Primary ischemic cell death

In the core of the territory of an occluded brain artery the earliest sign of cellular injury is neuronal swelling or shrinkage, the cytoplasm exhibiting microvacuolat-ion (MV), which ultrastructurally has been associated with mitochondrial swelling [33]. These changes are potentially reversible if blood flow is restored before mitochondrial membranes begin to rupture. One to two hours after the onset of ischemia, neurons undergo irreversible necrotic changes (red neuron or ischemic cell change (ICC)), characterized by condensed acidophilic cytoplasm, formation of triangular nuclear pyknosis and direct contact with swollen astrocytes. Electronmicroscopically mitochondria exhibit flocculent densities which represent denatu-rated mitochondrial proteins. After 2-4 hours, ische-mic cell change with incrustrations appears, which has been associated with formaldehyde pigments deposited after fixation in the perikaryon. Ischemic cell change must be distinguished from artifactual dark neurons which stain with all (acid or base) dyes and are not surrounded by swollen astrocytes (Figure 1.3).

With ongoing ischemia, neurons gradually lose their stainability with hematoxylin; they become mildly eosinophilic and, within 4 days, transform into ghost cells with a hardly detectable pale outline. Interestingly, neurons with ischemic cell change are mainly

Light microscopical characteristics of rat brain infarction Figure 1.3. Light-microscopical evolution of neuronalchanges after Acute ischemic changes experimentalmiddle cerebralocclusion.

Control swelling shrinkage

1 fx

1

i1

C • : •

2 hours sham surgery 4 hours

Necrotic changes red neuron ghost neuron

1 day

3 days

2 hours

Dark neuron artifact

1 day

3 days

sham surgery

Inflammation and cavitation of ischemic infarction

Necrotic neurons, ghosts and PMN leukocytes Necrotic neurons and PMN leukocytes

1.5 days 1.5 days

Lipid-laden macrophages and necrosis Cavitation with sparing of outer cortical layer

subacute infarct cystic infarct

Figure 1.4. Transformation of acute ischemic alterations into cystic infarct. Note pronounced inflammatory reaction prior to tissue cavitation. (Modified from Petito [32].)

located in the periphery and ghost cells in the center of the ischemic territory, which suggests that manifestation of ischemic cell change requires some residual or restored blood flow, whereas ghost cells may evolve in the absence of flow [32].

Primary ischemic cell death induced by focal ischemia is associated with reactive and secondary changes. The most notable alteration during the initial 1-2 hours is perivascular and perineuronal astrocytic swelling; after 4-6 hours the blood-brain barrier breaks down, resulting in the formation of vasogenic edema; after 1-2 days inflammatory cells accumulate throughout the ischemic infarct, and within 1.5 to 3 months cystic transformation of the necrotic tissue occurs together with the development of a peri-infarct astroglial scar.

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