Transcript The Role of Calcium in Ischemic Brain Damage:

The Role of Calcium in
Ischemic Brain Damage:
By: Christian Stork
1977; Nicholson et al:
• This research group showed that anoxia
triggers rapid translocation of calcium from
extra to intracellular spaces in neural
tissue.
• This work prompted speculation about why
certain neurons are selectively more
sensitive to ischemia, namely because of
a higher density of calcium channels in
their plasma membranes.
Theory: The Neurotoxic Cascade
• In 1990 Steven Rothman observed that
neurons which were over-exposed to
glutamate produced swelling and began
degeneration in hippocampal cell cultures.
Upon this Rothman predicated that
glutamate toxicity was mediating an
uncontrolled calcium and sodium influx
into post-syn. neurons during hypoxia.
Early explanations:
• John Werth proposed that most current flow
occurs in extracellular space. Tissue resistance
was found to be inversely related to interstitial
volume. So if the tissue swells, then resistance
is elevated in the tissue. Hence, inflammation is
implicated as a damage mediator.
• Werth’s real mark was made by demonstrating
the capacity of MK-801 to delay and diminish
cell swelling, by preventing ion influx, which
decreased resistance in tissues (and halted
inflammation).
The Theoretical Synthesis: A
Mechanism of Ischemic Damage
• A blood vessel is blocked. (Ischemia)
• Downstream neurons release excess glutamate.
• Glutamate binds NMDA receptors, triggering the
excessive influx of Ca, and Na ions.
• This uncontrolled influx of ions poisons postsynaptic neurons which release even more
glutamate which spreads and amplifies the
vicious cycle of neuronal death and destruction.
What about delayed Neuronal
Death?
• 3 schemes have been presented:
– 1. Sustained perturbation of the signal path continues with
changes in kinase and phosphatase activities, then ends with
altered gene and protein expression.
– 2. Cell death is due to sustained perturbation of cell calcium
metabolism, leading to a slow rise in intra-Ca, and eventual
mitochondrial calcium overload.
– 3. This third theory also predicts that ultimate cell damage is due
to mitochondrial failure, but through a different mechanism. The
idea is that mitochondrial movement is along the cytoskeletons is
halted when the cytoskeletons are broken down by calciumactivated proteases, and calcium-dependent microtubule
disassembly. Thus, impaired movement devastates the
mitochondrial capacity to generate ATP.
Themes:
• It is widely accepted that Calcium is one of the
triggers/mediators of ischemic cell death, yet the
mechanism remains to be elucidated.
• During ischemia, the lack of oxygen and glucose
inhibit the cells capacity to both extrude calcium
and sequester it in intracellular stores. All this
evidence does support the idea of a Calcium
Overload chain reaction leading to cell death.
An Exception via Zinc?
• Studies done at Johns Hopkins University
have shown that Zinc ions can enter
excitable cells in a voltage-dependent
manner.
• Not only were the Zinc ions shown to enter
through L-type CALCIUM channels, but
that they mediated voltage dependent
gene expression.
Time for more Studies:
• Demonstrating a clear link between
ischemia/reperfusion and the
accumulation of intracellular Zinc may
pave the road to understanding the likely
role Zinc plays as a second messenger in
mediating cell death post ischemia.
• Conclusions: Further investigation is
crucial to a true understanding of the
phenomenon.