Neuroprotection of Remotely Administered Hypothermia on Spleen in Ischemic Stroke

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In spite of decades of research, stroke therapies are limited to recanalization therapies that can only be used on < 10% of stroke patients; the vast majority of stroke patients cannot be treated by these methods. Even if recanalization is successful, the outcome is often poor due to subsequent reperfusion injury. A major damage mechanism operating in stroke is inflammatory injury due to excessive pro-inflammatory cascades. Our long- term research goal is to develop effective neuroprotection strategies to lengthen the therapeutic window and prevent brain damage after reperfusion. We propose here a novel, high risk/high reward approach of Remotely Administered Hypothermia (RAH) to mitigate inflammatory injury by inducing spleen hypothermia to suppress pro-inflammatory mediators in the acute phase of stroke, and thereby reduce brain injury and improve functional outcomes. Many studies have shown that, after stroke, splenic inflammatory cells, including neutrophils, monocytes/macrophages, and lymphocytes, are released and infiltrate the brain, heightening brain inflammation and exacerbating ischemia/reperfusion injury. Clinical studies have observed spleen contraction in acute stroke patients where functional outcome improved with the gradual recovery of spleen volume. These observations are supported by stroke animal studies showing spleen volume decrease during the acute phase of middle cerebral artery occlusion (MCAO), and transfer of splenocytes to stroke-injured brain areas. Activation and release of splenic cells is upstream of excessive brain inflammation in stroke. Therefore, regulation of splenic activity offers a therapeutic target for decreasing brain inflammation and improving stroke outcomes . Animal studies however, often use irreversible manipulations of the spleen, such as splenectomy or radiation-induced inhibition of spleen function, which clearly are not clinically practical. Here we use the rat MCAO model to investigate our novel approach to reversibly suppresses spleen inflammatory activity in the acute phase of stroke by administering spleen hypothermia to mitigate excessive brain inflammation. The powerful neuroprotective effect of hypothermia has long been recognized in focal ischemic stroke. However, the clinical use of whole-body hypothermia is limited due to adverse side effects. Our novel RAH of spleen does not have these adverse side effects and is effective at decreasing brain inflammation, reducing infarct volume, and improving functional outcomes. This high risk/high reward approach, in which contemporaneous in situ reperfusion and remote administration of neuroprotective therapy (spleen hypothermia) is readily clinically translatable. Successful completion of the proposed studies will lay the foundation for treating stroke patients with a reversible inhibition of proinflammatory spleen function that will preserve the positive benefits of spleen function in the post-acute phase of stroke.