The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

Abstract

Stroke not only causes initial cell death, but also a limited process of repair and recovery. As an overall biological process, stroke has been most often considered from the perspective of early phases of ischemia, how these inter-relate and lead to expansion of the infarct. However, just as the biology of later stages of stroke becomes better understood, the clinical realities of stroke indicate that it is now more a chronic disease than an acute killer. As an overall biological process, it is now more important to understand how early cell death leads to the later, limited recovery so as develop an integrative view of acute to chronic stroke. This progression from death to repair involves sequential stages of primary cell death, secondary injury events, reactive tissue progenitor responses, and formation of new neuronal circuits. This progression is radial: from the tissue that suffers the infarct secondary injury signals, including free radicals and inflammatory cytokines, radiate out from the stroke core to trigger later regenerative events. Injury and repair processes occur not just in the local stroke site, but are also triggered in the connected networks of neurons that had existed in the stroke center: damage signals are relayed throughout a brain network. From these relayed, distributed damage signals, reactive astrocytosis, inflammatory processes, and the formation of new connections occur in distant brain areas. In short, emerging data in stroke cell death studies and the development of the field of stroke neural repair now indicate a continuum in time and in space of progressive events that can be considered as the 3 Rs of stroke biology: radial, relayed, and regenerative.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…Stroke triggers new connections to form in motor, somatosensory, and premotor cortex adjacent to the stroke site, and in projections from cortex contralateral to the stroke site into distant connections in the striatum, midbrain, and spinal cord 11, 12, 13, 27, 28, 29, 30, 31, 32. In both the cortex contralateral to the stroke, and ipsilateral or peri‐infarct cortex, animal models indicate that axonal sprouting establishes new patterns of connections that are causally linked to recovery.…”

“…These studies come from several distinct models of stroke in rats, mice, and primates. Axonal sprouting cannot be definitively identified yet in human imaging studies, but the most extensive cortical remapping after stroke occurs in the same functional systems and relative areas of peri‐infarct cortex that undergo axonal sprouting in primates, rats, and mice 12. Also, the paradigmatic axonal sprouting marker GAP43 was first studied in its association with human stroke, where is induced in peri‐infarct tissue 34…”

“…Axonal connections are confined by the expression of glial growth inhibitory molecules, such as NogoA, EphrinA5, and chondroitin sulfate proteoglycans 11, 12, 27, 28, 29, 30, 31, 32, 33. Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13. Outside of stroke, behavioral activity in the normal adult brain, such as overuse or learning in a forelimb task, induces local changes in synaptic connections on a small scale within the corresponding motor cortex 33, 40, 41.…”

“…Axonal sprouting from the cortex contralateral to large strokes occurs in the projection from sensorimotor regions to the cervical spinal cord. This axonal sprouting response is into the portion of the cervical spinal cord that lost its corticospinal projection from the stroke site 12, 27. Blocking the myelin growth inhibitory protein NogoA or stimulating axonal sprouting with inosine enhances this axonal sprouting response 27, 28, 29, 30, 31.…”

“…These individual neural repair events interact in the aggregate and evolve over time to produce properties that are different, larger, and more important than the properties of the single reactive astrocyte or migrating neuroblast. In a definitional sense, the formation of new neurons,6, 7, 8 new oligodendrocytes,9, 10 or new connections11, 12, 13 has been interchangeably described as “repair” or “regeneration.” Both terms connote a process of renewal and growth of tissues after injury, and are literally true in a limited fashion in the central nervous system (CNS) after injury 12. This review will discuss emergent properties of neural repair from the epidemiology of stroke to the synapse, highlighting areas of clinical translation opportunity.…”