Unraveling axonal mechanisms of traumatic brain injury

Devoto, Victorio Martin Pozo; Lacovich, Valentina; Feole, Monica; Bhat, Pratiksha; Chovan, Jaroslav; Čarná, Mária; Onyango, Isaac G.; Dragišić, Neda; Sűsserová, Martina; Barrios-Llerena, Martin E.; Stokin, Gorazd B.

doi:10.1186/s40478-022-01414-8

Cited by 8 publications

(3 citation statements)

References 79 publications

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“…However, mechanoporation is not required for ionic fluxes to occur across the axolemma. It is well established that TBI leads to an immediate increase in intracellular calcium levels [31,32]. In vitro studies of dynamic stretch within unmyelinated axons show a massive influx of calcium immediately after injury [33][34][35][36], which is relative to the strain applied [35].…”

Section: Axolemmamentioning

confidence: 99%

“…The actin-spectrin skeleton is vulnerable to TBI. In an in vitro axonal injury model, axonal swellings within 50 s of injury developed where there was an increased spacing of the actin-spectrin rings in response to the mechanical force [32]. Furthermore, both α and β-spectrin are vulnerable to proteolysis by calpain and caspase-3, with the αII subunit producing 145/150 kDa and 120 kDa fragments, respectively [55].…”

Section: Sub-axolemmal Proteinsmentioning

confidence: 99%

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Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury

Krieg,

Leonard,

Turner

et al. 2023

Brain Sciences

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Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and secondary biochemical injury phases. Axons comprise an outer cell membrane, the axolemma which is anchored to the cytoskeletal network with spectrin tetramers and actin rings. Neurofilaments act as space-filling structural polymers that surround the central core of microtubules, which facilitate axonal transport. TBI has differential effects on these cytoskeletal components, with axons in the same white matter tract showing a range of different cytoskeletal and axolemma alterations with different patterns of temporal evolution. These require different antibodies for detection in post-mortem tissue. Here, a comprehensive discussion of the evolution of axonal injury within different cytoskeletal elements is provided, alongside the most appropriate methods of detection and their temporal profiles. Accumulation of amyloid precursor protein (APP) as a result of disruption of axonal transport due to microtubule failure remains the most sensitive marker of axonal injury, both acutely and chronically. However, a subset of injured axons demonstrate different pathology, which cannot be detected via APP immunoreactivity, including degradation of spectrin and alterations in neurofilaments. Furthermore, recent work has highlighted the node of Ranvier and the axon initial segment as particularly vulnerable sites to axonal injury, with loss of sodium channels persisting beyond the acute phase post-injury in axons without APP pathology. Given the heterogenous response of axons to TBI, further characterization is required in the chronic phase to understand how axonal injury evolves temporally, which may help inform pharmacological interventions.

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Section: Axolemmamentioning

confidence: 99%

Section: Sub-axolemmal Proteinsmentioning

confidence: 99%

Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury

Krieg,

Leonard,

Turner

et al. 2023

Brain Sciences

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“…It was found that GUO reduced the Ca 2+ -induced mitochondrial dysfunction and ROS production, contributing to restore cell metabolic and energetic homeostasis [71]. However, this finding was obtained in liver mitochondria and needs to be confirmed in cerebral tissue/cells, in which [Ca 2+ ]i changes are prominent as a consequence of traumatic brain injury [72] as well as in neurodegenerative diseases [73].…”

Section: Neuroprotective Effects Of Gbps Mainly Guo Against Brain Oxi...mentioning

confidence: 98%

Influence of Guanine-Based Purines on the Oxidoreductive Reactions Involved in Normal or Altered Brain Functions

Zuccarini

Pruccoli

Balducci

et al. 2023

JCM

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The production of reactive oxygen species (ROS) in the brain is homeostatically controlled and contributes to normal neural functions. Inefficiency of control mechanisms in brain aging or pathological conditions leads to ROS overproduction with oxidative neural cell damage and degeneration. Among the compounds showing therapeutic potential against neuro-dysfunctions induced by oxidative stress are the guanine-based purines (GBPs), of which the most characterized are the nucleoside guanosine (GUO) and the nucleobase guanine (GUA), which act differently. Indeed, the administration of GUO to in vitro or in vivo models of acute brain injury (ischemia/hypoxia or trauma) or chronic neurological/neurodegenerative disorders, exerts neuroprotective and anti-inflammatory effects, decreasing the production of reactive radicals and improving mitochondrial function via multiple molecular signals. However, GUO administration to rodents also causes an amnesic effect. In contrast, the metabolite, GUA, could be effective in memory-related disorders by transiently increasing ROS production and stimulating the nitric oxide/soluble guanylate cyclase/cGMP/protein kinase G cascade, which has long been recognized as beneficial for cognitive function. Thus, it is worth pursuing further studies to ascertain the therapeutic role of GUO and GUA and to evaluate the pathological brain conditions in which these compounds could be more usefully used.

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