Ironjustic
Mon, Aug-13-07, 17:16
<<snip>> implementation of iron chelation <<snip>>
doi:10.1016/j.pneurobio.2007.06.001 Copyright =C2=A9 2007
Elsevier Ltd All rights reserved. Iron dysregulation in
Alzheimer's disease: Multimodal brain permeable iron chelating
drugs, possessing neuroprotective-neurorescue and amyloid
precursor protein-processing regulatory activities as
therapeutic agents
Silvia Mandela, Tamar Amita, Orit Bar-Ama and Moussa B.H.
Youdim, a, aEve Topf and USA NPF Centers of Excellence,
Technion-Faculty of Medicine, Department of Pharmacology,
Israel Received 20 December 2006; revised 11 April 2007;
accepted 11 June 2007. Available online 19 June 2007.
Abstract
Considering the multi-etiological character of Alzheimer's
disease (AD), the current pharmacological approaches using
drugs oriented towards a single molecular target possess
limited ability to modify the course of the disease and thus,
offer a partial benefit to the patient. In line with this
concept, novel strategies include the use of a cocktail of
several drugs and/or the development of a single molecule,
possessing two or more active neuroprotective-neurorescue
moieties that simultaneously manipulate multiple targets
involved in AD pathology. A consistent observation in AD is a
dysregulation of metal ions (Fe2+, Cu2+ and Zn2+) homeostasis
and consequential induction of oxidative stress, associated
with beta-amyloid aggregation and neurite plaque formation. In
particular, iron has been demonstrated to modulate the
Alzheimer's amyloid precursor holo- protein expression by a
pathway similar to that of ferritin L-and H- mRNA translation
through iron-responsive elements in their 5=E2=80=B2UTRs. This
review will discuss two separate scenarios concerning multiple
therapy targets in AD, sharing in common the implementation of
iron chelation activity: (i) novel multimodal brain-permeable
iron chelating drugs, possessing neuroprotective-neurorescue
and amyloid precursor protein-processing regulatory
activities; (ii) natural plant polyphenols (flavonoids), such
as green tea epigallocatechin gallate (EGCG) and curcumin,
reported to have access to the brain and to possess
multifunctional activities, such as metal chelation-radical
scavenging, anti-inflammation and neuroprotection.
Keywords: Alzheimer's disease; A=CE=B2-peptide; Iron
homeostasis; APP mRNA; Multi-functional drugs; Iron-chelator
Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic
lateral sclerosis; APP, amyloid precursor protein; BDNF,
brain-derived neurotrophic factor; A=CE=B2, beta-amyloid
peptide; =CE=B2-CTF, beta-C-term= inal fragment; EGCG,
epigallocatechin gallate; DFO, desferrioxamine; ERK1/2,
extracellular signal-regulated kinases 1 and 2; GAP-43,
growth- associated protein-43; HFE, haemochromatosis; HO-1,
heme oxygenase; HIF, hypoxia-inducible factor; IREG-1, iron
regulated transporter protein-1; IRP, iron regulatory protein;
NFT, neurofibrillary tangles; PHF=CF=84, hyperphosphorylated
=CF=84; OS, oxidative stress; PD, Parkinson's disease; PKC,
protein kinase C; sAPP =CE=B1, soluble APP=CE=B1; ROS, reacti=
ve oxygen species
Corresponding author at: Department of Pharmacology,
Technion-Faculty of Medicine, P.O.B. 9697, 31096 Haifa,
Israel. Tel.: +972 4 8295290; fax: +972 4 8513145.
Progress in Neurobiology Volume 82, Issue 6, August 2007,
Pages 348-360
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
Stopalz@Gm
Tue, Aug-14-07, 17:16
On Aug 13, 4:57 pm, "ironjust...@aol.com"
<ironjust...@aol.com> wrote:
> <<snip>> implementation of iron chelation <<snip>>
>
> doi:10.1016/j.pneurobio.2007.06.001 Copyright =C2=A9 2007
> Elsevier Ltd All rights reserved. Iron dysregulation in
> Alzheimer's disease: Multimodal brain permeable iron
> chelating drugs, possessing neuroprotective-neurorescue and
> amyloid precursor protein-processing regulatory activities
> as therapeutic agents
>
> Silvia Mandela, Tamar Amita, Orit Bar-Ama and Moussa B.H.
> Youdim, a, aEve Topf and USA NPF Centers of Excellence,
> Technion-Faculty of Medicine, Department of Pharmacology,
> Israel Received 20 December 2006; revised 11 April 2007;
> accepted 11 June 2007. Available online 19 June 2007.
>
> Abstract
>
> Considering the multi-etiological character of Alzheimer's
> disease (AD), the current pharmacological approaches using
> drugs oriented towards a single molecular target possess
> limited ability to modify the course of the disease and
> thus, offer a partial benefit to the patient. In line with
> this concept, novel strategies include the use of a cocktail
> of several drugs and/or the development of a single
> molecule, possessing two or more active
> neuroprotective-neurorescue moieties that simultaneously
> manipulate multiple targets involved in AD pathology. A
> consistent observation in AD is a dysregulation of metal
> ions (Fe2+, Cu2+ and Zn2+) homeostasis and consequential
> induction of oxidative stress, associated with beta-amyloid
> aggregation and neurite plaque formation. In particular,
> iron has been demonstrated to modulate the Alzheimer's
> amyloid precursor holo- protein expression by a pathway
> similar to that of ferritin L-and H- mRNA translation
> through iron-responsive elements in their 5=E2=80=B2UTRs.
> This review will discuss two separate scenarios concerning
> multiple therapy targets in AD, sharing in common the
> implementation of iron chelation activity: (i) novel
> multimodal brain-permeable iron chelating drugs, possessing
> neuroprotective-neurorescue and amyloid precursor
> protein-processing regulatory activities; (ii) natural plant
> polyphenols (flavonoids), such as green tea epigallocatechin
> gallate (EGCG) and curcumin, reported to have access to the
> brain and to possess multifunctional activities, such as
> metal chelation-radical scavenging, anti-inflammation and
> neuroprotection.
>
> Keywords: Alzheimer's disease; A=CE=B2-peptide; Iron
> homeostasis; APP mRN=
A;
> Multi-functional drugs; Iron-chelator
>
> Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic
> lateral sclerosis; APP, amyloid precursor protein; BDNF,
> brain-derived neurotrophic factor; A=CE=B2, beta-amyloid
> peptide; =CE=B2-CTF, beta-C-te=
rminal
> fragment; EGCG, epigallocatechin gallate; DFO,
> desferrioxamine; ERK1/2, extracellular signal-regulated
> kinases 1 and 2; GAP-43, growth- associated protein-43; HFE,
> haemochromatosis; HO-1, heme oxygenase; HIF,
> hypoxia-inducible factor; IREG-1, iron regulated transporter
> protein-1; IRP, iron regulatory protein; NFT,
> neurofibrillary tangles; PHF=CF=84, hyperphosphorylated
> =CF=84; OS, oxidative stress; PD, Parkinso=
n's
> disease; PKC, protein kinase C; sAPP =CE=B1, soluble
> APP=CE=B1; ROS, reac=
tive
> oxygen species
>
> Corresponding author at: Department of Pharmacology,
> Technion-Faculty of Medicine, P.O.B. 9697, 31096 Haifa,
> Israel. Tel.: +972 4 8295290; fax: +972 4 8513145.
>
> Progress in Neurobiology Volume 82, Issue 6, August 2007,
> Pages 348-360
>
> Who loves ya. Tom
>
> Jesus Was A Vegetarian!http://jesuswasavegetarian.7h.com
>
> Man Is A Herbivore!http://tinyurl.com/a3cc3
>
> DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
Please, pay attention, this is quite new, the paper published
at the J Neurol (Barcelona) at the beginning of 2007
THE ALTERNATIVE THEORY FOR THE ALZHEIMER PROCESS
DIFFUSION TEXT ALZHEIMER PROJECT ARGENTINE, AUGUST 2007
The Chronic Progressive Dementization, (CPD), the scientific
name of that vulgarly called alzheimer, is a quite different
question than depression, different types of psychosis and
obviously of sometimes surprising behaviors of the normal
aging, and in the long run much more serious.
Although the final phase of cerebral disintegration is
similar, there are two types of processes: the one that occurs
in young adults or greater adults, and another different one
that it happens in very greater adults, around 80 years or
more. In these, at the final phase the problem it is
=E2=80=9Csimply=E2=80=9D the loss of the vital motivation= ,
the exhaustion of desire to continue living. Abandonment of
dreams, as Miguel de Unamuno would say on the cession of such
dreams that Don Quixote in favor of Sancho did, and then,
obviously, dying.
Persons with risk for a CPD (alzheimer) are those that
generally have an introverted personality, few and restricted
social relations, with and isolation tendency, coping deficit
for difficulties and losses, tendency to depend on others, to
had constructed their personal identity in the shade of
another one (the woman of the doctor, the husband of=E2=80=A6)
or some other equivalent transference, tendency to be
obstinate to proper painful events or of the other=E2=80=99s
life, which is diagnosed in general like depression.
THEN, IN ANY WAY IT TOUCHES TO ANYONE.
There is nothing of chance=E2=80=99s dependence, neither
suddenly nor no magician in it. Logically with advance into
years the probability that these people suffer a painful loss
increases, obviously, like everybody. With its coping deficit
the risk increases enormously when they have a painful loss,
for example her husband who gave or lent the personal
identity, or a son or daughter who gave sense to their life,
of their work that justified the existence to him, of their
corporal and mental capacity to which he had bet or
concentrated, and when not counting on a familiar network and
a social network that stopped its fall after the duel
impossible to elaborate and to go on, the person collapses.
It is the beginning of the aim. It can have 40 years old (the
younger case than we have was a woman of 38 years), or 80 yo.
It does not related to aging, but only that when they advance
the years is more probable that we suffer painful losses.
Until this moment its brain is totally normal, does not show
absolutely anything abnormal and is totally useless to want to
see something in images or less even in electroencephalograms,
that it is something so coarse and inadequate as a toad
arrives of a luxurious piano of tail.
The landslide of the person, its =E2=80=9Cdelivery=E2=80=9D
as much in the = dictionary of the Real Spanish Academy like
in the original dictionaries of all the languages, is
expressed in the idea to wish to die, in the fixation of the
attention in its own one and wished death. Then the abnormal
thing begins, the unnatural thing, the destructive thing,
because in fact we are programmed biologically, ancestrally,
for all the opposite, as it is to explore, to fight, to
defend to us, to hunt (in the literal sense and the symbolic
sense), to attack, to ask to us, to inquire to us, and our
attention concentrated in each objective part of a basic
alert status that we never lose, except for when we slept
very well. We are not programmed to give to us tamely, as it
is not it in any animal.
How takes place then the cerebral damage that leads to
the death?
To understand this we need to explain some very basic things,
although surprising little known. In the first place that we
have nine senses: vision, hearing, equilibrium, tact, space
perception/orientation, taste, sense of smell, sense of
strange it (or familiarity sense) and of the corporal
perception. All these senses, and perhaps others more, are
active in the basic alert status and they have two components:
an automatic one of immediate reaction (one falls in love a
light and blinking, it smells sulphydric vapors, the substance
that is put to the gas tubes to detect a loss immediately, and
I separate, etc.), and another component of recognition, in
which the stimuli are sent to the brain and there it is
collated if that information has been loaded. They are the
sensorial recognition systems we have.
Then, EVERYTHING WHAT WE DO, EVERYTHING WHAT WE THOUGHT, BY
MORE BANAL OR INSIGNIFICANT THAN IS, IS RECORDED IN THE BRAIN
IN FORM OF NEURONAL NETWORK IN WHICH PARTICIPATE NEURONS OF
THIS SENSORIAL RECOGNITION =C2=B4S SYSTEMS OF THE NINE
CHANNELS, INEXORABLY.
And those networks that are armed in our brain also were
reinforced when we return to make the same act or the same
thought. But in addition BECAUSE IN FACT ALL IS CONCECTED WITH
ALL, WHICH WE ARE GOING TO DO WAS CONNECTED IN MORE OR LESS
STRAIGHT FORWARD FORM WITH WHICH ALREADY WE HAVE DONE AND
LOADED LIKE NEURONAL NETWORKS IN OUR BRAIN.
Some of those connections have a great importance in the every
day actions and others very remotely: although the door seems
to be very heavy, already we know that the force that we must
make to open it isn=E2=80=99t so high. Or for example the
natural attraction by rhythm that are multiple or sub multiple
of the heart rate (that we listened for the first time in our
mother=E2=80=99s uterus), seems like related with this indeed.
That is to say, to live means to be stimulating everything
somehow what we have done, lived and thought. It seems
exhausting, but it is a fascinating question.
However, when a person fix attention to death, that is
something abstract that does not required any motor or
cognitive reply, AND RESORTING TO THE NATURAL AND AVAILABLE
MECHANISM DISPOSED IN ALL PERSONS THEY TO BLOCK THE RECEPTION
OF OTHER STIMULI WHEN WE CONCENTRATED THE ATTENTION IN
SOMETHING INTENSIVELY ATTRRACTED, THESE PEOPLE HAPPEN TO
BLOCK, at the outset in oscillating form, with variations
throughout a day or of days, THE SENSORIAL STIMULI OF THE
DIFFERENT CHANNELS. It is a biological basic mechanism since
we must be concentrated in the tiger that attacks to us and we
cannot disperse with the colored birds that are jumping back:
it=E2=80=99s a survival principle. Who know more the utility
of this principle are the pickpockets of the human
agglomerates: one of them produces a smaller but clear
aggression on the victim. In reaction the victim is put in
guard and concentrates its attention on the aggressor, while
his companion removes the wallet or cuts the
portfolio=E2=80=99s strap, because= we have blocked the tact
and the corporal perception when putting to us in guard in
front of the aggressor and concentrating the attention in him.
The displacement of the attention towards different objectives
is a normal and a routinely task, but in the people who enter
CPD process they are persistently blocking the reception of
stimuli by the different sensorial channels and the consequent
arrived to the brain, so that the neurons of the sensorial
recognition systems that comprise of the sensorial networks
doesn=E2=80=99t receive stimuli, with which in the long run
lose the synaptic connections and the networks are disarmed.
Something equivalent to the atrophy of a muscle we never use.
This avoid progressively all the recognition tasks. No longer
they recognize, no longer have capacity of recovery of recent
events (weak neuronal networks, with low sensorial
stimulation), and however still can recover events of the
past. But not anyone, but THOSE IN WHICH THE LIVED EVENTS
(SENSORIAL NETWORKS ARMED IN THE PAST) WERE POSSIBLE WITH A
GREAT STIMULATION (EMOTIONAL), PROLONGED REINFORCED AND
CONNECTED WITH MULTIPLE OTHER SENSORIAL NETWORKS, LIKE THE
DOOR OF OUR HOME AT OUR CHILDHOOD, by where we did not
shelter, by where we shook to arrive all smeared, by where we
arrived to eat, etc.
Thus, those faults of the systems of sensorial recognition
were the more consistent biological indicators to detect that
a person is in a dementia of this type.
THE PROGRESSIVE DISINTEGRATION OF THE NEURONAL NETWORKS IN OUR
BRAIN BY STIMULATION DEFICIT OF THE RECOGNITION SENSORIAL
SYSTEMS IS THE ESSENCE OF THE DEMENTIZATION PROCESS, AND LEADS
TO THE DEATH BECAUSE AN AUTOMATIC ESSENTIAL SYSTEM HAS
CONNECTIONS WITH SENSORIAL NETWORKS YOU, THAT WHEN ALSO THEY
GET TO BE AFFECTED, CAUSES THE DEATH.
Then isn=E2=80=99t properly a disease (=E2=80=9Csigns and
symptoms that res= ponds to a well-known cause=E2=80=9D),
isn=E2=80=99t genetic, it doesn=E2=80=99t have = relation with
aging (confusion comes from that to greater age is the
probability of suffering painful losses, that are a very
frequent trigger one, since we have already said), does not
begin with any damage in the brain but that concludes in the
long run in this, isn=E2=80=99t a problem of the memo= ry but
of the attention, and before this one of the desire, and
before this one of the satisfaction search, and before this
one of the biological and psychological impulsions arranged by
the will, and even before the basal state of alert that
characterizes to us. One of the last forms of the expression
of the process is the problem with the memory, but in fact the
difficulty to recover events is the last link of a very long
chain, and to have concentrated in it and not in the
attention=E2=80=99s deficit of can be the reason of the
delayed to understa= nd the process, we think.
And finally, isn=E2=80=99t irreversible, since it is possible
and it gives clear and forceful result, to elevate to those
people the self-esteem and the attention to him, and to
permute the abstract idea to him of death wished by the one of
real life that surrounds it, the shade by the light that
surrounds us to all to little that we lend a little attention,
taken care of and love, and inserting it in a new extolling
routine for the dairy life. It is not easy, is an abyss of
difference with giving a tablet, but it is tremendously
positive as much for the affected ones as for which we worked
with the protocols derived from the psycho-social neuro
sensorial disintegrative theory of the chronic progressive
dementization.
Prof.Lic.Luis Mar=C3=ADa S=C3=A1nchez de Machado,
Neurobiologist, Director, Alzheimer=C2=B4s Project Argentina
TE 0054 3442 431442 stopalz@gmail.com www.stopalz.org