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Thursday, 29 September 2011

Toll-like receptor on brain glial cells - a new target to reduce acute toxic effects of alcohol?

@HealthMed Researchers in Adelaide, Australia led by Mark Hutchinson have attracted international media interest with headlines heralding a new treatment to protect from hazards of alcohol. How close is the research to human treatment? And is there a risk this could be a drug of abuse for people over-indulging in alcohol and hoping to avoid harmful effects? My discussion below complements two radio interviews, one with a Californian station, the other with BBC Radio Ulster. To listen to the interviews, use the podcast links at the foot of this blog.

This was an experimental study looking in mice at ways to prevent some of the harmful effects of a single large dose of alcohol. The authors were following up previous research suggesting a link between alcohol and the immune system. The Toll-like Receptor 4 is a member of a family of inflammation-inducing receptors, first described in the fruit fly. TLR-4 is present on immune defence white blood cells in the circulation. TLR-4 is also present on glial cells in the brain. Glial cells make up around 90% of cells in the brain and have an important defence role against brain infection.

The scientists used two approaches to find out whether TLR-4 is involved in unwanted effects of a large single intake of alcohol: animals with genetic absence of TLR-4 and its pro-inflammatory signalling pathway partner MyD88; and the drug (+)-naloxone.  This is the mirror-image version of the (-)-naloxone in clinical use to treat an overdose of an opiate such as diamorphine (heroin) or morphine. (+)-naloxone blocks TLR-4 without blocking the enkephalin receptor through which opiates act.

Hutchinson and colleagues studied two adverse effects of alcohol overdose: sedation and unsteadiness. Their model of sedation was the time taken to regain normal posture (loss of righting reflex). Their model of unsteadiness was the mouse equivalent of keeping balance on a rolling log.
What did they find? The drug (+)-naloxone halved the duration of sedation after acute alcohol and shortened the recovery time for loss of balance.  These effects could have been due to 'off-target' effects of the naloxone, however findings were similar in animals genetically deficient in TLR-4 and MyD88 - reduction in severity and duration of sedation and unsteadiness. The authors also showed that alcohol switched on inflammatory protein production by cells from the hippocampal part of the brain; and they ruled out differences in alcohol metabolism between models.

What do these results mean for people?
Firstly, they are important in raising the question whether genetic variation in activity of TLR-4 inflammatory pathways plays a role in explaining major differences in tolerance of alcohol.
These results provide an interesting complementary mechanism for protective effects of naloxone on alcohol-toxicity to those reported by Badawy and Evans 30 years ago using different experimental methods.
Secondly, these findings suggest that targeting TLR-4 in the brain may be a new way to reverse some of the serious adverse effects of major alcohol overdose in patients attending emergency departments.
What about (+)-naloxone as the drug to use? Studies would be needed to confirm that TLR-4 is also important in alcohol-mediated toxicity in humans, and if so to understand more about the wider range of adverse effects of alcohol which may be prevented or reduced.

What about cautions? 
- This is experimental research which would need to be repeated in human subjects with TLR-4 blocking strategies which pose minimal toxic risk.
- Naloxone has to be given by injection - it is not sufficiently absorbed by mouth to be clinically active.
- Use (+)-naloxone is no exception to the rule that all drugs can have harmful effects. There is concern that risks of harmful effects from (+)- naloxone mean that is unlikely to be safe to use in general alcohol users.
-  (+)-naloxone may block some of the wanted mood-altering effects of more moderate alcohol intake. For example, it is known to affect other brain pathways e.g. blocking stimulant effects of cocaine and amphetamines. This may well lead to loss with this drug of the wanted effects of alcohol.
- The published study showed reduction in severity and duration of alcohol's effects not their prevention: if confirmed in people, general hazards of alcohol, for example when driving, would remain.
- (+)- naloxone is unlikely to prevent the 'hangover' from alcohol, which is recognized to be due to many factors, including dehydration (alcohol is a diuretic), low blood sugar, and other chemicals (congeners) present in alcoholic drinks and contributing to colour and taste.

The most interesting aspects of this study are that:
- if confirmed in further research in humans, assessment of TLR-4 variability may be developed as a test for susceptibility to alcohol;
- safe, effective TLR-4 inhibitors for use in humans could be a treatment for some of the physical effects of a severe overdose of alcohol in people presenting to hospital.

See the article
Podcasts of radio interviews with Professor Donald Singer about research on alcohol, the immune system and new potential treatment:
Interview with Jon Bristow on San Francisco KGO Radio     12.17 PDT 29th Sep, 2011.

© DRJ Singer

1 comment:

  1. Hello,

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