X-Message-Number: 31953
Date: Wed, 9 Sep 2009 20:39:23 -0700 (PDT)
From:
Subject: Research could prevent stroke's damage
[Suppressing TRPM7 eliminated neurological damage. Could thyme also eliminate
stroke damage? Thyme contains carvacrol, which inihibits TRPM7.]
Snip: > "But the rats whose TRPM7 had been suppressed exhibited none of the
expected damage. In fact, the treated rats performed just as well in memory
tests as rats that had never been subjected to oxygen deprivation. And they
exhibited no other side effects from the treatment."
http://www.theglobeandmail.com/news/national/research-could-prevent-strokes-damage/article1278339/
Research could prevent stroke's damage
New method from Canadian-led research team keeps rats' brain cells alive even
when blood stops flowing
JILL COLVIN
>From Monday's Globe and Mail Last updated on Tuesday, Sep. 08, 2009 02:41AM EDT
A Canadian-led research team believes it has discovered a way to prevent the
most devastating effects of stroke.
During a stroke, the brain is deprived of oxygen and nutrients, which strangles
neurons, causing debilitating long-term impairment in motor function, memory and
speech.
There are currently no drugs available to prevent the death of these cells and
protect patients from their life-altering effects.
But a team of researchers, led by Michael Tymianski, a neurosurgeon at the
Krembil Neuroscience Centre at Toronto Western Hospital, has found a method that
protects neurons in rats, paving the way for new drugs that may keep cells
alive even when blood stops flowing.
Previous studies in the field have focused mainly on finding new ways to restore
blood to the brain as quickly as possible or on trying to block toxic chemicals
that build up when cells experience stress, said Tony Hakim, a director of the
Canadian Stroke Network, which supported the study.
But the current research, reported yesterday in the journal Nature Neuroscience,
takes a new approach, focusing on an ion channel named TRPM7 ("Trip-M7").
TRPM7 is found in cells throughout the body and the researchers had a hunch that
the channels play a key role in cell death following oxygen deprivation.
To test their theory, Dr. Tymianski's team took healthy rats and injected a
virus that suppressed the expression of TRPM7 directly into the hippocampus -
the delicate brain region that is crucial for learning and memory.
They then cut off blood flow to the rats' brains for 15 minutes and compared the
extent of damage days later to rats whose brains had not been treated before
deprivation.
As expected, untreated rats with intact TRPM7 suffered severe neurological
damage, with long-term impairment, including difficulty learning and remembering
how to navigate a maze.
But the rats whose TRPM7 had been suppressed exhibited none of the expected
damage. In fact, the treated rats performed just as well in memory tests as rats
that had never been subjected to oxygen deprivation. And they exhibited no
other side effects from the treatment.
"To the best of our knowledge, our results are the first to demonstrate that
suppressing TRPM7 in adult mammals is feasible and that this markedly reduces
delayed neuron death after ischemia," they write.
Because TRPM7 is found in virtually every tissue of the body, the team thinks
they may have discovered the key to preventing cell death caused by reduced
oxygen and nutrient supply, not just in neurons, but in other cells as well.
"It has tremendous implications," Dr. Tymianski said. "It is conceivable that
the same types of processes occur in other tissues where there's ischemia as
well."
This means the findings could apply to cell death seen in heart attacks,
diabetes-related kidney and retinal problems, glaucoma, Parkinson's disease and
Alzheimer's disease.
The next step, he said, will be to develop drugs that target TRPM7 channels that
can eventually be administered to stroke patients to stave off the devastating
effects of oxygen deprivation.
Dr. Tymianski said he hopes to have drugs ready for testing on other animals in
a year or two.
But University of Calgary neurologist and Heart & Stroke Foundation spokesman
Michael Hill urged caution in interpreting the results. This is not the first
time, he said, that receptors found to be crucial in cell death in the lab have
failed to translate into viable therapies.
"Whether it can be translated to humans remains to be seen," he said.
____________________________________________
Free text:>
http://www.nature.com/neuro/journal/vaop/ncurrent/pdf/nn.2395.pdf
Nature Neuroscience
Published online: 6 September 2009 | doi:10.1038/nn.2395
Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in
brain ischemia
Hong-Shuo Sun1, Michael F Jackson2,3, Loren J Martin4, Karen Jansen5, Lucy
Teves1, Hong Cui1, Shigeki Kiyonaka6, Yasuo Mori6, Michael Jones1, Joan P
Forder1, Todd E Golde5, Beverley A Orser2,4,7, John F MacDonald2,3 & Michael
Tymianski1,2,4,8
Abstract
Cardiac arrest victims may experience transient brain hypoperfusion leading to
delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented
this in adult rats by inhibiting the expression of transient receptor potential
melastatin 7 (TRPM7), a transient receptor potential channel that is essential
for embryonic development, is necessary for cell survival and trace ion
homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was
suppressed in CA1 neurons by intrahippocampal injections of viral vectors
bearing shRNA specific for TRPM7. This had no ill effect on animal survival,
neuronal and dendritic morphology, neuronal excitability, or synaptic
plasticity, as exemplified by robust long-term potentiation (LTP). However,
TRPM7 suppression made neurons resistant to ischemic death after brain ischemia
and preserved neuronal morphology and function. Also, it prevented
ischemia-induced deficits in LTP and preserved performance in fear-associated
and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is
feasible, well tolerated and inhibits delayed neuronal death in vivo.
_______________________________
Cell Calcium. 2009 Mar;45(3):300-9. Epub 2009 Jan 9.
Carvacrol is a novel inhibitor of Drosophila TRPL and mammalian TRPM7 channels.
Parnas M, Peters M, Dadon D, Lev S, Vertkin I, Slutsky I, Minke B.
Department of Physiology, Kuhne Minerva Center for Studies of Visual
Transduction, Faculty of Medicine, The Hebrew University, Jerusalem 91120,
Israel.
Transient receptor potential (TRP) channels are essential components of
biological sensors that detect changes in the environment in response to a
myriad of stimuli. A major difficulty in the study of TRP channels is the
lack of pharmacological agents that modulate most members of the TRP
superfamily. Notable exceptions are the thermoTRPs, which respond to either
cold or hot temperatures and are modulated by a relatively large number of
chemical agents. In the present study we demonstrate by patch clamp whole
cell recordings from Schneider 2 and Drosophila photoreceptor cells that
carvacrol, a known activator of the thermoTRPs, TRPV3 and TRPA1 is an
inhibitor of the Drosophila TRPL channels, which belongs to the TRPC
subfamily. We also show that additional activators of TRPV3, thymol,
eugenol, cinnamaldehyde and menthol are all inhibitors of the TRPL channel.
Furthermore, carvacrol also inhibits the mammalian TRPM7 heterologously
expressed in HEK cells and ectopically expressed in a primary culture of
CA3-CA1 hippocampal brain neurons. This study, thus, identifies a novel
inhibitor of TRPC and TRPM channels. Our finding that the activity of the
non-thermoTRPs, TRPL and TRPM7 channels is modulated by the same compound as
thermoTRPs, suggests that common mechanisms of channel modulation
characterize TRP channels.
PMID: 19135721
[Thyme oil contains carvacrol.]
Br J Nutr. 2000 Jan;83(1):87-93.
Effect of thyme oil and thymol dietary supplementation on the antioxidant status
and fatty acid composition of the ageing rat brain.
Youdim KA, Deans SG. Aromatic and Medicinal Plant Group, Scottish
Agricultural College, Auchincruive, Ayr, UK.
The present study measured changes in antioxidant enzyme activity in, and the
phospholipid fatty acid composition of the ageing rat brain and tested whether
dietary supplementation with thyme oil or thymol could provide beneficial
effects. There were significant declines in superoxide dismutase (EC 1.15.1.1)
and glutathione peroxidase (EC 1.11.1.9) activities and the total antioxidant
status in the untreated rats with age, while thyme-oil- and thymol-fed rats
maintained significantly higher antioxidant enzyme activities and total
antioxidant status. The proportions of 18:2n-6, 20:1n-9, 22:4n-6 and 22:5n-3 in
the brain phospholipids resulting from all three dietary treatments were
significantly higher in 28-month-old rats than in 7-month-old rats. Only 20:1n-9
levels in 28-month-old thyme-oil- and thymol-treated rats were significantly
higher than in the age-matched control. The proportion of 22:6n-3 in brain
phospholipids, which declined with age in control rats, was also significantly
higher in rats given either supplement. This latter finding is particularly
important as optimum levels of 22:6n-3 are required for normal brain function.
These results highlight the potential benefit of thyme oil as a dietary
antioxidant.
PMID: 10703468
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