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What about exogenous S-Nitrosoglutathione (GSNO - which reduces the levels of peroxynitrite)?
Tom(ek)
Posted: Monday, June 27, 2016 4:16 AM
Joined: 12/21/2011
Posts: 62


I'm not sure if it was discussed here.

Example with strokes:


Blocking a vicious cycle nNOS/peroxynitrite/AMPK by S-nitrosoglutathione: implication for stroke therapy

 
"Redox-modulating agent of the NO metabolome, S-nitrosoglutathione (GSNO), confers neurovascular protection by reducing the levels of peroxynitrite, a product of aberrant NOS activity."

"GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser1412. The Ser1412 phosphorylation is associated with increased nNOS activity. Supporting the notion that nNOS activity and peroxynitrite are deleterious following IR, inhibition of nNOS by its inhibitor 7-nitroindazole or reducing peroxynitrite by its scavenger FeTPPS decreased IR injury. GSNO also decreased the activation of AMP Kinase (AMPK) and its upstream kinase LKB1, both of which were activated in IR brain."

"Taken together, these results indicate an injurious nNOS/peroxynitrite/AMPK cycle following stroke, and GSNO treatment of IR inhibits this vicious cycle, resulting in neuroprotection and improved neurological function. GSNO is a natural component of the human body, and its exogenous administration to humans is not associated with any known side effects."

Read the full article:

http://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-015-0179-x  
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502912/

 


Tom(ek)
Posted: Monday, June 27, 2016 9:14 AM
Joined: 12/21/2011
Posts: 62


Additionally:

S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion

"We have previously reported that treatment of rats subjected to permanent bilateral common carotid artery occlusion (pBCCAO), a model of chronic cerebral hypoperfusion (CCH), with S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, improved cognitive functions and decreased amyloid-beta accumulation in the brains. Since CCH has been implicated in tau hyperphosphorylation induced neurodegeneration, we investigated the role of GSNO in regulation of tau hyperphosphorylation in rat pBCCAO model. The rats subjected to pBCCAO had a significant increase in tau hyperphosphorylation with increased neuronal loss in hippocampal/cortical areas. GSNO treatment attenuated not only the tau hyperphosphorylation, but also the neurodegeneration in pBCCAO rat brains. The pBCCAO rat brains also showed increased activities of GSK-3beta and Cdk5 (major tau kinases) and GSNO treatment significantly attenuated their activities. GSNO attenuated the increased calpain activities and calpain-mediated cleavage of p35 leading to production of p25 and aberrant Cdk5 activation. In in vitro studies using purified calpain protein, GSNO treatment inhibited calpain activities while 3-morpholinosydnonimine (a donor of peroxynitrite) treatment increased its activities, suggesting the opposing role of GSNO vs. peroxynitrite in regulation of calpain activities. In pBCCAO rat brains, GSNO treatment attenuated the expression of inducible nitric oxide synthase (iNOS) expression and also reduced the brain levels of nitro-tyrosine formation, thereby indicating the protective role of GSNO in iNOS/nitrosative-stress mediated calpain/tau pathologies under CCH conditions. Taken together with our previous report, these data support the therapeutic potential of GSNO, a biological NO carrier, as a neuro- and cognitive-protective agent under conditions of CCH.""We have previously reported that treatment of rats subjected to permanent bilateral common carotid artery occlusion (pBCCAO), a model of chronic cerebral hypoperfusion (CCH), with S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, improved cognitive functions and decreased amyloid-beta accumulation in the brains. Since CCH has been implicated in tau hyperphosphorylation induced neurodegeneration, we investigated the role of GSNO in regulation of tau hyperphosphorylation in rat pBCCAO model. The rats subjected to pBCCAO had a significant increase in tau hyperphosphorylation with increased neuronal loss in hippocampal/cortical areas. GSNO treatment attenuated not only the tau hyperphosphorylation, but also the neurodegeneration in pBCCAO rat brains. The pBCCAO rat brains also showed increased activities of GSK-3beta and Cdk5 (major tau kinases) and GSNO treatment significantly attenuated their activities. GSNO attenuated the increased calpain activities and calpain-mediated cleavage of p35 leading to production of p25 and aberrant Cdk5 activation. In in vitro studies using purified calpain protein, GSNO treatment inhibited calpain activities while 3-morpholinosydnonimine (a donor of peroxynitrite) treatment increased its activities, suggesting the opposing role of GSNO vs. peroxynitrite in regulation of calpain activities. In pBCCAO rat brains, GSNO treatment attenuated the expression of inducible nitric oxide synthase (iNOS) expression and also reduced the brain levels of nitro-tyrosine formation, thereby indicating the protective role of GSNO in iNOS/nitrosative-stress mediated calpain/tau pathologies under CCH conditions. Taken together with our previous report, these data support the therapeutic potential of GSNO, a biological NO carrier, as a neuro- and cognitive-protective agent under conditions of CCH."

 https://www.infona.pl/resource/bwmeta1.element.elsevier-4d788de0-f959-3633-976d-d82fdd5d3aac

Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact

 "GSNO is a promising candidate to be evaluated in humans after brain trauma because it not only protects the traumatic penumbra from secondary injury and improves overall tissue structure but also maintains the integrity of BBB and reduces neurologic deficits following CCI in a rat model of experimental TBI."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777134/

Topical HPMC/S-Nitrosoglutathione Solution Decreases Inflammation and Bone Resorption in Experimental Periodontal Disease in Rats

 "The present study suggests that the protective effect of GSNO on the alveolar bone resorption is at least in part due to its anti-inflammatory, anti-oxidant and immunomodulatory properties. We demonstrated that the HPMC/GSNO 10 mM solution significantly reduced the TNF-alpha mRNA in gingival tissue of animals treated with this formulation as well as the gingival levels of TNF-alpha and IL-1beta, when compared with the control HPMC solution group."

 

"Topical application of HMPC/GSNO 10 mM solution attenuated the gingival oxidative stress, reestablishing the levels of GSH and decreasing nitrotyrosine expression and MDA concentration. Together, these results suggest that the protective effect of the HPMC/GSNO solution is at least partially related to its inhibitory effect on oxidative stress. Moreover, other studies have indicated that GSNO decreases the formation of nitrotyrosine and lipid peroxidation in blood, increasing the reduced GSH/oxidized GSH (GSH/GS-SG) ratio in the brain [39–41]."

http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0153716

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846037/

 

 It's time to test it for Alzheimer's Disease.


Lane Simonian
Posted: Monday, June 27, 2016 10:24 AM
Joined: 12/12/2011
Posts: 4998


This may well be a valuable treatment for Alzheimer's disease in that it reduces peroxynitrite levels and increases the beneficial form of nitric oxide in the brain.  I think S-nitrosoglutathione should be tested for Alzheimer's disease, too.  Thank you, Tom(ek).


Tom(ek)
Posted: Tuesday, June 28, 2016 5:29 PM
Joined: 12/21/2011
Posts: 62


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

 "In summary, our data for the first time documents that systemic GSNO administration reduces vascular inflammatory response (expression of ICAM-1 and VCAM-1) and the Abeta burden and protects against cognition decline in an animal model of chronic cerebral hypoperfusion, a model for mild cognitive impairment associated with development of late-onset AD. Studies using cell culture models, primary neurons, microglia (BV2) and endothelial cell (bEND3) lines also document that GSNO mediated mechanisms inhibit beta-secretase activity and thus Abeta generation in neurons and Abeta endocytosis in microglia and endothelial cells as an index of Abeta clearance from brain. Taken together, these findings document that GSNO mediated mechanisms may prove to have therapeutic potential in chronic cerebral hypoperfusion associated with mild cognitive impairment and development of late-onset AD."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040220/

Protective Roles of S-nitrosoglutathione (gsno) in Rat Chronic Cerebral Hypoperfusion-Induced Mild Cognitive Impairment

 "We here report that long-term administration of GSNO (50microg/kg/day for 4 months) improved learning and memory functions of BCCAO treated rats with reducing brain Abeta levels. GSNO inhibited proinflammatory signaling in bEnd3 brain endothelial cells and thus reduced gene expression related to endothelial inflammation (i.e. ICAM-1, VCAM, and MMP-9). In addition, GSNO increased uptake of Abeta by cultured bEnd3 cell with increasing S-nitrosylation of dynamin-2 protein, a protein regulating cellular endocytosis activity. Conclusions: Taken together, these data first time document a potential therapeutic activity of GSNO on neurovascular pathologies involved in CCH and AD."

http://www.alzheimersanddementia.com/article/S1552-5260(10)02349-6/fulltext

S-Nitrosoglutathione Administration Ameliorates Cauda Equina Compression Injury in Rats

 "Induction of iNOS and other inflammatory mediators is inhibited by GSNO via down regulation of the NF-kB transcription factor [22,23,26]. The level of peroxynitrite in the brain is also decreased after GSNO treatment in rat models of IR and TBI [34,51]. All these observations strengthen the therapeutic potential of GSNO in treating neurogenic as well as inflammation-mediated pain in LSS.

In conclusion, exogenous administration of GSNO, reduces neuronal degeneration, demyelination and apoptotic cell death and also increases the pain threshold and improves motor function in a rat model of CEC. Hence, GSNO is a potential and ideal candidate to be evaluated in LSS patients."

http://file.scirp.org/pdf/NM20120300004_79246126.pdf


Tom(ek)
Posted: Wednesday, June 29, 2016 4:59 PM
Joined: 12/21/2011
Posts: 62


S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats

 "Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury."

"Results

SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors.

Conclusion

Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI."

 "GSNO reduces peroxynitrite and neuroinflammation, increases NO and GSH, and protects the integrity of the BBB and the neurovascular unit following TBI. Furthermore, it stimulates the mechanisms of the neurorepair in the injured animals. Therefore, GSNO has therapeutic potential to be investigated in human TBI."

 


Lane Simonian
Posted: Wednesday, June 29, 2016 6:28 PM
Joined: 12/12/2011
Posts: 4998


Excellent studies and information.  Further follow up studies for people with Alzheimer's disease appears to be quite warranted.
Tom(ek)
Posted: Thursday, June 30, 2016 2:33 AM
Joined: 12/21/2011
Posts: 62


Lane, it's an excellent international information exchange between continents

You showed me the problem with peroxynitrite.


Tom(ek)
Posted: Thursday, June 30, 2016 3:44 AM
Joined: 12/21/2011
Posts: 62


Modulation of Nitrosative Stress via Glutathione-Dependent Formaldehyde Dehydrogenase and S-Nitrosoglutathione Reductase

"Additionally, the protein showed improved GSNO-induced 293T cell viability/growth and protected the cells against apoptosis under oxidative stress (GSNO treated). The mechanism by which Tc-GFD exhibits a protective function against oxidative stress may be due to its ability to enhance GSNO consumption (Figure 7). Our results may provide an alternative approach to the development of a protection strategy against nitrosative stress. In addition, this study may provide a rationale for the development of treatments for neurodegenerative diseases, such as prion’s, Alzheimer’s, Parkinson’s and Huntington’s diseases. One of the major neuropathological changes of these diseases is defined by the neuronal cell apoptosis"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159844/


Lane Simonian
Posted: Thursday, June 30, 2016 9:50 AM
Joined: 12/12/2011
Posts: 4998


I certainly have appreciated and benefited from this "excellent international information exchange between continents (perfectly said)." I would never have known about the important functions of BH4 without you.

I am trying to figure out whether S-nitrosoglutathione or S-nitrosoglutathione reductase is protective against nitro-oxidative stress.  The answer may vary by disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600557/




Tom(ek)
Posted: Friday, July 1, 2016 3:15 AM
Joined: 12/21/2011
Posts: 62


I've got new puzzle for you Lane.

Where am I from? What is my country?

https://en.wikipedia.org/wiki/Thomas_(name)



Lane Simonian
Posted: Friday, July 1, 2016 9:53 AM
Joined: 12/12/2011
Posts: 4998


You know that I like puzzles except for the ones that I cannot figure out. I think you once told me that you were from Eastern Europe.  I was thinking Slovakia but now that I look at the Wikipedia list of Thomases, Poland fits Tomek.  Best wishes to you Tom(ek).
Tom(ek)
Posted: Saturday, July 2, 2016 3:02 PM
Joined: 12/21/2011
Posts: 62


Central Europe:

 
Gdansk, Poland:

Lane Simonian
Posted: Sunday, July 3, 2016 10:28 AM
Joined: 12/12/2011
Posts: 4998


Thank you for the map and video, Tom(ek).  I did not realize that Russia still held territory between Lithuania and Poland.  

I really enjoyed seeing the videos of Gdansk and the surrounding countryside--beautiful.


Tom(ek)
Posted: Thursday, July 14, 2016 4:42 AM
Joined: 12/21/2011
Posts: 62


Something about tyrosine kinase Fyn and GSNO.

Amyloid-Beta/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease

"Our results indicate that ABeta, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship

between these factors could be of therapeutic benefit."

 http://www.jneurosci.org/content/31/2/700.full

  Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.

"RESULTS:

AZD0530 potently inhibits Fyn and prevents both ABeta-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B

Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic

depletion, without altering APP or ABeta metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation

and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity.
INTERPRETATION:

Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a

promising candidate to test as a potential therapy for AD."

http://www.ncbi.nlm.nih.gov/pubmed/25707991


Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons

Received: 1 May 2016 / Accepted: 4 July 2016 / Published: 12 July 2016

"In a rat cerebral I/R model, endogenous NO synthesized by nNOS in brain tissue enhanced the S-

nitrosylation and phosphorylation of Fyn, while GSNO, 7-NI (a nNOS inhibitor) and MK-801 (an NMDAR antagonist) could decrease the elevated levels of these

post-translational modifications induced by cerebral I/R. Morphological analyses using cresyl violet staining showed that these compounds had

neuroprotective effects against cerebral I/R-induced injury."

 
"In the present study, we observed that, during cerebral I/R, the nNOS inhibitor (7-NI), the NMDAR antagonist (MK-801), and the NO donor (GSNO) may

suppress not only the S-nitrosylation but also the phosphorylation of Fyn. The relationship between the S-nitrosylation and phosphorylation of Fyn has

remained unclear. The drugs (GSNO, 7-NI, and MK-801) that can decrease endogenously produced NO markedly inhibited the phosphorylation of Fyn. One

possible mechanism is that Fyn S-nitrosylation might affect the phosphorylation of Fyn, but this requires further precise elucidation. Because

phosphorylation of Fyn regulates its activation, inhibiting Fyn S-nitrosylation may suppress subsequent activation. In the present study, morphological

analyses validated that the drugs (7-NI, MK-801 and GSNO) that could inhibit Fyn S-nitrosylation also conferred neuronal protection after ischemia in vivo"

http://www.mdpi.com/1422-0067/17/7/1100/htm


 

 


Lane Simonian
Posted: Friday, July 15, 2016 12:02 PM
Joined: 12/12/2011
Posts: 4998


This is good information, Tom(ek).  Fyn is a member of the Src family of kinases.  Its activation increases peroxynitrite (ONOO-) formation and peroxynitrite formation in turn increases Fyn activation.

http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

Activation of src tyrosine kinases by peroxynitrite.

 

A NMDA receptor antagonist, a nNos inhibitor, and a peroxynitrite scavenger should be a good combination for treating Alzheimer's disease (not sure about a NO donor, though).


Tom(ek)
Posted: Thursday, July 21, 2016 3:59 AM
Joined: 12/21/2011
Posts: 62


 1998

Neuroprotection by S-nitrosoglutathione of brain dopamine neurons from oxidative stress. 

http://www.ncbi.nlm.nih.gov/pubmed/9472981

 

1999

The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. 

 

Recent results demonstrated that S-nitrosoglutathione (GSNO) and nitric oxide (*NO) protect brain dopamine neurons from hydroxyl  radical (*OH)-induced oxidative stress in vivo because they are potent antioxidants. GSNO and *NO terminate oxidant stress in the brain by

 (i) inhibiting iron-stimulated hydroxyl radicals formation or the Fenton reaction,

 (ii) terminating lipid peroxidation,

 (iii) augmenting the antioxidative potency of glutathione (GSH),

 (iv) mediating neuroprotective action of brain-derived neurotrophin (BDNF), and

 (v) inhibiting cysteinyl proteases.

 In fact, GSNO--S-nitrosylated GSH--is approximately 100 times more potent than the classical antioxidant GSH. In addition, S-nitrosylation of cysteine residues by GSNO inactivates caspase-3 and HIV-1 protease, and prevents apoptosis and neurotoxicity. GSNO-induced antiplatelet aggregation is also mediated by S-nitrosylation of clotting factor XIII. Thus the elucidation of chemical reactions involved in this GSNO pathway (GSH GS* + *NO-->[GSNO]-->GSSG + *NO-->GSH) is necessary for understanding the biology of *NO, especially its beneficial antioxidative and neuroprotective effects in the CNS. GSNO is most likely generated in the endothelial and astroglial cells during oxidative stress because these cells contain mM GSH and nitric oxide synthase. Furthermore, the transfer of GSH and *NO to neurons via this GSNO pathway may facilitate cell to neuron communications, including not only the activation of guanylyl cyclase, but also the nitrosylation of iron complexes, iron containing enzymes, and cysteinyl proteases. GSNO annihilates free radicals and promotes neuroprotection via its c-GMP-independent nitrosylation actions. This putative pathway of GSNO/GSH/*NO may provide new molecular insights for the redox cycling of GSH and GSSG in the CNS.

http://www.ncbi.nlm.nih.gov/pubmed/10630687

 

2000

Effects of atypical antioxidative agents, S-nitrosoglutathione and manganese, on brain lipid peroxidation induced by iron leaking from tissue disruption. 

 

S-Nitrosoglutathione, melatonin, 17 beta-estradiol, and manganese have been successfully tested in cell/animal models for their potential neuroprotective effects.

http://www.ncbi.nlm.nih.gov/pubmed/10863543

 

2000

Neuroprotective strategies in Parkinson's disease: protection against progressive nigral damage induced by free radicals. 

http://www.ncbi.nlm.nih.gov/pubmed/16787846

 

2005 Apr 1

Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity. 

Ju TC1, Chen SD, Liu CC, Yang DI.

Author information

Abstract

Amyloid beta-peptide (Abeta) is a major constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. We have previously demonstrated ceramide production secondary to Abeta-induced activation of neutral sphingomyelinase (nSMase) in cerebral endothelial cells and oligodendrocytes, which may contribute to cellular injury during progression of AD. In this study, we first established the "Abeta --> nSMase --> ceramide --> free radical --> cell death" pathway in primary cultures of fetal rat cortical neurons. We also provided experimental evidence showing that S-nitrosoglutathione (GSNO), a potent endogenous antioxidant derived from the interaction between nitric oxide (NO) and glutathione, caused dose-dependent protective effects against Abeta/ceramide neurotoxicity via inhibition of caspase activation and production of reactive oxygen species (ROS). This GSNO-mediated neuroprotection appeared to involve activation of cGMP-dependent protein kinase (PKG), phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK). Activation of the cGMP/PKG pathway induced expression of thioredoxin and Bcl-2 that were beneficial to cortical neurons in antagonizing Abeta/ceramide toxicity. Consistently, exogenous application of thioredoxin exerted remarkable neuroprotective efficacy in our experimental paradigm. Results derived from the present study establish a neuroprotective role of GSNO, an endogenous NO carrier, against Abeta toxicity via multiple signaling pathways. 

http://www.ncbi.nlm.nih.gov/pubmed/15749390

 

2010

5th Congress of Federation of Asian-Oceanian Neuroscience Societies and XXVIII Annual Conference of Indian Academy of Neuroscience 

 

Dr. M Jatana, India discussed about Amelioration by nitrosylation of neuroinflammatory brain injury and concluded that s-nitrosoglutathione (GNSO) protects against traumatic brain injury and dementia by blocking the vicious eNOS / peroxynitrite cycle via nitrosylation in rats.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116939/

 


Serenoa
Posted: Thursday, July 21, 2016 7:06 AM
Joined: 4/24/2012
Posts: 484


Wow, lots of good info, thanks Tom(ek). I was trying to see if this molecule interacts with cholesterol and found that it does inhibit oxidized LDL (if you haven't already posted this one).

 

Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1accumulation via redox-dependent mechanisms
 
"Oxidized low-density lipoprotein (oxLDL) and macrophages play a central role inatherosclerosis. Here, we obtained evidence that oxLDL induced hypoxia-inducible factor-1 (HIF-1) protein accumulation in human macrophages (Mono-Mac-6) un-der normoxia. HIF-1 accumulation was attenuated by pretreatment with the antioxi-dant N-acetyl-L-cysteine (NAC), the nitricoxide (NO) donor S-nitrosoglutathione (GSNO)..."
 
http://www.bloodjournal.org/content/bloodjournal/101/12/4847.full.pdf?sso-checked=true

Lane Simonian
Posted: Thursday, July 21, 2016 10:35 AM
Joined: 12/12/2011
Posts: 4998


This is indeed great research and information, Tom(ek).

I missed an important mechanism in the article in your first post.

IR [cerebral ischemia reprerfusion] increased the activity of nNOS, the levels of neuronal peroxynitrite and phosphorylation at Ser1412 of nNOS. GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser1412.

Recent reports document that S-nitrosylation of nNOS regulates its activity [1117], in addition to phosphorylation/dephosphorylation [18]. In resting neurons, nNOS is inhibited mainly by S-nitrosylation of Cys331; however, immediately following stroke injury, nNOS is activated by NMDA receptor-mediated excitotoxicity and a sustained calcium influx through site-specific phosphorylation (Ser1412) and denitrosylation (Cys331). In such an environment, nNOS-derived NO is converted to peroxynitrite by an instantaneous diffusion-limited reaction with superoxide [19]. Peroxynitrite can activate AMPK via the activation of upstream AMPK kinase LKB1, thus maintaining a vicious cycle of its own production [20].

The overall goal of the present study is to investigate whether GSNO provides neuroprotection by reducing the levels of peroxynitrite via the inhibition of nNOS activity. Our initial studies show that treatment of IR animals with GSNO reduced phosphorylation at Ser1412, possibly via the inhibition of LKB1 and AMPK activities, and thus attenuated nNOS activity and peroxynitrite-mediated brain injury. The GSNO treatment also improved neurological functions.


Tom(ek)
Posted: Friday, July 22, 2016 4:27 AM
Joined: 12/21/2011
Posts: 62


Thank you Serenoa and Lane.
Now I see two issues/challenges:

1) we can read about dose-dependent protective effects - we should have more detailed analysis of dose and its effect,
2) more tests in vivo and clinical trials.

Second issue depends on money. The pharmaceutical industry is a huge business. Business = money = in case of pharmaceutical company it means patented drug.

I'm not sure how it is with GSNO.
I found some list of suppliers and producers: BOC Sciences (USA), Chemos GmbH (Germany), Gihi Chemicals Co., Limited (P.R.China), Santa Cruz Biotechnology, Inc. (USA).

It is possible that companies won't see the business in clinical trials of GSNO and istead of it they will try to test for example some 'fancy' S-Nitrosoglutathione Reductase inhibitor which can be patented or they will try to create some combination of GSNO with some other compound.

I will give you some examples related to neurotransmitters.

http://www.alzheimer-opiekuni.pl/Metabolizm/file.gif

 In case of dopamine its precursor L-DOPA is a known drug used to treat some symptoms of Parkinson's disease. Sometimes it is combined with carbidopa.
In case of serotonine we know selective serotonin reuptake inhibitors (SSRIs) as medicaments but its precursor -  naturally occurring amino acid 5-Hydroxytryptophan (5-HTP) is only a dietary supplement due to a severe lack of high quality research and clical trials.


Lane Simonian
Posted: Saturday, July 23, 2016 10:14 AM
Joined: 12/12/2011
Posts: 4998


This is exactly it.  Even phase one clinical trials are expensive and finding money to test natural compounds is difficult to come by.  Memantine is off patent so its "inventor" Stuart Lipton is testing a new drug--nitromemantine--probably better than the NMDA antagonist memantine, but probably not as good as nnos inhibitor nitroglutathione. When given a thorough testing there are probably a number of natural products or off-patented drugs that may be useful for the treatment of Alzheimer's disease, but getting from point A to point B is a major challenge.