Assessment of Cell Death: Apoptosis, Necrosis, or In Between - Animal Models of Acute Neurological Injuries: Injury and Mechanistic Assessments - page 18

stress, aging, or disease), has also been shown to play an important
role in neuronal structural integrity and homeostasis. Depending
on the particular stress, and the type and amount of cellular mate-
rial to be recycled, one or more of the three characterized autophagic
pathways can be activated. Damaged protein aggregates or effete
organelles (in particular mitochondria) are subject to lysosomal
degradation, the products of which are then channeled into macro-
molecular synthesis pathways. Autophagic cell death has been
documented in neurodegenerative diseases as well as in the ischemic
penumbra ( 29 ), but its role as a mechanism or consequence of
other forms of cell death (including necrosis), in the latter has not
yet been resolved. There is considerable evidence in lymphoid and
tumor cells for both positive and negative cross-talk between
autophagic and apoptotic pathways, with the former acting to
mitigate damage and promote cell survival (tidy up the mess from
a relatively minor insult) and the latter taking over (and inhibiting
autophagy) when the insult or cellular damage reaches the “point
of no return.” Although the extent to which this crosstalk occurs
in the CNS has not been well documented, down-regulation of
autophagy pathway-specifi c factors, such as Beclin-1, is neuropro-
tective in a rodent model of MCAO ( 30 ). Autophagy has been
documented as well in rodent models of TBI ( 31 ).

4.4. Infl ammation-
Induced PCD

Infl ammation plays a role in all ischemia-mediated pathology in the
CNS, but is particularly acute in traumatic, ischemia/reperfusion,
major focal, and hemorrhagic insults. An infl ammatory response
can be quite complex, expanding and evolving with the maturing
lesion, and involving all components of the neurovascular unit.
Deleterious infl ammatory mediators, such as TNF- , IL-6,

NO, ROS, etc., can participate in the activation of apoptosis,
necroptosis, and PARP-1-mediated cell death; all of these effector
molecules have been shown to be induced in a range of ischemic
insults. Furthermore, plasma levels of a number of well-established
markers of infl ammation are known to rise within hours of an
ischemic episode. Pyroptosis (Greek: pyro , fi re or fever + ptosis , falling
away), an infl ammation-triggered, caspase 1-mediated regulated
cell death program, has received little attention in the stroke litera-
ture. Although this pathway is most associated with a systemic
response to microbial infection, ischemic infl ammatory responses
are often quite signifi cant, and identifying this pathway may aid
in identifying potential therapeutic targets ( 32 ). Although some
late biochemical and morphological markers of apoptosis (nuclear
condensation), necrosis (cellular swelling), can be observed in cells
undergoing pyroptosis, the appearance of activated caspase-1 (also
known as Interleukin-Converting Enzyme or ICE), as well as it's
cleavage products, IL-1

α , IL-1 β

β , and IL-18, are unique to this pathway.