Biology Reference
In-Depth Information
A great deal of effort is now focused on characterizing the status
and ultimate fate of cells in the penumbra and the relatively
unaffected tissue further outward: those that have not yet been
committed down a particular death pathway or have not gone past
the “point of no return” within a particular pathway, and are still
within therapeutic reach ( 1 ). In theory, specifi c targeting of the
appropriate pathways at the appropriate times could potentially
save the majority of the tissue in this region. While some progress
has been made in this area, accomplishing this goal will require an
accurate picture not only of the identity and relative extent to
which each type of pro-death pathway is activated but also of how
the timing of each occurs relative to the expansion of a particular
lesion. It is becoming increasingly clear that timing is an important
factor in the accurate measurement of different pro-survival and
pro-death signaling pathways.
Not only has it become apparent that several types of regulated
cell death pathways can be triggered by an ischemic insult, but that
they can, at least to some extent, cross-regulate each other.
Supporting this idea, mixed types of cell death have been reported
after a hypoxic, ischemic, or metabolic insult ( 2-8 ). Mixed cell
death can refer either to different forms of cell death (i.e., apoptosis
and necrosis) occurring in different or in the same cells, or to a
transition in the same cell from one type of cell death pathway into
another (e.g., a continuum from necrosis to apoptosis or vice versa)
( 9 ). A number of names describing similar or distinct forms of
mixed cell death have appeared in the literature in recent years,
including necroptosis, necrapoptosis, apopnecrosis, programmed
necrosis, and hybrid death ( 3, 4, 10-14 ). While each refers to a specifi c
or unique aspect of cell death or mechanism, all imply an interaction
between oncotic, necrotic, and apoptotic pathways. The recent infl ux
of terms for mixed cell death has challenged us to derive an accurate
and comprehensive classifi cation of the various forms of cell death.
This situation should improve as we gain a better understanding
of the mechanistic basis for various pathways. We prefer the term
“hybrid cell death” because it encompasses all types of mixed cell
death, and does not introduce new terms into the fi eld.
A detailed understanding of pathway intermediates and their
regulation may offer the possibility of developing novel, specifi c,
and more effi cacious therapies against ischemia-induced brain
damage. Our notion, therefore, of “salvageable tissue” will likely
need to be revised to expand beyond the penumbra in order to
include more of the necrotic core. In addition, it is entirely possible
in the near future that we may be able to rescue far more at-risk
ischemia-challenged tissue in the central nervous system (CNS)
than we previously thought was possible. In this chapter we attempt
to collect in one place a wide range of information on the charac-
teristics, mechanisms and consequences of various experimental
models of ischemia in the mammalian CNS. Rather than offer an
Search WWH ::




Custom Search