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Sources: Paul R, et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med 2001;7:222-227. Marshall JW, et al. NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke 2001;32:190-198.
Despite extensive promising data in animal research, no drug has shown benefit in humans as a neuroprotective agent in an evolving acute ischemic stroke. The experiments by Paul and colleagues, but less by Marshall and colleagues, represent important and encouraging departures from these previously failed treatment strategies. In the first report, Paul et al studied PP1, in mice, a drug that dampens the early edema and microvascular compression that accompanies the beginning abnormalities of acute stroke. The second study reports that NXY-059, a free radical spin trap agent, reduces both infarct size and clinical morbidity from stroke. Marshall et al used a primate rather than a rodent stroke model.
The brain produces vascular endothelial growth factor (VEGF) in response to ischemia and promotes vascular permeability with both cytotoxic and vasogenic brain edema. This process is mediated by the Src kinases, a family of enzymes that regulate VEGF induced vasoreactivity. Paul et al demonstrate that mice lacking the pp60 (Src) gene develop reduced infarct volumes compared to wild-type animals subjected to middle cerebral artery (MCA) occlusion. Paul et al further show that application of a Src inhibitor (PP1) reduces infarct volumes by about 70% when delivered 15 minutes after stroke. When administered up to six hours after stroke, smaller, but still impressive, 40% reductions in stroke size developed. Stroke volumes measured histologically were confirmed by MRI and clinical scales. Perhaps more importantly, mice treated with PP1 showed improved cerebral blood flow. As Paul et al and Marshall et al indicate, by inhibiting VEGF induced brain edema, PP1 likely decreased extrinsic compression of surrounding microvasculature, thereby permitting more robust flow and oxygen supply into the peri-infarct ischemic penumbra.
Presently established approaches to the treatment of acute stroke involve either restoration of blood flow, such as with intravenous or intra-arterial tPA, or aim at neuroprotection involving agents to mitigate glutamate or NMDA receptor-associated excitotoxic cell death. PP1 represents a hybrid of these strategies, in that it reduces VEGF-associated osmotic edema and facilitates blood flow, but works on a cellular or microvascular, rather than a macrovascular, level. As such, it might extend the therapeutic window, and be helpful at time points substantially later than existing "neuroprotective" agents. Whereas the cascade of excitotic cell death may normally become irreversible after the first minutes following stroke, this novel dynamic process of edema and microvascular compression may either ameliorate the injury for six hours or even permanently reduce the size of the infarction.
It is well recognized that free radical production plays a major role in cerebral ischemia. Unfortunately, prior agents, such as Trilazad, a free radical scavenger, have failed to achieve benefit in human trials. NXY-059 and other agents known as free radical spin traps, function by a different mechanism than Trilazad. Many have shown promising data on rodent trials but not at the bedside.
Marshall et al uniquely studied NXY-059, a novel nitrone with radical-trapping properties that provide neuroprotective effects in rodents. They have now tested the agent in a MCA occlusion model of 12 marmoset monkeys. The drug was given five minutes after permanently occluding the right MCA in a dose known to be tolerable in humans. Treated monkeys showed better functional activity with their hemiparetic arm at three and 10 weeks following stroke. Even more importantly, cognitive abnormalities, such as visual-spatial dysfunction and hemineglect, improved markedly in treated animals compared with controls. Animals were asked to locate food in tubes aligned in front of them from left to right, or to reach through slots in plexiglass screens oriented toward the left, right, above, or below. On pathological study, volumes of stroke were reduced by 50% compared to controls. This occurred in both gray and white matter compartments.
As Marshall et al indicate, the drug was given immediately after stroke onset in order to establish efficacy in this primate model, rather than to prove a therapeutic window. Extensive rodent experiments have suggested that NXY-059 is effective up to five hours after stroke onset, although this may not be completely reliable extrapolated to monkeys or to humans.
If monkeys can be tested with much more sophisticated behavioral algorithms than can rodents, drug effects come much more closely to human experience in terms of the challenges faced when rehabilitating from stroke. Also interesting is that NXY-059 was protective for both gray matter (neurons) and white matter (axons). As Paul et al and Marshall et al indicate, even the most promising prior agents based on animal models have shown marked selectivity for the cerebral cortex without providing any benefit for the white matter. Human strokes are heterogeneous, affecting not only the cortex, but also subcortical white matter or deep tracts within the internal capsule and brainstem. NXY-059 may or may not, therefore, act more globally within the brain, targeting a wider variety of brain structures.
These two reports focus on finally ameliorating the post-injury size of acute cerebral infarctions due to sudden cerebral arterial thrombi or emboli. Thrombotic ischemia, depending on size of the artery and its immediately adjacent oxygen-deprived tissue, creates, within a matter of minutes, the beginning of severe pericapillary anoxia. This progressively injures capillary ependema and invokes increased osmols as surrounding cells explode into smaller molecules. Like a slow circular ripple from a relatively small ischemic center, the process swells and steadily squeezes the enlarging penumbral zone of the beginning, relatively small, infarct. For the next 48 hours or more, the ultimate damage becomes ever larger than the initial artery’s region of supply simply because of the unyielding adjacent tissue, dural mater, and skull. Both these abstracts approach this physiological enemy of osmotic swelling and one may turn out to have considerable reduction of brain damage due to cerebral thrombosis.
Having said the above, however, the Marshall et al report possesses a serious fault. Namely, they applied their therapeutic agent within five minutes after clamping the middle cerebral artery of their monkeys. Many claims for success in stroke are based on giving animals various forms of pharmacological agents before or within a few minutes after onset. All but tPA have failed. It seems regrettable to use monkeys for an experiment that fails to provide a significant protocol that can change clinical therapy. —Alan Segal