A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

Abstract

Abstract-The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy. Key Words: neuroprotection Ⅲ neurogenesis Ⅲ reactive microglia Ⅲ stroke P reviously, we have demonstrated that central nervous system (CNS) trauma spontaneously evokes a beneficial, T-cell-mediated immune response, which reduces neuronal loss. 1 In the damaged CNS tissue, CNS-specific T cells accumulate and become reactivated on recognizing and interacting with their corresponding autoantigens presented to them by local antigen-presenting cells. 2,3 This in turn leads to the production of specific neurotrophic factors (eg, brainderived neurotrophic factor) by T cells, and to the proper activation of microglia/macrophages. 4,5 Enhancing the activity of CNS-specific T cells (by a well-regulated passive or active immunization) was found to be beneficial in various animal models of CNS injuries. 6 -8 The ability to maintain autoimmunity in healthy individuals, without developing autoimmune disease, was shown to be regulated by naturally occurring CD4 ϩ CD25 ϩ regulatory T cells. However, recovery from CNS injury can benefit from a transient elimination or decreased activity of these cells. 9 Compounds that can downregulate the constitutive suppression of regulatory T cells (Treg) were therefore considered by us as potential candidates.We found that poly-YE, a high-molecular-weight (22 to 45 kDa) copolymer that was shown to exert modulatory effects on the immune system, 10,11 is capable of downregulating the activity of the regulatory T cells, and used this copolymer to facilitate the spontaneous response of effector T cells recognizing antigens associated with a ...

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Intravascular cell replacement therapy for stroke

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Immune System Involvement in the Degeneration, Neuroprotection, and Restoration after Stroke

“…In the same way, Poli-Y immunomodulator has also shown an increment in cortical and hippocampal neurogenesis, as well as reduction of neural loss [88].…”

“…"fter subjecting rats to experimental stroke, those treated with poly-YE presented diminished infarct size and neurological deicit [88].…”