[extropy-chat] Re:Resuscitation: and Armchair Cryonicists-hypothermic liferaft
Extropian Agroforestry Ventures Inc.
megao at sasktel.net
Wed Dec 15 13:56:05 UTC 2004
United States Patent Application 20040097534
Kind Code A1
Choi, Byung-Kil ; et al. May 20, 2004
------------------------------------------------------------------------
Composition for the protection and regeneration of nerve cells
containing berberine derivatives
Abstract
Disclosed is a composition for protecting nerve cells, promoting nerve
cell growth and regenerating nerve cells comprising berberine,
derivatives thereof or pharmaceutically acceptable salts thereof. The
composition has protective effects against apoptosis of neuronal stem
cells and differentiated neuronal stem cells, an effect of inducing the
regeneration of nerve cells, a regenerative effect on neurites, a
neuroregenerative effect on central nerves and peripheral nerves, a
reformation effect on neuromuscular junctions, and a protective effect
against apoptosis of nerve cells and a neuroregenerative effect in
animals suffering from dementia and brain ischemia. Therefore, the
composition can be used as a therapeutic agent for the prevention and
treatment of neurodegenerative diseases, ischemic nervous diseases or
nerve injuries, and for the improvement of learning capability.
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
[0150] Next, the head of the rat was fixed on a stereotaxic apparatus to
operate on the occiput, and then the tail was fixed so that it descended
downwardly at an angle of 30.degree.. After incising the occipital bone,
an electrocauterizing needle having a diameter of 1 mm or less was
inserted into the alar foramina positioned at lower part of the first
cervical vertebra under the occipital bone. At this time, this approach
must be carefully done so as not to damage the muscles in the alar
foramina. Thereafter, the vertebral artery was electrically cauterized
by intermittently applying current. After the complete
electrocauterization of the vertebral artery was confirmed, suturing was
carried out using operating clips. After 24 hours, the operating clips
were removed. Finally, the common carotid arteries were occluded using
the silicone tube rings for 10 minutes to induce ischemia. If light
reflex did not disappear within 1 minute, the cervical portion was
further tightly sutured. Rats which did not show the complete
disappearance of light reflex were excluded from the experiment because
they underwent no damage to the CA1 region. After 10 minutes, the common
carotid arteries were loosened to reperfuse. For 20 minutes after the
reperfusion, loss of consciousness was observed. At this time, only rats
which showed consciousness loss period within 20.+-.5 minutes were
selected for subsequent experiments.
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
2) Experimental Results
(1) Concentration of Berberine, Influence of Body Temperature and
Ischemia Inducing Time
[0157] The highest concentration of berberine was set to 300 .mu.g/0.1
kg, and 600 .mu.l (1 mg/ml) of berberine was intraperitoneally injected
to white rats weighing 200 g. In order to determine an optimal ischemia
induction time, 2.about.3 rats were selected and ischemia-induced over
5, 10, 20 and 30 minutes, respectively. 1 week after reperfusion, they
were sacrificed and their hippocampal tissue sections were obtained to
observe the number of damaged nerve cells. 10 minutes after ischemia
induction, damaged pyramidal cells in the hippocampal CA1 region were
found to be reduced to 1/4 of their original numbers. The ischemia
induction time of 10 minutes was determined to be most optimal for
evaluating the effects of berberine.
[0158] For statistically analyzing the effects of berberine, a sham
operated group having undergone an operation in the same manner without
ischemia induction was used. For comparing the effects of berberine, a
control group administered with physiological saline at the same dose as
berberine was used. Berberine was intraperitoneally injected into all
experimental groups.
[0159] It is well known that reduction in body temperature during
ischemia induction prevents damage to nerve cells in the hippocampus and
thus exhibits neuroprotective effects. Therefore, in order to evaluate
the neuroprotective effect of berberine, after ischemia induction and
reperfusion, the body temperature of all rats was maintained at a
constant (37.+-.1.degree. C.) for 6 hours.
(2) Observation of Damaged Nerve Cells
[0160] When ischemia was induced by 4-VO and then reperfusion was
performed, nerve cells in the neocortex, striatum, hippocampal CA1
region and cerebellum were damaged. Among them, pyramidal nerve cells in
the hippocampal CA1 region were the most susceptible to the induced
ischemia, and started to undergo cell death 72 hours after reperfusion.
In order to observe delayed neuronal death in the hippocampal CA1
region, 1 week after reperfusion, the time when almost all nerve cells
were damaged, white rats were sacrificed and tissue sections from the
hippocampus were observed under an optical microscope. In a sham
operated group having undergone no ischemia, normal hippocampal nerve
cells were observed in the stratum pyramidale (490 .mu.m long)(see,A and
B of FIG. 21).
[0161] C and D of FIG. 21 as control groups show apoptosis. When cells
are induced to undergo apoptosis by an external or an internal stimulus,
they shrink to lose their original shapes. This shrinkage breaks the
junctions with other adjacent cells so that the interaction between
cells is disrupted. When the shrinkage proceeds to some extent, the cell
membranes form apoptotic bodies like a bulla. In the hippocampal CA1
region of the control group administered with physiological saline (D of
FIG. 21), it was observed that nerve cells underwent apoptotic
morphological changes after ischemia induction. In addition, it was
observed that tissues was relaxed and separated from adjacent cells,
unlike B of FIG. 21. From these observations, it was confirmed that the
cell bodies of nerve cells lost their original pyramidal shape and were
condensed, thereby appearing to be single cells. Furthermore, it was
confirmed that subsequent nuclear chromatin condensation and nuclear
envelope collapse led to apoptosis of nerve cells. On the contrary,
nerve cells in the hippocampal CA1 region administered with berberine
were similar to normal cells in terms of their morphology (see, E and F
of FIG. 21). At this time, because necrotic nerve cells around the CA1
region were very difficult to distinguish from microglias, only viable
pyramidal nerve cells in the CA1 region were counted. In F of FIG. 21,
separated cells were observed above and below the hippocampal region and
cell bodies were condensed. This demonstrates that the damage to nerve
cells was great enough to induce apoptosis. Nevertheless, it was
observed that a great number of nerve cells were protected from
apoptosis and their original pyramidal morphology was maintained. This
suggests that berberine has a protective effect against damages to nerve
cells in the hippocampal CA1 region induced by 4-VO. Although it was not
confirmed what stage during apoptosis influences nerve cell survival, it
was certain that berberine has a significant protective effect against
apoptosis of nerve cells (see, E and F of FIG. 21).
(3) Protective Effect of Berberine Against Damage to Nerve Cells
[0162] In order to examine the neuroprotective effect of berberine after
ischemia induction, berberine was intraperitoneally injected 0 and 90
minutes after ischemia induction.
[0163] In the sham groups, the density of viable cells was measured to
be 308.+-.6.6 cells/mm.sup.2 (at 37.degree. C.). In the control groups
administered with physiological saline, the density of viable cells was
measured to be 28.+-.3.8 cells/mm.sup.2 (at 37.degree. C.). There was
cell loss in these two groups. On the other hand, in the experimental
groups administered with berberine, the density of viable cells was
measured to be 257.+-.9.6 cell/mm.sup.2. In conclusion, berberine was
determined to have a significant neuroprotective effect (p<0.05).
[0164] As described above, the composition according to the present
invention regenerates axons and dendrites of nerve cells, thereby having
a protective effect against nerve cell injuries, a positive effect on
nerve cell growth and a regenerative effect on nerve cells. In addition,
the composition according to the present invention can be used as a
therapeutic agent for the prevention and treatment of neurodegenerative
diseases or nerve injuries, in particular, dementia, Parkinson's
disease, Alzheimer's disease, epilepsy, palsy, ischemic brain diseases,
trauma to the spinal cord and peripheral nerve injuries.
[0165] Although the preferred embodiments of the present invention have
been disclosed for illustrative purposes, those skilled in the art will
appreciate that various modifications, additions and substitutions are
possible, without departing from the scope and spirit of the invention
as disclosed in the accompanying claims.
* * * * *
Aside from its carrier capacity DMSO was chosen for its ability to
inhibit damage from a light freeze
There are a number of complementary chemistries besides from the ones
cited readily available.
Eugen Leitl wrote:
>On Wed, Dec 15, 2004 at 03:01:49AM -0600, Extropian Agroforestry Ventures Inc. wrote:
>
>
>
>>The concept goes thusly:
>>The liferaft =
>>-sleeping /body bag like sack made so that no 2 arms or legs touch each
>>other or body
>>-zipper + ziplock seal
>>- control/RFID biomonitor keypad with on outside
>>-stage 1- evacuate liner to ensure good skin contact with sack
>>-person put inside without outer clothes , shoes etc
>>-put cooling hood or cap over all of head less face, face cover ziplock
>>cover after body cooled off
>>-start in 2 parts; activation of emergency cooling packs layer of sack
>>to quick cool body; hood cooling cycle
>>
>>
>
>Useless. This gives you no advatage over an ice bath.
>
>
>
>>co2 based for higher cooling rate
>>
>>
>
>More than useless. You can't go below 0 C, or you'll get freezing injury.
>
>
>
>>-infusion of adjuvants may include:
>>Caffeinol as neuroprotectant; berberine in DMSO solution as
>>neuroprotectant; cannabidiol in DMSO solution as neuroprotectant
>>-optional defib cycle to pump neuroprotectants into cooling body uniformly
>>
>>
>
>You have to maintain the circulation. Best do achieve this is life support.
>
>
>
>>The adjuvants are designed to allow the brain to survive a longer
>>cool-off time than the usual 3-5 minutes.
>>
>>
>
>Sorry, but your science is garbage. I'm being delibertely harsh here, because
>otherwise you won't get the message.
>
>
>
>>as well as allow for easier re-start of body by hospital medical team
>>-once body temp is near 32F optional external hookups to maintain cooled
>>body during extended transport
>>
>>Once the working prototype is designed and tested , the actual mfg
>>costs may be quite reasonable
>>
>>
>
>If you have to live in the sticks, you have to rely on people. No machinery
>is going to help.
>
>
>
>>Morris Johnson
>>
>>Hara Ra wrote:
>>
>>
>>>For Eugen:
>>>
>>> Thanks for taking my point and clarifying it. If you read my sig
>>>file, I don't think I am an "Armchair cryonicist". Please correct me
>>>if you think so, and explain why.
>>>
>>>
>
>Of course I wasn't commenting on what you wrote, but on periodical resurgence
>of well-meaning-but-clueless armchair cryonicists.
>
>
>
>>>PS We currently do no longer use the Thumper, which is an obscene
>>>bastard of equipment fully capable of major injury to both patient and
>>>rescue team. Respiratory support is no longer in the protocol, because
>>>
>>>
>
>Oh yeah, if the cup breaks off you'll get a massive metal rod puncturing the
>ribcage.
>
>
>
>>>basically all patients are over the 4 minute limit, and restoring O2
>>>is a bad idea. We use an Ambi product, a suction cup with handles, to
>>>
>>>
>
>Not if you add neuroprotectants via IV push, and maintain artificial
>circulation.
>
>
>
>>>maintain circulation for the 3-5 minutes it takes to circulate the
>>>medicines (a proprietary cocktail of anticoaguants, clot busters and
>>>other stuff)
>>>
>>>
>
>
>
>
>------------------------------------------------------------------------
>
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>
>
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