Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children and adolescents or in the elderly, and it is well known that immune responses and the neuroregenerative capacities of the brain, among other factors, vary over a lifetime. Thus, age-at-injury can influence the consequences of TBI. Furthermore, age-at-injury also influences the pharmacological effects of drugs. However, the post-TBI inflammatory, neuronal and functional consequences have been mostly studied in experimental young adult animal models. The specificity and the mechanisms underlying the consequences of TBI and pharmacological responses are poorly understood in extreme ages. In this review, we detail the variations of these age-dependent inflammatory responses and consequences after TBI, from an experimental point of view. We investigate the evolution of microglial, astrocyte and other immune cells responses, and the consequences in terms of neuronal death and functional deficits in neonates, juvenile, adolescent and aged male animals, following a single TBI. We also describe the pharmacological responses to anti-inflammatory or neuroprotective agents, highlighting the need for an age-specific approach to the development of therapies of TBI.

Whole Body Vibration Attenuates Brain Damage and Neuroinflammation Following Experimental Traumatic Brain Injury

“…As one of the most important mechanisms of TBI, neuroinflammation occurs immediately after the primary injury, and participates in many aspects of the secondary injury. TBI-induced neuroinflammation is a sterile inflammatory response that is characterized by the activation of resident glial cells, recruitment of peripheral immune cells, and the release of inflammatory cytokines ( Nizamutdinov and Shapiro, 2017 ; Delage et al, 2021 ). Following TBI, morphological and functional changes occur within microglia and astrocytes, leading to the disruption of both neuronal-glial and glial-glial interactions ( Bal-Price and Brown, 2001 ).…”

Non-Communicable Neurological Disorders and Neuroinflammation

“…Post-TBI neuroinflammation involves microglia and astrocytes. Microglia activate immediately after the trauma, but may last for a very long time, up to many years post TBI [reviewed in ( 9 , 10 )]. A pro-inflammatory, so-called M1 phenotype, appears first, while an anti-inflammatory, M2, phenotype appears in later stages and may last only for brief periods.…”

“…A pro-inflammatory, so-called M1 phenotype, appears first, while an anti-inflammatory, M2, phenotype appears in later stages and may last only for brief periods. Eventually after up to 5 weeks post-TBI the M1 phenotype may prevail and perpetuate damage and tissue degeneration ( 10 ). A dichotomic view has proposed also for astrocytes, by classifying them in pro-inflammatory (A1) and anti-inflammatory (A2).…”

“…As for microglia, this view may be useful as a simplified model, but is largely overcome by data showing that these cells have several phenotypes according to the different stimuli received. Nevertheless, the activation of pro-inflammatory astrocytes has been reported after TBI, starting from few hours after the injury and persisting for decades ( 10 , 11 ). Neuroinflammatory mechanisms contribute to clear the injured brain and spinal cord of damage and to foster tissue regenerative mechanisms, especially remyelination.…”

“…The consequences of TBI and SCI, however, include cell senescence ( 12 ), that may contribute to secondary injury. While this may be the substrate for neurodegenerative mechanisms secondary to repeated head concussions, this may also explain why the severity of long-term consequences after TBI or SCI is increased in elderly ( 10 , 12 ).…”