The back and forth of axonal injury and repair after stroke

Abstract

Purpose of review The axon plays a central role in both the injury and repair phases after stroke. This review highlights emerging principles in the study of axonal injury in stroke and the role of the axon in neural repair after stroke. Recent findings Ischemic stroke produces a rapid and significant loss of axons in the acute phase. This early loss of axons results from a primary ischemic injury that triggers a wave of calcium signaling, activating proteolytic mechanisms and downstream signaling cascades. A second progressive phase of axonal injury occurs during the subacute period and damages axons that survive the initial ischemic insult but go on to experience a delayed axonal degeneration driven in part by changes in axoglial contact and axonal energy metabolism. Recovery from stroke is dependent on axonal sprouting and reconnection that occurs during a third degenerative/regenerative phase. Despite this central role played by the axon, comparatively little is understood about the molecular pathways that contribute to early and subacute axonal degeneration after stroke. Recent advances in axonal neurobiology and signaling suggest new targets that hold promise as potential molecular therapeutics including axonal calcium signaling, axoglial energy metabolism and cell adhesion as well as retrograde axonal mitogen-activated protein kinase pathways. These novel pathways must be modeled appropriately as the type and severity of axonal injury vary by stroke subtype. Summary Stroke-induced injury to axons occurs in three distinct phases each with a unique molecular underpinning. A wealth of new data about the molecular organization and molecular signaling within axons is available but not yet robustly applied to the study of axonal injury after stroke. Identifying the spatiotemporal patterning of molecular pathways within the axon that contribute to injury and repair may offer new therapeutic strategies for the treatment of stroke.

Mesenchymal Stromal Cells Promote Axonal Outgrowth Alone and Synergistically with Astrocytes via tPA

“…Axons play a central role in both the injury and repair phases after stroke [39]. The microfluidic chamber provides an excellent system for separating soma and dendrites from axons [35–37].…”

Motor compensation and its effects on neural reorganization after stroke

“…This is accompanied by dendritic restructuring 100–102 and highly coordinated changes in glia and vasculature 13,103,104 , as reviewed elsewhere 105,106 . This regenerative process proceeds in many different brain regions to variable degrees and follows various time courses, depending on the anatomical connectivity of the injured region 107 . Tissue near the core region of damage, and all areas that previously had substantial direct afferent or efferent projections to or from the damaged area, can be expected to undergo regenerative responses, such that even focal stroke results in widespread and bihemispheric changes in synaptic connectivity patterns.…”

Neuropathophysiology of Brain Injury

“…Axonal damage and degeneration occur during the acute and subacute periods following stroke and TBI. 44, 45 Recovery from stroke requires formation of new connections in injured and noninjured tissues that depends on axonal sprouting. There are many trophic and intercellular signaling processes that mediate axonal regeneration and can be targeted pharmacologically or with cell-based therapies to enhance stroke recovery.…”