NogoA Neutralization Promotes Axonal Restoration After White Matter Injury In Subcortical Stroke

Abstract

Blocking axonal growth inhibitor NogoA has been of great interest for promoting axonal recovery from neurological diseases. The present study investigates the therapeutic effects of blocking NogoA, inducing functional recovery and promoting white matter repair in an experimental animal model of stroke. Adult male rats were subjected to white matter injury by subcortical ischemic stroke. Twenty-four hours after surgery, 250 ug of anti-NogoA or anti-IgG-1 were administered through the tail vein. The quantity of NogoA protein was determined by immunohistochemistry in the brain and peripheral organs. In addition, functional status, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers were analyzed. Moreover, an in vitro study was performed in order to strengthen the results obtained in vivo. A lower quantity of NogoA protein was found in the brain and peripheral organs of the animals that received anti-NogoA treatment. The animals receiving anti-NogoA treatment showed significantly better results in terms of functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group at 28 days. White matter integrity was in part restored by antibody-mediated inhibition of NogoA administration in those animals that were subjected to an axonal injury by subcortical stroke. This white matter restoration triggered functional recovery.

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

“…An improved understanding of the physiological and pathological role of RTNs would allow for the design of rational therapeutic approaches to target neurodegenerative diseases [ 5 ]. Pre-clinical and clinical evidence indicates that Nogo-A or NgR1 inhibitors could be novel drug candidates for some neurodegenerative diseases [ 90 , 103 , 104 ]. Three different antibodies (GSK1223249, NG-101, AXER-204) which effectively restore the function of damaged nerve fibres have been developed.…”

NEP1‑40 promotes myelin regeneration via upregulation of GAP‑43 and MAP‑2 expression after focal cerebral ischemia in rats

“…This inhibition can be reversed by an anti-Nogo-A antibody (3). Previously, available data has attempted to elucidate that inhibition of Nogo-A may promote extensive growth of axons and behavioral recovery after injury (11). However, the exact mechanism underlying Nogo-A failure in myelin repair remains unclear.…”

Pleiotropic Effects of Exosomes as a Therapy for Stroke Recovery

“…Restorative and regenerative therapies to amplify endogenous processes for tissue repair including neurogenesis, angiogenesis, and axonal outgrowth after stroke would be promising as a novel therapeutic strategy. Treatment agents must be delivered to the site of ischemic injury, and many attempts have been made by intravenous injection and stereotactic and intraventricular administration [11][12][13]. In patients with stroke, axons decrease in the peri-infarct area, but they start to regrow at the end of the acute stage, and they are substantially increased in the chronic phase to as much as intact levels [14].…”

“…Cell-based therapy facilitates not only neurogenesis and angiogenesis [15][16][17], but also axonal regeneration, together with oligodendrogenesis [18,19]. On the other hand, pharmacological therapies such as the inhibition of NogoA also enhance axonal outgrowth [11]. Previous studies examined whether Phosphatase and Tensin Homolog Deleted from Chromosome (PTEN)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 beta (GSK-3β) signaling were implicated in the mechanisms of axonal outgrowth in rodent ischemic brains [14,20].…”