Anesthetics and ALS

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Re: Anesthetics and ALS

Postby sixwings » Mon Aug 05, 2013 10:10 am

The following study explains why sevoflurane may be a much more interesting anesthetic than propofol for our purposes. It shows that, while sevoflurane potentiates both GABA-A and glycine receptors in spinal neurons, propofol mostly acted on GABA-A receptors. This supports the conclusion that sevoflurane is a much more interesting anesthetic for ALS therapy. Hopefully, some of our more daring PALS will experiment with sevoflurane anesthesia and file a report soon.
Propofol and sevoflurane depress spinal neurons in vitro via different molecular targets.
Grasshoff C, Antkowiak B.

Section of Experimental Anesthesiology, Department of Anesthesiology, University of Tuebingen, Germany. christian.grasshoff@uni-tuebingen.de

Abstract
BACKGROUND:

The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol.

METHODS:

The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15).

RESULTS:

Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%).

CONCLUSIONS:

The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

Source: http://www.ncbi.nlm.nih.gov/pubmed/15505453
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Re: Anesthetics and ALS

Postby sixwings » Mon Aug 05, 2013 10:48 am

Although I have seen studies that show evidence for propofol's action on glycine receptors, it seems that most studies conclude that its primary targets are GABA-A receptors. While this would make propofol an effective drug for some variants of ALS, I believe that most ALS patients would experience greater benefits from the volatile anesthetics, especially sevoflurane. Here's one more research study that supports this position.
Different actions of volatile and intravenous anesthetics on interneurons in organotypic spinal cord slices[pdf]

Background: Immobility is an important aspect of anesthesia. It is now well accepted that ablation of spontaneous and stimulus-induced movements by
general anesthetics is spinally mediated. Comparing the effects of sevoflurane and propofol on spontaneous action potential firing, we have recently shown that the capacity of propofol, but not sevoflurane, in depressing spinal neurons is limited. This finding is explained by the observation that the effects of propofol were almost exclusively mediated by GABAA receptors, whereas sevoflurane acted predominantly via glycine and GABAA receptors.

Source: http://openwetware.org/images/1/17/2004_poster_cg.pdf
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Re: Anesthetics and ALS

Postby soccer » Wed Aug 07, 2013 9:18 am

I had 800mg over 2 hours and no improvements I believe. Can it stop progression, not sure? I will have monthly treatments for 6 months and see what happens.
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Re: Anesthetics and ALS

Postby sixwings » Wed Aug 07, 2013 10:21 am

soccer wrote:I had 800mg over 2 hours and no improvements I believe. Can it stop progression, not sure? I will have monthly treatments for 6 months and see what happens.

This is unfortunate, soccer. You should have noticed an effect within a day after the procedure. I do not recommend that you continue with it. It's obvious that propofol does not work for everybody. It seems that some patients are more prone to glycine receptor deficiencies than GABA-A. Propofol is more effective against GABA-A receptor deficiencies and less so against glycine. This is the reason that I recommend a volatile anesthetic such as sevoflurane. Thanks for reporting this.
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Re: Anesthetics and ALS

Postby Cypress » Thu Aug 08, 2013 4:06 am

Sevoflurane will be administered on the 14 th!
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Re: Anesthetics and ALS

Postby sixwings » Thu Aug 08, 2013 7:45 am

That's great news, Cypress.
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Re: Anesthetics and ALS

Postby sixwings » Thu Aug 08, 2013 9:42 am

This study is not about ALS but it shows the power of anesthetics to affect neurodegenerative diseases like multiple sclerosis. Emphasis added.

Sevoflurane reduces clinical disease in a mouse model of multiple sclerosis

Paul E Polak, Randall O Dull, Sergey Kalinin, Anthony J Sharp, Richard Ripper, Guy Weinberg, David E Schwartz, Israel Rubinstein and Douglas L Feinstein

Corresponding author: Douglas L Feinstein dlfeins@uic.edu

Abstract

Background

Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. We tested the hypothesis that in mice immunized to develop experimental autoimmune encephalomyelitis (EAE), a well established model of multiple sclerosis (MS), treatment with the commonly used inhalational anesthetic sevoflurane would attenuate disease symptoms.

Methods

C57Bl6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35 to 55 to induce a chronic demyelinating disease. At day 10 after immunization, the mice were subjected to 2 h of 2.5% sevoflurane in 100% oxygen, or 100% oxygen, alone. Following treatment, clinical scores were monitored up to 4 weeks, after which brain histology was performed to measure the effects on astrocyte activation and lymphocyte infiltration. Effects of sevoflurane on T cell activation were studied using splenic T cells isolated from MOG peptide-immunized mice, restimulated ex vivo with MOG peptide or with antibodies to CD3 and CD28, and in the presence of different concentrations of sevoflurane. T cell responses were assessed 1 day later by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for proliferation, lactate dehydrogenase (LDH) release for cell death, and inflammatory activation by production of interleukin (IL)-17 and interferon (IFN)γ.

Results

Clinical scores in the oxygen-treated group increased until day 28 at which time they showed moderate to severe disease (average clinical score of 2.9). In contrast, disease progression in the sevoflurane-treated group increased to 2.1 at day 25, after which it remained unchanged until the end of the study. Immunohistochemical analysis revealed reduced numbers of infiltrating leukocytes and CD4+ cells in the CNS of the sevoflurane-treated mice, as well as reduced glial cell activation. In splenic T cells, low doses of sevoflurane reduced IFNγ production, cell proliferation, and increased LDH release.

Conclusions

These results are the first to show attenuation of EAE disease by an inhaled anesthetic and are consistent with previous reports that inhaled anesthetics, including sevoflurane, can suppress T cell activation that, in the context of autoimmune diseases such as MS, could lead to reduced clinical progression.

Source: http://www.jneuroinflammation.com/content/9/1/272
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Re: Anesthetics and ALS

Postby quest » Thu Aug 08, 2013 2:44 pm

Louis,

I'm Questioner from ALSTDI forum (quest being the root of question). How about a strategy discussion sub-forum? What is your strategy at this point for pushing anesthesia for affordable, accessible availability asap? Was getting kicked off ALSTDI part of that strategy?

What are the most current stats you know of for those testing anesthesia? I suggest a spreadsheet or database where details about each treatment can be recorded, such as what anesthesia, dose, over what time period, how many prior treatments, what benefits, length of benefits, how they were documented or validated, pre-treatment symptoms/impairment, and any other possibly relevant factors. This way, one could see at a glance - rather than scrolling down through posts at a forum) what worked or didn't and sort and correlate with the specifics of the treatment to discern any patterns.
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Re: Anesthetics and ALS

Postby sixwings » Thu Aug 08, 2013 5:29 pm

Questioner, thank you for joining the discussion on this forum. My strategy has always been to convince the PALS community of the viability of anesthetics as an effective treatment for ALS. Tactically speaking, the best thing that could happen for our cause is a spectacular recovery like what happened to Ted Harada. I believe this can happen soon if someone with limb-onset ALS went from being wheelchair-bound or using a walker to being fully restored. I know it can happen because it happened once to my wife. If such a recovery can be captured in a YouTube video, it can go viral and attract the attention of the media.

I am convinced that documenting minor improvements such as better speech, swallowing or breathing is not going to cut it. It will be shot down by the malcontents as useless anecdotal evidence. But showing a patient going from major leg paralysis to walking around on video would strike an emotional chord in the hearts of PALS everywhere.

All that stuff that's being discussed on ALSTDI about raising awareness is a waste of time, in my opinion. Nobody cares and we have some determined and vicious enemies who will stop at nothing to derail this project.
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Re: Anesthetics and ALS

Postby sixwings » Wed Aug 14, 2013 10:09 am

I have modified the ALS/Anesthetics Hypothesis to reflect my growing realization that propofol, although effective against bulbar-onset ALS, is not the best anesthetic for ALS in general. The reason is that propofol is not very good at potentiating the glycine alpha-1 receptors which are the predominant receptors in the spinal cord and the brain stem. From now on, I will only promote certain volatile anesthetics (e.g., sevoflurane, desflurane, etc.) and the local anesthetics lidocaine and procaine. The local anesthetics are especially attractive because they do not require an anesthesiologist or a visit to a hospital. Because of the much lower inherent risk, spinal anesthesia with a local anesthetic can be done at a small pain clinic or even at home.
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