among doctors of the first major improvement in treating the horror disease since the 1990s.
Pianist Pauline Stevens has regained the ability to play the piano after being placed on the experimental Anavex 2-73 drug trial at Caulfield Hospital.
Award-winning artist Valerie Lynch has also rediscovered the ability to paint after beginning the medication, stunning her doctors, family and friends.
When Melbourne was selected as the first city in the world to test Anavex a year ago, lead researcher Associate Professor Steve Macfarlane had no idea how much of an impact it would make.
“They seem to be significantly improved in terms of what they can do. It is function that has improved and in many cases mood as well,” Prof Macfarlane said.
“To me, seeing real improvements to patients is much more important than seeing a statistically significant improvement on a rating scale.
Also this video:
http://video.news.com.au/v/455096/Steve-Macfarlane-explains-the-Alzheimers-worldfirst-drug-trial-at-Caulfield-Hospital
My guess from how Macfarlane and others are beginning to tip their hats: this drug will stabilize some forms of cognition after a fairly mild initial improvement and lead to some improvements in some activities of daily living, both of which can be sustained. Combine it with other antioxidants and one can do even better.
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Joined: 12/12/2011
Posts: 5179
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The results announced at 31 weeks for the Anavex trial were mildly encouraging. Seven patients taking Anavex 2-73 alone saw on average a two point improvement in MMSE (mini-mental state examination) and no decline in activities of daily living. Twenty-five patients taking Anavex 2-73 plus donepezil (Aricept) saw a slight decline in MMSE scores and activities of daily living consistent with what would see from taking Aricept alone.
This comes from the company's press release:
Overall, efficacy results demonstrate what appears to be a converging and consistent response for all quantitative endpoints through 31 weeks, including cognitive and functional measures: Mini Mental State Examination (MMSE), Alzheimer’s Disease Co-operative Study – Activities of Daily Living (ADCS-ADL), Cogstate and electroencephalographic activity and event-related potentials (EEG/ERP).
In a disease state where progression is invariable over time, a sustained or stable MMSE and ADCS-ADL score is considered a positive outcome.
“The demonstration of an extended period of both cognitive and functional stability out to 31 weeks in a patient population that would normally be expected to experience ongoing cognitive decline is an encouraging milestone in the development of ANAVEX 2-73. The 31-week data also validates the earlier observation of improvements on tasks within the Cogstate battery. The specificity and consistency of these benefits suggest that ANAVEX 2-73 can sustain activation of attentional and working memory functions with repeated dosing in Alzheimer’s disease,” said Associate Professor Stephen Macfarlane, FRANZCP, Head of Clinical Governance, Dementia Centre HammondCare, who is conducting the study. “Of noticeable interest was also HAM-D data showing beneficial effects of ANAVEX 2-73 on insomnia, agitation and anxiety at 31 weeks, which might suggest an additional important role of ANAVEX 2-73 for the amelioration of behavioral and psychological symptoms of dementia (BPSD).”
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Joined: 12/12/2011
Posts: 5179
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The 41 week results for Anavex 2-73 were recently announced: no serious adverse effects and there was a stabilization in both cognition and functions of daily living:
NEW YORK, NY – November 22, 2016 – Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL) today announced a positive 41-week update from its Phase 2a study in mild-to-moderate Alzheimer’s disease (AD) patients for ANAVEX 2-73, which targets cellular homeostasis.
At 41 weeks, Alzheimer’s patients taking a daily oral dose of ANAVEX 2-73 in the exploratory, not yet dose optimized Phase 2a clinical trial, showed a stabilization of cognitive and functional measures. This data of stabilization is promising since Alzheimer’s disease is a progressive disease where current therapeutics are only able to temporarily slow the worsening of dementia symptoms and not stop the disease from progressing.
At 41 weeks, oral daily dosing between 10mg and 50mg, ANAVEX 2-73 was well tolerated, and no patients discontinued treatment due to adverse events. There were no clinically significant treatment-related adverse events, and no serious adverse events.
Pre-specified exploratory analyses included the cognitive (MMSE) and the functional (ADCS-ADL) changes from baseline. A continued stabilization of both cognitive (MMSE) and functional (ADCS-ADL) measures in patients treated with ANAVEX 2-73 was observed. This correlation was positive with all measured scores (MMSE, ADCS-ADL, Cogstate, HAM-D and EEG/ERP).
George Perry, PhD, Dean and Professor at the University of Texas at San Antonio and Editor-in Chief of the Journal of Alzheimer’s Disease, commented, “Although this is an open label study with 32 patients, I have never seen mild-to-moderate Alzheimer’s patients maintain near baseline cognitive and activities of daily living function and positive correlation with all other measures over a 41-week trial period in any prior study with an approved or experimental drug. It is quite plausible that complex CNS diseases like Alzheimer’s may require a comprehensive approach, including restoration of cellular homeostasis.”
Anavex 2-73 limits excitotoxicity via NMDA receptors thus limiting the death of neurons. I am still not sure how good a peroxynitrite scavenger it is. Aromatherapy with various essential oils, panax ginseng, and cbd oil also limit excitotoxicity and are excellent peroxynitrite scavengers. We are on the brink of effectively treating Alzheimer's disease.
Happy Thanksgiving!
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Joined: 9/30/2015
Posts: 1155
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Lane, wow! You are amazing reading and understanding all this information.. I read but little gets in.. What does is good news.. I like that they are working on this so much and that one day they will find the answers I am sure of. Thanks for keeping us all informed.
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Joined: 12/12/2011
Posts: 5179
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Thanks so much, Julie. I like to say all diseases are simple once you figure them out; it is the figuring them out part that is difficult. But it seems to me that we are getting closer to figure out Alzheimer's disease. And if so, effective treatments cannot be far behind.
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Joined: 12/12/2011
Posts: 5179
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Considering the other drug alternatives, these results for ANAVEX 2-73 were relatively good:
Abstract
OC60: 9-MONTHS AND 12-MONTHS SAFETY AND EXPLORATORY EFFICACY DATA OF ANAVEX 2-73 IN A PHASE 2A STUDY IN MILD-TO-MODERATE ALZHEIMER’S DISEASE PATIENTS. Stephen Macfarlane1, Marco Cecchi2, Paul Maruff3, Kristina M Kapiak4, Christopher U Missling4 ((1) Caulfield Hospital, Melbourne, Australia; (2) Neuronetrix, Louisville, KY, USA; (3) Cogstate Ltd., Melbourne, Australia; (4)
Results: Safety: ANAVEX 2-73 demonstrated a favorable safety profile when administered to a clinical population of elderly AD patients with varying degrees of physical fragility. The most common side effects across all AE categories tended to be of mild severity grade 1, and were resolved with dose reductions that were anticipated within the adaptive design of the study protocol. Positive unexpected therapeutic response events, such as improved mood, improved social engagement and increased independent activities were recorded. Exploratory Efficacy: 9-months and 12-months data of all available patients demonstrate that ANAVEX 2-73 preserves average MMSE and ADCS-ADL (PART B) scores across the entire patient group. ANAVEX 2-73 continues to show benefits over baseline for both Cogstate and QEEG/ERP.Conclusions: The safety of ANAVEX 2-73 was assessed and MTD was determined. Despite not optimal dosing in the longitudinal PART B of the study, both cognitive and functional performance is sustained over at least 9 months, suggesting that the effect of the compound does not seem to worsen AD symptoms with repeated dosing. In a disease state where progression is invariable over time, a stable MMSE and ADCS-ADL score is considered a positive outcome.
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Joined: 11/3/2016
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I am devastated with watching my young mother decline, she is in the mid stages and has had Alzheimer's for the last 4 years. I am grateful for your knowledge and insight. I pray everyday that SOMETHING becomes available soon. What is the best medication RIGHT now, to help improve her daily life?
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Joined: 12/12/2011
Posts: 5179
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Welcome, Sonya and thank you. I keep looking for answers to Alzheimer's disease every day: too late for my relatives who had the disease but maybe not too late for those who currently have Alzheimer's or for the rest of us.
Unfortunately, the current drugs approved for Alzheimer's disease either only temporarily slow down the progression of the disease (acetylcholinesterase inhibitors such as Aricept, for instance) or help some people with activities of daily living for awhile (the NMDA receptor agonist Namenda).
At this point, the best treatments for the disease may not involve drugs. This includes direct inhalation aromatherapy with essential oils high in eugenol (such as clove, bay laurel, rosemary, and lemon balm) for a few seconds once or twice a day (that is how we treated our mother), Korean red ginseng, and CBD oil from marijuana (more cannabidiol than THC for most people). The latter has shown promise in mice studies and in some people (see alz+ posts on the individuals with Alzheimer's disease forums). Here are the clinical trial results for the other "alternative" treatments (heat processed ginseng is Korean red ginseng steamed at higher temperatures).
http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/
https://www.ncbi.nlm.nih.gov/pubmed/22780999
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Joined: 10/18/2015
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Anavex Update: facebook.com/theprojecttv/videos/10154154448498441
This is an interview with an A2-73 super responder after at least 1 year taking A2-73.
The numbers from CTAD are simply Miraculous. www.anavex.com
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Joined: 12/20/2016
Posts: 100
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The current only possible available help is from Dr. Dale Bredesen. Visit his web site, and use their email to find out if there is any practitioner in your area who can assist your situation.
web-site: mpi-cognition.com
phone: 1-800-450-0805.
He also has four online papers (two of them could be helpful.)
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Joined: 12/12/2011
Posts: 5179
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This from someone with an interest in Anavex 2-73 but the analysis is still spot on:
1) What is the problem we are trying to solve?
Common mechanisms of neurodegeneration
- Excitotoxicity and calcium overload
- Oxidative and nitrosative stress
- Endoplasmic reticulum (ER) stress
- Mitochondrial dysfunction - Reactive gliosis
2) Is A2-73 promising amongst SR1 active molecules to solve these problems?
Neuroprotective actions by sigma ligands
- Modulation of calcium homeostasis and glutamate activity
- Attenuation of reactive species production
- Modulation of ER and mitochondrial function
- Modulation of glial activity
A2-73 acts as an agonist at M1 and S1 [sigma-1] receptors, acts as an antagonist to M2, M3, NMDA receptors, and at high enough doses as an antagonist to sodium and calcium channels [the last two are likely the most important]...In general, the compound seems to lower oxidative stress, reduce mitochondrial dysfunction, prolong [the onset of] apoptosis [programmed cell death] and thus cell life, and reboot the cellular machinery to clear mis-folded proteins via the usual cell process.
Recent studies now suggest the possibility that s-1Rs could exert neuroprotective effects via targeted disruption of protein-protein interactions between NMDARs and their associated intracellular signaling machinery, specifically the neuronal nitric oxide synthase (nNOS). This targeted disruption of protein-protein interactions between NMDARs and nNOS results in lower levels of nitric oxide generation, thus having a neuroprotective effect.
And to go back to the necessary strategy for treating Alzheimer's disease
In conclusion, through this review, we have tried to give our perspective on the wide variety of interaction between NMDAR-mediated oxidative stresses with the etiology of Alzheimer’s disease. NMDAR-mediated oxidative stress mechanisms are likely to play an important role in the synapse dysfunction in the pathogenesis of AD. Moreover, mitochondrial-mediated oxidative stress and apoptosis are also suggested to be contributing factors in AD pathogenesis. Furthermore, oxidative stress-mediated kinase and tau phosphorylation provides a connection of synapse dysfunction in AD. As we are not getting complete remedies from antioxidant therapy or known NMDAR antagonist drug used for AD pathology, should we go for combinational therapy? Or are there so many intermediate molecules between NMDAR to neurodegeneration? Should we go for target intermediate molecules? Therefore, understanding the role of oxidative stress-associated molecule and kinases in synapse dysfunction during AD pathogenesis may also lead to the development of mechanism-based therapeutics and better constructive strategies.
Time will tell if this is enough, but of the current drugs in clinical trials Anavex 2-73 likely has the greatest chance of success. Pairing it with a peroxynitrite scavenger such as CBD oil or panax ginseng would like enhance the effect of the drug.
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