hi all

some more interesting news
with very interesting potential

janet

> ----------------------------------------------------------------------
> Cell structures may be key to diseases
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>
> Copyright 1997 Nando.net
> Copyright 1997 Pittsburgh Post-Gazette
>
> (Mar 18, 1997 01:02 a.m. EST) -- After years of studying the care and
> feeding of brain cells, Ian Reynolds can boil down his advice for
> maintaining a healthy brain to just five words: Be nice to your
> mitochondria.
>
> In a popular culture where mitochondria come up in conversation about
> as often as a politician turns down a campaign contribution, it's not
> likely to challenge "Show me the money" as a catch phrase.
>
> But neuroscientists such as Reynolds increasingly suspect that the
> mitochondria inside nerve cells may prove important in the treatment
> of strokes, brain trauma and such neurodegenerative diseases as
> Parkinson's disease, Alzheimer's disease and Huntington's disease.
>
> Mitochondria are structures within each cell that produce adenosine
> triphosphate, or ATP, a fuel source that keeps the rest of the cell
> running. It is the failure of these tiny mitochondria that seem to
> result in the death of brain cells that underlie all of those
> diseases.
>
> Reynolds, a pharmacologist at the University of Pittsburgh Medical
> Center, last September reported in the Journal of Neuroscience that he
> had found a portion of the mitochondrion that only functions when it
> is about to die.
>
> "We've called this thing a suicide mechanism," said the London-born
> Reynolds, a beefy 37-year-old who has been at Pitt since 1988.
>
> If a drug can be found that kept that mechanism from working, doctors
> might be able to preserve more brain cells -- and thus brain function
> -- following a stroke or brain injury and perhaps slow the progression
> of diseases such as Parkinson's and Alzheimer's.
>
> "People are jumping all over it," Reynolds said of the discovery,
> noting five related research papers have since been published.
>
> "The evidence is not absolutely conclusive," cautioned Dr. Steven
> Rothman, a neurologist at Washington University in St. Louis. But
> mitochondrial changes may well turn out to be a key to new treatments
> for some brain injuries and diseases.
>
> For instance, cyclosporine, a drug widely used to prevent organ
> rejection following transplantation, appears to block the mechanism
> Reynolds described, Rothman said. The combination of the suicide
> mechanism and possible methods of blocking it has made this an
> extremely active area of research, he added.
>
> It all adds to science's understanding of cell death that has
> developed rapidly since the 1980s.
>
> Brain cells, called neurons, can be killed rapidly by cutting off
> their supply of blood and oxygen, as occurs during a stroke or brain
> trauma. Aside from rapidly restoring blood flow, little can be done to
> save those cells. But scientists know that these injuries also can
> trigger processes in the brain that lead to the death of neurons not
> immediately affected by the injury.
>
> It was research by Rothman and other researchers during the 1980s that
> established that these neurons were somehow being poisoned by
> neurotransmitters -- the very chemicals the brain uses to pass
> messages between cells. Further work by researchers such as Dr. Roger
> Simon at the Insitute of Psychiatry in London, now chief of neurology
> at Pitt, showed that the guilty neurotransmitter was glutamate.
>
> Glutamate accounts for about 70 percent of the "excitatory" signals
> transmitted in the brain, Reynolds said. When brain cells die, they
> release massive amounts of glutamate. The released glutamate is picked
> up by other, still healthy cells. The glutamate overwhelms these
> cells, however, overstimulating them and causing them to die.
>
> Neuroscientists have thus concluded that blocking the effects of
> glutamate might prove an effective treatment for stroke and trauma;
> indeed, a number of glutamate blockers or antagonists already are
> being tested in local hospitals on stroke patients. In the case of
> brain trauma, however, research by Pitt's Dr. Donald Marion has shown
> that cooling the body for a day or two can be as effective if not more
> effective than these experimental drugs.
>
> One problem with glutamate-inhibiting drugs is that they block not
> only the unwanted glutamate but all glutamate, including that used in
> normal brain functioning, Reynolds said. That can cause unwanted side
> effects, such as hallucinations.
>
> A better class of drug would block only a chemical or process not
> involved in normal brain function, he noted. The search for such a
> mechanism has drawn Reynolds and his colleagues ever deeper into the
> workings of the cell.
>
> Glutamate, they know, causes calcium to enter the cell, leading to
> cell death. And calcium, it seems, makes a bee line to the
> mitochondria.
>
> The mitochondria convert glucose into ATP, which serves as an energy
> source for the rest of the cell. The calcium signals the mitochondria
> to speed up production of ATP.
>
> But too much calcium eventually upsets the balance of enzymes and
> electrical charges necessary to produce ATP. Production slows to the
> point that the mitochondria begin consuming ATP.
>
> "That's the start of the end for the cell," Reynolds said. At this
> point, his laboratory studies of neurons have shown that something
> called the permeability transition pore opens in the mitochondrion's
> outer membrane, shutting down its operation. As the mitochondria die,
> the cell loses the power to sustain itself and it too dies.
>
> "The only time when we know this 'pore' is turned on is cases when
> the neuron is going to die," Reynolds said. "What we need,
> unquestionably, are drugs to block that thing.
>
> In the case of brain trauma or stroke, a drug that blocked the
> permeability transition pore might keep some cells from dying until
> blood flow was restored and brain chemistry settled down to normal
> within a matter of hours or days, Reynolds said.
>
> In degenerative diseases, such as Alzheimer's or Parkinson's, neurons
> die over a period of years. Each disease is caused by a slightly
> different mechanism, but in each the net effect is to make neurons a
> bit more fragile, so that they are more vulnerable to injuries, or
> changes in oxygen and nourishment that would not affect a healthy
> cell. In these cases, a drug that blocked the permeability transition
> pore might make these cells a bit more resilient to these upsets,
> slowing the progression of the disease.
>
> Though cyclosporine can block the pore, the dosages required are too
> high to be practical, Reynolds said, so another drug will have to be
> discovered or invented before treatment is a reality. And whether such
> a drug would make a difference in clinical use is a matter of
> speculation, he acknowledged.
>
> "It's a theory that's based on reality," Reynolds said. "But we may be
> able to be bold because we're ignorant."
>
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