Assessment of Cell Death: Apoptosis, Necrosis, or In Between - Animal Models of Acute Neurological Injuries: Injury and Mechanistic Assessments - page 13

exhaustive treatment of each of the many potential topics in this
very broad and complex area, we have tried to compliment the
other information presented in this topic and present a general
overview of each of the generally accepted types of cell death found
in the literature. For most of these, we have provided summaries,
derived from a literature-based consensus, of how an investigator
employing a specifi c experimental model for the fi rst time could
assess the pathophysiological outcome for a particular tissue type.

2. General Points
on Ischemia-
Mediated Cell
Death in CNS
Tissues

Extensive rodent-based animal model studies carried out over the past
25 years have produced several broad generalities about ischemia-
mediated injury to the CNS. These include: (1) tissue/cells most
proximal to the lesion will suffer a catastrophic loss of energy and
structural integrity due to the severity of the insult, and within
minutes or hours undergo necrotic cell death. As the effects of the
insult radiate outward, cellular response will depend a great deal on
a given cell's proximity to the initial site of insult. Necrosis in the
core region is gradually replaced by more regulated/programmed
forms of cell death. In the outer shell of the affected region—the
penumbra—regulated cell death programs, both caspase-dependent
and caspase-independent apoptosis and other types of programmed
cell death (PCD) will begin to predominate. A great deal of effort
is currently being focused on understanding the cellular and molec-
ular biology of the penumbra with an eye towards identifying
the most appropriate therapeutic strategies for this potentially
salvageable tissue; (2) the type(s) and extent of cell death can be
signifi cantly infl uenced by gender ( 15 ), genetic background ( 16 ),
co-morbidities ( 17 ), environment ( 18 ), and developmental stage
( 19 ); (3) many studies have demonstrated that, as a result of the
need to eliminate “excess” neurons (those that fail to establish or
become part of a productive synaptic circuit), apoptosis is more
predominate in prenatal and neonatal stroke or trauma with an
increasing proportion of necrotic (or non-apoptotic cell death) cell
death with age ( 20 ). Recent evidence, however, indicates that even
in the developing brain, PCD may not appear with the typical features
or hallmarks of apoptosis usually seen in cultured cells ( 6 ).

3. General Issues
and Caveats

It is important to bear in mind that many widely employed assess-
ments of cellular viability, such as the measurement of active caspase
3, or TUNEL staining, or (in particular) morphological analysis,