Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of "traumatic penumbra," represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery.

Intranasal human-recombinant NGF administration improves outcome in children with post-traumatic unresponsive wakefulness syndrome

“…Typically, neurons damaged in the primary injury undergo necrotic cell death, while neurons that succumb to secondary injury faced apoptotic cell death. The traumatic penumbra surrounds the primary lesion and represents the portion of damaged brain tissue that can potentially be regenerated [ 44 ]. Neurogenesis and neuronal repair are high during the first month after brain injuries and decreases thereafter [ 45 – 47 ].…”

Mesenchymal “stem” cells, or facilitators for the development of regenerative macrophages? Pericytes at the interface of wound healing

“…More recently, the use of apoptotic MSCs to mitigate sepsis by promotion of M2 polarization in macrophages has been demonstrated (Pan et al, 2022), which suggests that even allogeneic MSCs induced to become apoptotic could be used to treat conditions that could be improved by increasing the number of M2 macrophages. Acute conditions that affect the brain, in which neuroinflammation greatly contributes to a negative outcome (da Silva Meirelles et al, 2017;Regner et al, 2017), represent a scenario in which these strategies may be particularly useful. After acute brain injury, local and systemic inflammatory responses initiate early, and play key roles in the secondary injury progression that evolves to neuronal loss and neurological deficits (Kumar et al, 2017).…”

Prognostic utility of early plasma matrix metalloproteinases -2 and -9 concentrations after severe traumatic brain injury

“…This primary injury triggers a secondary wave of events (i.e., excitoxicity, oxidative stress, metabolic crisis, changes in BBB permeability, inflammatory response, ischemia, and edema), occurring within seconds to minutes after the brain lesion and lasting for days, months, or years. ( 1 , 4 , 7 ) The ongoing brain damage, which is characteristic of secondary injury, evolves to increased intracranial pressure that can culminate in brain death, particularly in the first 72 hours post-trauma. ( 7 )…”

“…( 1 , 4 , 7 ) The ongoing brain damage, which is characteristic of secondary injury, evolves to increased intracranial pressure that can culminate in brain death, particularly in the first 72 hours post-trauma. ( 7 )…”

“…However, the inflammatory pathway signaling molecules involved in brain injury affect the gene transcription of MMPs. ( 7 - 9 ) Matrix metalloproteinases are upregulated in TBI and can degrade crucial components of the cerebrovascular matrix, leading to disruption of the BBB and exacerbation of edema post-TBI. ( 9 ) Several studies in animal models have suggested that MMP-2 and -9, which are inducible MMPs found in the ECM, cerebrospinal fluid, and blood, ( 9 ) play important roles in neuroinflammation and secondary injury progression after TBI.…”