Prolonged hemorrhagic shock and stroke model

Stroke is common in North America, claiming some 500,000 victims each year. The most common cause is arteriosclerosis, which results in narrowing and obstruction of blood vessels. Red blood cells, being 8 micron in diameter, have difficulty flowing through these partially obstructed vessels to supply the needed oxygen to the brain (Fig. 4.3). PolyHb, being a solution, can perfuse partially obstructed vessels better than red blood cells to supply the needed oxygen. However, when an ischemic brain is perfused with an oxygen-rich solution, reactive oxygen species will be generated, resulting in ischemia-reperfusion injury. These oxygen radicals can lead to increased leakiness of the blood-brain barrier, brain edema and cell death (Fig. 4.3).

The therapeutic agent, PolyHb-SOD-CAT, has the dual function of an oxygen carrier and the ability to remove oxygen radicals.Thus, we used a transient global ischemia-reperfusion rat brain model to compare the use of this PolyHb-SOD-CAT solution with four other oxygen carrying solutions: 1) PolyHb; 2) PolyHb with CAT and CAT added as solution without crosslinking to polyHb; 3) purified Hb; and 4) oxygenated saline solution. Reperfusions are initiated 1 h after ischemia and the effects on blood-brain barrier and brain edema are followed for 6h. Reperfusion with PolyHb-SOD-CAT solution did not result in brain

PolyHb PolyHb-SOD-CAT

Ipfiang, 1964,1971) (D'Agnillo^Ghang 1998)

PolyHb PolyHb-SOD-CAT

Ipfiang, 1964,1971) (D'Agnillo^Ghang 1998)

ARTERIAL OBSTRUCTION: STROKE, INFARCTION, ETC

Red blood celIsO

0? Lack (Ischemia)

PolyHb solution

Supply oxygen, but

Oxygen radicals

polyHb-SOD-CAT solution

Remove oxygen radicals

Fig. 4.3. Stroke is common and in North America and about 500,000 persons suffered from this each year. The most common cause is arteriosclerosis which results in narrowing and obstruction of blood vessels. Red blood cells being 8 micron in diameter have difficulty flowing through these partially obstructed vessels to supply the needed oxygen to the brain. PolyHb being a solution can perfuse partially obstructed vessels better than red blood cells to supply the needed oxygen. However, when an ischemic brain is perfused with an oxygen-rich solution, reactive oxygen species would be generated resulting in ischemia-reperfusion injury. Unlike PolyHb, PolyHb-SOD-CAT has the dual function of an oxygen carrier and the ability to remove oxygen radicals. (Figure adapted from Chang, Nature Rev Drug Discovery, 2005i.)

edema and the effect on blood-brain barrier is minimal. On the other hand, when compared with the sham control, the use of the other four solutions resulted in brain edema and disruption of the blood-brain barriers (BBB). Theses studies show that in this transient global ischemia-reperfusion rat brain model, the PolyHb-SOD-CAT solution can carry oxygen to ischemic brain tissue without causing significant ischemia-reperfusion injury.

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