Targets for Neural Repair Therapies After Stroke

A couple paragraphs from this one, complete paper at the URL. You need to know about this.
http://stroke.ahajournals.org/content/41/10_suppl_1/S124.full

1. S. Thomas Carmichael, MD, PhD

+ Author Affiliations

1. From the Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, Calif.

1. Correspondence to S. Thomas Carmichael, MD, PhD, Associate Professor, Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095. E-mail scarmichael@mednet.ucla.edu

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Abstract

Studies of neural repair after stroke have developed from a relatively small number of laboratories doing highly creative discovery science to a field in which reproducible evidence supports distinct pathways, processes, and molecules that promote recovery. This review focuses on some emerging targets for neural repair or recovery in stroke and on their limitations.

Key Words:

• adhesion molecules
• astrocytes
• basic science
• matrix proteins
• neuroregeneration
• stroke recovery
• trophic factors

Stroke induces a process of axonal sprouting in neighboring or connected cortical neurons that is associated with repair and recovery.^1–3 Adult central nervous system (CNS) myelin or adult oligodendrocytes contain several inhibitors of axonal sprouting. These include the myelin-associated proteins Nogo, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein (MAG).^4,5 Nogo has emerged as a key axonal growth inhibitory protein. Pharmacological blockade of Nogo induces axonal sprouting and functional recovery in spinal cord injury^4,5 and in stroke.⁶ Nogo inhibits axonal growth through Nogo receptor 1, a glycosyl-phosphoinositide linked protein, and through the recently described immunoglobulin receptor PIR1.⁷ NgR1 signals through the tumor necrosis factor family members TROY or p75 and Lingo-1.^4,5 Several groups have developed soluble Nogo antagonists, often receptor decoys or peptide antagonists,⁸ or Lingo-1 antagonists.⁹ A Nogo blocking antibody is currently in clinical trials in spinal cord injury as delivered into the cerebrospinal fluid intrathecally.¹⁰ A small Nogo antagonist peptide has shown promise in preclinical stroke and spinal cord injury models.^6,11

MAG and oligodendrocyte myelin glycoprotein clearly block axonal outgrowth in vitro, but their role in in vivo axonal growth inhibition in the adult is less clear. Genetic knockout of MAG does not promote axonal outgrowth in vivo.^4,5 Oligodendrocyte myelin glycoprotein knockouts do not selectively support axonal sprouting in isolation.¹² Thus, therapies directed toward these 2 molecules do not have strong preclinical support in vivo. Still, an anti-MAG antibody is in clinical trial,¹³ perhaps reflecting interest driven by the strong in vitro action of MAG. When combined with Nogo knockout, the triple elimination of all 3 myelin inhibitors promotes greater axonal outgrowth and functional recovery than Nogo knockout alone.¹⁴ This suggests a degree of compensation within myelin signaling that may provide for adjunctive therapies in stroke or spinal cord injury. A receptor decoy that consists of NgR1 and NgR2 motifs that blocks Nogo, MAG, and oligodendrocyte myelin glycoprotein interactions with NgR1 and NgR2 has been developed and enhances axonal outgrowth in vitro.