Abstract
Considerable strides in medical interventions during the acute phase of traumatic brain injury (TBI) have brought improved overall survival rates. However, following TBI, people often face ongoing, persistent and debilitating long-term complications. Here, we review the recent literature to propose possible mechanisms that lead from TBI to long-term complications, focusing particularly on the involvement of a compromised blood–brain barrier (BBB). We discuss evidence for the role of spreading depolarization as a key pathological mechanism associated with microvascular dysfunction and the transformation of astrocytes to an inflammatory phenotype. Finally, we summarize new predictive and diagnostic biomarkers and explore potential therapeutic targets for treating long-term complications of TBI.
Key points
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Spreading depolarization (SD) is a hallmark of the immediate electrophysiological brain response to traumatic brain injury (TBI).
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SD induces mitochondrial injury preferentially in the cellular elements of the vascular system, leading to breakdown of the blood–brain barrier (BBB).
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BBB dysfunction can last for days to months or even years after TBI and might be associated with oedema, astrocytic and microglial activation, neuroinflammation, extracellular matrix alterations and modification of neuronal networks.
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BBB dysfunction contributes to the long-term neurological complications of TBI, including facilitated brain ageing, cognitive impairments, depression and post-traumatic epilepsy.
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Emerging methods for the assessment of SDs, mitochondrial dysfunction, neuroinflammation and BBB integrity, together with new treatment strategies that aim to facilitate repair of the neurovascular unit, offer new hope for the prevention of TBI-related complications.
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References
Maas, A. I. R. et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 16, 987–1048 (2017).
James, S. L. et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 56–87 (2019).
Dewan, M. C. et al. Estimating the global incidence of traumatic brain injury. J. Neurosurg. 130, 1080–1097 (2019).
Cnossen, M. C. et al. Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in 66 neurotrauma centers participating in the CENTER-TBI study. Crit. Care 21, 233 (2017).
Dash, H. H. & Chavali, S. Management of traumatic brain injury patients. Korean J. Anesthesiol. 71, 12–21 (2018).
Valente, J. H. et al. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with mild traumatic brain injury: approved by ACEP Board of Directors, February 1, 2023 Clinical Policy Endorsed by the Emergency Nurses Association (April 5, 2023). Ann. Emerg. Med. 81, e63–e105 (2023).
Bosch, M. et al. Implementing evidence-based recommended practices for the management of patients with mild traumatic brain injuries in Australian emergency care departments: study protocol for a cluster randomised controlled trial. Trials 15, 281 (2014).
Adelson, P. D., Alali, A. S. & Calland, J. F. American College of Surgeons Trauma Quality Improvement Program Guidelines, Best Practices in the Management of Traumatic Brain Injury https://www.facs.org/quality-programs/trauma/quality/best-practices-guidelines/ (2015).
Maas, A. I. R. et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 21, 1004–1060 (2022).
Carney, N. et al. Guidelines for the management of severe traumatic brain injury. Neurosurgery 80, 6–15 (2017).
Hawryluk, G. W. J. et al. A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med. 45, 1783–1794 (2019).
Stein, S. C., Georgoff, P., Meghan, S., Mizra, K. & Sonnad, S. S. 150 Years of treating severe traumatic brain injury: a systematic review of progress in mortality. J. Neurotrauma 27, 1343–1353 (2010).
Stein, D. G. Embracing failure: what the phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 29, 1259–1272 (2015).
Alves, J. L., Rato, J. & Silva, V. Why does brain trauma research fail? World Neurosurg. 130, 115–121 (2019).
Hay, J. R., Johnson, V. E., Young, A. M. H., Smith, D. H. & Stewart, W. Blood–brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J. Neuropathol. Exp. Neurol. 74, 1147–1157 (2015).
Weissberg, I. et al. Imaging blood–brain barrier dysfunction in football players. JAMA Neurol. 71, 1453–1455 (2014).
Veksler, R. et al. Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players. Brain 143, 1826–1842 (2020).
van Vliet, E. A. et al. Long-lasting blood–brain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiol. Dis. 145, 105080 (2020).
Shlosberg, D., Benifla, M., Kaufer, D. & Friedman, A. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat. Rev. Neurol. 6, 393–403 (2010).
Chodobski, A., Zink, B. J. & Szmydynger-Chodobska, J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl. Stroke Res. 2, 492–516 (2011).
Tomkins, O. et al. Blood–brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. Neurobiol. Dis. 25, 367–377 (2007).
Dreier, J. P. & Reiffurth, C. The stroke-migraine depolarization continuum. Neuron 86, 902–922 (2015).
Hartings, J. A. et al. Prognostic value of spreading depolarizations in patients with severe traumatic brain injury. JAMA Neurol. 77, 489–499 (2020).
Parker, E. et al. Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction. Brain 145, 2049–2063 (2022).
Serlin, Y., Shelef, I., Knyazer, B. & Friedman, A. Anatomy and physiology of the blood–brain barrier. Semin. Cell Dev. Biol. 38, 2–6 (2015).
Abbott, N. J., Rönnbäck, L. & Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).
van Vliet, E. A., Aronica, E. & Gorter, J. A. Blood–brain barrier dysfunction, seizures and epilepsy. Semin. Cell Dev. Biol. 38, 26–34 (2015).
Hawkins, B. T. & Davis, T. P. The blood–brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173 (2005).
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010).
Rodríguez-Baeza, A., Reina-de la Torre, F., Poca, A., Martí, M. & Garnacho, A. Morphological features in human cortical brain microvessels after head injury: a three-dimensional and immunocytochemical study. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 273A, 583–593 (2003).
Griffiths, D. R. et al. Chronic cognitive and cerebrovascular function after mild traumatic brain injury in rats. J. Neurotrauma 39, 1429–1441 (2022).
Bhowmick, S., D’Mello, V., Caruso, D., Wallerstein, A. & Abdul-Muneer, P. M. Impairment of pericyte–endothelium crosstalk leads to blood–brain barrier dysfunction following traumatic brain injury. Exp. Neurol. 317, 260–270 (2019).
Aboghazleh, R. et al. Brainstem and cortical spreading depolarization in a closed head injury rat model. Int. J. Mol. Sci. 22, 11642 (2021).
Strong, A. J. et al. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 33, 2738–2743 (2002).
Jeffcote, T. et al. Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. Neurocrit. Care 20, 21–31 (2014).
Aboghazleh, R., Alkhamous, B., Turan, B. & Tuncer, M. C. Spreading depolarization: a phenomenon in the brain. Arch. Ital. Biol. 160, 30–43 (2022).
Dreier, J. P. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat. Med. 17, 439–447 (2011).
Canals, S. et al. Longitudinal depolarization gradients along the somatodendritic axis of CA1 pyramidal cells: a novel feature of spreading depression. J. Neurophysiol. 94, 943–951 (2005).
Dreier, J. P. et al. Correlates of spreading depolarization, spreading depression, and negative ultraslow potential in epidural versus subdural electrocorticography. Front. Neurosci. 13, 373 (2019).
Dreier, J. P. et al. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J. Cereb. Blood Flow Metab. https://doi.org/10.1177/0271678X16654496 (2017).
Somjen, G. G. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol. Rev. 81, 1065–1096 (2001).
Dreier, J. P. et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 129, 3224–3237 (2006).
Hartings, J. A. et al. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol. 10, 1058–1064 (2011).
Woitzik, J. et al. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 80, 1095–1102 (2013).
Sramka, M., Brozek, G., Bures, J. & Nádvorník, P. Functional ablation by spreading depression: possible use in human stereotactic neurosurgery. Appl. Neurophysiol. 40, 48–61 (1977).
Avoli, M. et al. Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro. Ann. Neurol. 30, 589–596 (1991).
Fabricius, M. et al. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain 129, 778–790 (2006).
Dohmen, C. et al. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann. Neurol. 63, 720–728 (2008).
Mohammad, L. M. et al. Spreading depolarization may represent a novel mechanism for delayed fluctuating neurological deficit after chronic subdural hematoma evacuation. J. Neurosurg. 134, 1294–1302 (2021).
Jing, J., Aitken, P. G. & Somjen, G. G. Interstitial volume changes during spreading depression (SD) and SD-like hypoxic depolarization in hippocampal tissue slices. J. Neurophysiol. 71, 2548–2551 (1994).
Müller, M. & Somjen, G. G. Intrinsic optical signals in rat hippocampal slices during hypoxia-induced spreading depression-like depolarization. J. Neurophysiol. 82, 1818–1831 (1999).
Revah, O., Lasser-Katz, E., Fleidervish, I. A. & Gutnick, M. J. The earliest neuronal responses to hypoxia in the neocortical circuit are glutamate-dependent. Neurobiol. Dis. 95, 158–167 (2016).
Nilsson, P. et al. Epileptic seizure activity in the acute phase following cortical impact trauma in rat. Brain Res. 637, 227–232 (1994).
Folkersma, H. et al. Increased cerebral (R)-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study. J. Neuroinflammation 8, 67 (2011).
Vespa, P. et al. Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury: a microdialysis study. J. Neurosurg. 89, 971–982 (1998).
Palmer, A. M., Marion, D. W., Botscheller, M. L., Bowen, D. M. & DeKosky, S. T. Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. NeuroReport 6, 153–156 (1994).
Gáspár, O. et al. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability. Drug Des. Dev. Ther. 7, 981–987 (2013).
Parker, P. D. et al. Non-canonical glutamate signaling in a genetic model of migraine with aura. Neuron 109, 611–628.e8 (2021).
Enger, R. et al. Dynamics of ionic shifts in cortical spreading depression. Cereb. Cortex 25, 4469–4476 (2015).
Andrew, R. D. et al. Questioning glutamate excitotoxicity in acute brain damage: the importance of spreading depolarization. Neurocrit. Care 37, 11–30 (2022).
Jalini, S., Ye, H., Tonkikh, A. A., Charlton, M. P. & Carlen, P. L. Raised intracellular calcium contributes to ischemia-induced depression of evoked synaptic transmission. PLoS One 11, e0148110 (2016).
Fayuk, D., Aitken, P. G., Somjen, G. G. & Turner, D. A. Two different mechanisms underlie reversible, intrinsic optical signals in rat hippocampal slices. J. Neurophysiol. 87, 1924–1937 (2002).
Balestrino, M., Young, J. & Aitken, P. Block of (Na+, K+)ATPase with ouabain induces spreading depression-like depolarization in hippocampal slices. Brain Res. 838, 37–44 (1999).
Kirov, S. A., Fomitcheva, I. V. & Sword, J. Rapid neuronal ultrastructure disruption and recovery during spreading depolarization-induced cytotoxic edema. Cereb. Cortex 30, 5517–5531 (2020).
Kager, H., Wadman, W. J. & Somjen, G. G. Conditions for the triggering of spreading depression studied with computer simulations. J. Neurophysiol. 88, 2700–2712 (2002).
Lindquist, B. E. & Shuttleworth, C. W. Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices. Neuroscience 223, 365–376 (2012).
Lindquist, B. E. & Shuttleworth, C. W. Evidence that adenosine contributes to Leao’s spreading depression in vivo. J. Cereb. Blood Flow Metab. 37, 1656–1669 (2016).
Murai, S. et al. Depolarization time and extracellular glutamate levels aggravate ultraearly brain injury after subarachnoid hemorrhage. Sci. Rep. 12, 10256 (2022).
Mosley, N. et al. Cortical spreading depolarization, blood flow, and cognitive outcomes in a closed head injury mouse model of traumatic brain injury. Neurocrit. Care 37, 102–111 (2022).
Von Baumgarten, L., Trabold, R., Thal, S., Back, T. & Plesnila, N. Role of cortical spreading depressions for secondary brain damage after traumatic brain injury in mice. J. Cereb. Blood Flow Metab. 28, 1353–1360 (2008).
Aiba, I. & Noebels, J. L. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci. Transl. Med. 7, 282ra46 (2015).
Hosseini-Zare, M. S., Gu, F., Abdulla, A., Powell, S. & Žiburkus, J. Effects of experimental traumatic brain injury and impaired glutamate transport on cortical spreading depression. Exp. Neurol. 295, 155–161 (2017).
Leo, L. et al. Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet. 7, e1002129 (2011).
Reiffurth, C., Alam, M., Zahedi-Khorasani, M., Major, S. & Dreier, J. P. Na+/K+-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes. J. Cereb. Blood Flow Metab. 40, 622–638 (2020).
Hartings, J. A. et al. Spreading depolarizations and late secondary insults after traumatic brain injury. J. Neurotrauma 26, 1857–1866 (2009).
Dreier, J. P. et al. Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135, 259–275 (2012).
Shuttleworth, C. W. et al. Which spreading depolarizations are deleterious to brain tissue? Neurocrit. Care 32, 317–322 (2020).
Frank, R., Bari, F., Menyhárt, Á. & Farkas, E. Comparative analysis of spreading depolarizations in brain slices exposed to osmotic or metabolic stress. BMC Neurosci. 22, 33 (2021).
MacLean, M. A. et al. Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury. Sci. Adv. 9, eadj2417 (2023).
van Hameren, G. et al. Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury. Neurobiol. Dis. 186, 106269 (2023).
Zhao, H. T. et al. Neurovascular dynamics of repeated cortical spreading depolarizations after acute brain injury. Cell Rep. 37, 109794 (2021).
Lückl, J. et al. The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex. Brain 141, 1734–1752 (2018).
Kramer, D. R., Fujii, T., Ohiorhenuan, I. & Liu, C. Y. Interplay between cortical spreading depolarization and seizures. Stereotact. Funct. Neurosurg. 95, 1–5 (2017).
Revankar, G. S. et al. in Seizures in Critical Care: A Guide to Diagnosis and Therapeutics Vol. 77 (Springer, 2017).
Marino, S., Marani, L., Nazzaro, C., Beani, L. & Siniscalchi, A. Mechanisms of sodium azide-induced changes in intracellular calcium concentration in rat primary cortical neurons. Neurotoxicology 28, 622–629 (2007).
Pisani, A. et al. Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine. Epilepsia 45, 719–728 (2004).
Dietz, R. M., Weiss, J. H. & Shuttleworth, C. W. Zn2+ influx is critical for some forms of spreading depression in brain slices. J. Neurosci. 28, 8014 (2008).
Dreier, J. P. et al. How spreading depolarization can be the pathophysiological correlate of both migraine aura and stroke. Acta Neurochir. Suppl. 120, 137–140 (2015).
Foreman, B. et al. The relationship between seizures and spreading depolarizations in patients with severe traumatic brain injury. Neurocrit. Care 37, 31–48 (2022).
Tamim, I. et al. Spreading depression as an innate antiseizure mechanism. Nat. Commun. 12, 2206 (2021).
Dreier, J. P. et al. Is spreading depolarization characterized by an abrupt, massive release of Gibbs free energy from the human brain cortex? Neuroscientist 19, 25–42 (2012).
Hablitz, J. J. & Heinemann, U. Alterations in the microenvironment during spreading depression associated with epileptiform activity in the immature neocortex. Dev. Brain Res. 46, 243–252 (1989).
Van Harreveld, A. & Stamm, J. S. Spreading cortical convulsions and depressions. J. Neurophysiol. 16, 352–366 (1953).
Hubbard, W. B. et al. Acute mitochondrial impairment underlies prolonged cellular dysfunction after repeated mild traumatic brain injuries. J. Neurotrauma 36, 1252–1263 (2019).
Zhou, N., Gordon, G. R. J., Feighan, D. & MacVicar, B. A. Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression. Cereb. Cortex 20, 2614–2624 (2010).
Palzur, E., Edelman, D., Sakas, R. & Soustiel, J. F. Etifoxine restores mitochondrial oxidative phosphorylation and improves cognitive recovery following traumatic brain injury. Int. J. Mol. Sci. 22, 12881 (2021).
Galeffi, F., Somjen, G. G., Foster, K. A. & Turner, D. A. Simultaneous monitoring of tissue PO2 and NADH fluorescence during synaptic stimulation and spreading depression reveals a transient dissociation between oxygen utilization and mitochondrial redox state in rat hippocampal slices. J. Cereb. Blood Flow Metab. 31, 626–639 (2011).
Toglia, P. & Ullah, G. Mitochondrial dysfunction and role in spreading depolarization and seizure. J. Comput. Neurosci. 47, 91–108 (2019).
Kislin, M. et al. Reversible disruption of neuronal mitochondria by ischemic and traumatic injury revealed by quantitative two-photon imaging in the neocortex of anesthetized mice. J. Neurosci. 37, 333–348 (2017).
Lauritzen, M. Pathophysiology of the migraine aura: the spreading depression theory. Brain 117, 199–210 (1994).
Piilgaard, H. & Lauritzen, M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J. Cereb. Blood Flow Metab. 29, 1517–1527 (2009).
Ayata, C. et al. Pronounced hypoperfusion during spreading depression in mouse cortex. J. Cereb. Blood Flow Metab. https://doi.org/10.1097/01.WCB.0000137057.92786.F3 (2004).
Koide, M., Sukhotinsky, I., Ayata, C. & Wellman, G. C. Subarachnoid hemorrhage, spreading depolarizations and impaired neurovascular coupling. Stroke Res. Treat. https://doi.org/10.1155/2013/819340 (2013).
Shin, H. K. et al. Vasoconstrictive neurovascular coupling during focal ischemic depolarizations. J. Cereb. Blood Flow Metab. 26, 1018–1030 (2006).
Strong, A. J. et al. Peri-infarct depolarizations lead to loss of perfusion in ischaemic gyrencephalic cerebral cortex. Brain 130, 995–1008 (2007).
Hinzman, J. M. et al. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 137, 2960–2972 (2014).
Dreier, J. P. et al. Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J. Neurosurg. 93, 658–666 (2000).
Schuh-Hofer, S. et al. The cerebrovascular response to elevated potassium — role of nitric oxide in the in vitro model of isolated rat middle cerebral arteries. Neurosci. Lett. 306, 61–64 (2001).
Tóth, R. et al. Astrocyte Ca2+ waves and subsequent non-synchronized Ca2+ oscillations coincide with arteriole diameter changes in response to spreading depolarization. Int. J. Mol. Sci. 22, 3442 (2021).
Ayata, C. & Lauritzen, M. Spreading depression, spreading depolarization, and the cerebral vasculature. Physiol. Rev. 95, 953–993 (2015).
Kniesel, U. & Wolburg, H. Tight junctions of the blood–brain barrier. Cell. Mol. Neurobiol. 20, 57–76 (2000).
Nag, S., Venugopalan, R. & Stewart, D. J. Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood–brain barrier breakdown. Acta Neuropathol. 114, 459–469 (2007).
Nag, S., Manias, J. L. & Stewart, D. J. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol. 118, 197–217 (2009).
De Bock, M. et al. Into rather unexplored terrain-transcellular transport across the blood–brain barrier. Glia 64, 1097–1123 (2016).
Knowland, D. et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82, 603–617 (2014).
Kang, E. J. et al. Blood–brain barrier opening to large molecules does not imply blood–brain barrier opening to small ions. Neurobiol. Dis. 52, 204–218 (2013).
Tagge, C. A. et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141, 422–458 (2018).
Gursoy-Ozdemir, Y. et al. Cortical spreading depression activates and upregulates MMP-9. J. Clin. Invest. 113, 1447–1455 (2004).
Sadeghian, H. et al. Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis. Ann. Neurol. 84, 409–423 (2018).
Mayhan, W. G. & Didion, S. P. Glutamate-induced disruption of the blood–brain barrier in rats. Stroke 27, 965–970 (1996).
Vazana, U. et al. Glutamate-mediated blood–brain barrier opening: implications for neuroprotection and drug delivery. J. Neurosci. 36, 7727–7739 (2016).
Prager, O. et al. Seizure-induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction. Epilepsia 60, 322–336 (2019).
Yeung, D., Manias, J. L., Stewart, D. J. & Nag, S. Decreased junctional adhesion molecule — a expression during blood–brain barrier breakdown. Acta Neuropathol. 115, 635–642 (2008).
Schmitt, R. et al. Mitochondrial dysfunction and apoptosis in brain microvascular endothelial cells following blast traumatic brain injury. Cell. Mol. Neurobiol. 43, 3639–3651 (2023).
Uddin, M. A. et al. Hsp90 inhibition protects the brain microvascular endothelium against oxidative stress. Brain Disord. 1, 100001 (2021).
Jing, Y. et al. Aloin protects against blood–brain barrier damage after traumatic brain injury in mice. Neurosci. Bull. 36, 625–638 (2020).
Wu, Q. et al. Mdivi-1 alleviates blood–brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int. J. Biochem. Cell Biol. 94, 44–55 (2018).
Sun, J. et al. Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury. Acta Biomater. 140, 573–585 (2022).
Tao, X. et al. Protective actions of PJ34, a poly(ADP-ribose)polymerase inhibitor, on the blood–brain barrier after traumatic brain injury in mice. Neuroscience 291, 26–36 (2015).
Malemud, C. J. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front. Biosci. 11, 1696–1701 (2006).
Sashindranath, M. et al. Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation. Lab. Invest. 91, 1079–1091 (2011).
Guilfoyle, M. R. et al. Matrix metalloproteinase expression in contusional traumatic brain injury: a paired microdialysis study. J. Neurotrauma 32, 1553–1559 (2015).
Rosenberg, G. A. et al. TIMP-2 reduces proteolytic opening of blood–brain barrier by type IV collagenase. Brain Res. 576, 203–207 (1992).
Minta, K. et al. Dynamics of cerebrospinal fluid levels of matrix metalloproteinases in human traumatic brain injury. Sci. Rep. 10, 18075 (2020).
Nichols, P. et al. Blood–brain barrier dysfunction significantly correlates with serum matrix metalloproteinase-7 (MMP-7) following traumatic brain injury. NeuroImage Clin. 31, 102741 (2021).
Harada, K., Suzuki, Y., Yamakawa, K., Kawakami, J. & Umemura, K. Combination of reactive oxygen species and tissue-type plasminogen activator enhances the induction of gelatinase B in brain endothelial cells. Int. J. Neurosci. 122, 53–59 (2012).
Kim, G. W. et al. Neurodegeneration in striatum induced by the mitochondrial toxin 3-nitropropionic acid: role of matrix metalloproteinase-9 in early blood–brain barrier disruption? J. Neurosci. 23, 8733 (2003).
Kuru Bektaşoğlu, P. et al. Neuroprotective effect of plasminogen activator inhibitor-1 antagonist in the rat model of mild traumatic brain injury. Inflammation 44, 2499–2517 (2021).
Muradashvili, N., Benton, R. L., Saatman, K. E., Tyagi, S. C. & Lominadze, D. Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice. Metab. Brain Dis. 30, 411–426 (2015).
Sashindranath, M. et al. The tissue-type plasminogen activator–plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain 135, 3251–3264 (2012).
Griemert, E.-V. et al. Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury. Ann. Neurol. 85, 667–680 (2019).
Kadry, H., Noorani, B. & Cucullo, L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17, 69 (2020).
Takata, F., Nakagawa, S., Matsumoto, J. & Dohgu, S. Blood–brain barrier dysfunction amplifies the development of neuroinflammation: understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front. Cell. Neurosci. 15, 661838 (2021).
Stanimirovic, D. B. & Friedman, A. Pathophysiology of the neurovascular unit: disease cause or consequence. J. Cereb. Blood Flow Metab. https://doi.org/10.1038/jcbfm.2012.25 (2012).
Heinemann, U., Kaufer, D. & Friedman, A. Blood–brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia 60, 1251–1257 (2012).
MacLean, M. A., Kamintsky, L., Leck, E. D. & Friedman, A. The potential role of microvascular pathology in the neurological manifestations of coronavirus infection. Fluids Barriers CNS 17, 55 (2020).
Kaufer, D. & Friedman, A. Damage to a protective shield around the brain may lead to Alzheimer’s and other diseases. Sci. Am. https://www.scientificamerican.com/article/damage-to-a-protective-shield-around-the-brain-may-lead-to-alzheimers-and-other-diseases/ (2021).
George, K. K., Heithoff, B. P., Shandra, O. & Robel, S. Mild traumatic brain injury/concussion initiates an atypical astrocyte response caused by blood–brain barrier dysfunction. J. Neurotrauma 39, 211–226 (2021).
Schachtrup, C. et al. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. J. Neurosci. 30, 5843–5854 (2010).
Ivens, S. et al. TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).
Ralay Ranaivo, H. & Wainwright, M. S. Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. Brain Res. 1313, 222–231 (2010).
Simon, D. W. et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat. Rev. Neurol. 13, 171–191 (2017).
Shohami, E., Novikov, M., Bass, R., Yamin, A. & Gallily, R. Closed head injury triggers early production of TNFa and IL-6 by brain tissue. J. Cereb. Blood Flow Metab 14, 615–619 (1994).
Kovacs, Z. I. et al. Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation. Proc. Natl Acad. Sci. USA 114, E75–E84 (2017).
Ronaldson, P. T. & Davis, T. P. Regulation of blood–brain barrier integrity by microglia in health and disease: a therapeutic opportunity. J. Cereb. Blood Flow Metab. https://doi.org/10.1177/0271678X20951995 (2020).
Kim, H. et al. Reactive astrocytes transduce inflammation in a blood–brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin. Nat. Commun. 13, 6581 (2022).
Kim, S. Y., Buckwalter, M., Soreq, H., Vezzani, A. & Kaufer, D. Blood–brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 53, 37–44 (2012).
Liu, L. et al. Microglial calcium waves during the hyperacute phase of ischemic stroke. Stroke https://doi.org/10.1161/STROKEAHA.120.032766 (2021).
Zhang, J. et al. Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage. Neural Regen. Res. 19, 825–832 (2024).
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B. & el Khoury, J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron https://doi.org/10.1016/j.neuron.2017.07.010 (2017).
Engel, S. et al. Dynamics of microglial activation after human traumatic brain injury are revealed by delayed expression of macrophage-related proteins MRP8 and MRP14. Acta Neuropathol. 100, 313–322 (2000).
Gentleman, S. M. et al. Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci. Int. 146, 97–104 (2004).
Beschorner, R. et al. CD14 expression by activated parenchymal microglia/macrophages and infiltrating monocytes following human traumatic brain injury. Acta Neuropathol. 103, 541–549 (2002).
Mody, I., Lambert, J. D. & Heinemann, U. Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J. Neurophysiol. 57, 869–888 (1987).
Kovács, R., Heinemann, U. & Steinhäuser, C. Mechanisms underlying blood–brain barrier dysfunction in brain pathology and epileptogenesis: role of astroglia. Epilepsia 53, 53–59 (2012).
Beitchman, J. A. et al. Experimental traumatic brain injury induces chronic glutamatergic dysfunction in amygdala circuitry known to regulate anxiety-like behavior. Front. Neurosci. 13, 1434 (2020).
Warren, K. M., Reeves, T. M. & Phillips, L. L. MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. J. Neurotrauma 29, 1922–1940 (2012).
Phillips, L. L., Chan, J. L., Doperalski, A. E. & Reeves, T. M. Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury. Neural Regen. Res. 9, 362–376 (2014).
Aungst, S. L., Kabadi, S. V., Thompson, S. M., Stoica, B. A. & Faden, A. I. Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J. Cereb. Blood Flow Metab. 34, 1223–1232 (2014).
Kim, S. Y., Porter, B. E., Friedman, A. & Kaufer, D. A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy. J. Neurosci. Res. 94, 794–803 (2016).
Pijet, B. et al. Elevation of MMP-9 levels promotes epileptogenesis after traumatic brain injury. Mol. Neurobiol. 55, 9294–9306 (2018).
Frankowski, J. C. et al. Brain-wide reconstruction of inhibitory circuits after traumatic brain injury. Nat. Commun. 13, 3417 (2022).
Hanly, J. G. et al. Resting state functional connectivity in SLE patients and association with cognitive impairment and blood–brain barrier permeability. Rheumatology 62, 685–695 (2023).
Sharp, D. J., Scott, G. & Leech, R. Network dysfunction after traumatic brain injury. Nat. Rev. Neurol. 10, 156–166 (2014).
Vespa, P. M. et al. Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy. Neurology 75, 792–798 (2010).
Swartz, B. E. et al. Hippocampal cell loss in posttraumatic human epilepsy. Epilepsia 47, 1373–1382 (2006).
Dulla, C. G., Coulter, D. A. & Ziburkus, J. From molecular circuit dysfunction to disease: case studies in epilepsy, traumatic brain injury, and Alzheimer’s disease. Neuroscientist 22, 295–312 (2015).
Marchi, N., Granata, T., Ghosh, C. & Janigro, D. Blood–brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53, 1877–1886 (2012).
Cook, C. J. et al. Effective connectivity within the default mode network in left temporal lobe epilepsy: findings from the Epilepsy Connectome Project. Brain Connect. 9, 174–183 (2018).
Fordington, S. & Manford, M. A review of seizures and epilepsy following traumatic brain injury. J. Neurol. 267, 3105–3111 (2020).
Tomkins, O. et al. Blood–brain barrier breakdown following traumatic brain injury: a possible role in posttraumatic epilepsy. Cardiovasc. Psychiatry Neurol. 2011, 765923 (2011).
Izzy, S. et al. Association of traumatic brain injury with the risk of developing chronic cardiovascular, endocrine, neurological, and psychiatric disorders. JAMA Netw. Open 5, e229478 (2022).
Futtrup, J. et al. Blood–brain barrier pathology in patients with severe mental disorders: a systematic review and meta-analysis of biomarkers in case–control studies. Brain Behav. Immun. Health 6, 100102 (2020).
Greene, C., Hanley, N. & Campbell, M. Blood–brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders. Transl. Psychiatry 10, 373 (2020).
Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017).
Oral, E., Halici, Z., Cinar, I., Ozcan, E. & Kutlu, Z. Evaluation of endothelial dysfunction in bipolar affective disorders: serum endocan and urotensin-II levels. Clin. Psychopharmacol. Neurosci. 17, 211–221 (2019).
Kamintsky, L. et al. Blood–brain barrier imaging as a potential biomarker for bipolar disorder progression. Neuroimage Clin. 26, 102049 (2020).
Calkin, C., McClelland, C., Cairns, K., Kamintsky, L. & Friedman, A. Insulin resistance and blood–brain barrier dysfunction underlie neuroprogression in bipolar disorder. Front. Psychiatry 12, 636174 (2021).
Kamintsky, L. et al. Blood–brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment. Ann. Rheum. Dis. 79, 1580–1587 (2020).
Çavuş, I. et al. Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: microdialysis study of 79 patients at the Yale Epilepsy Surgery Program. Ann. Neurol. 80, 35–45 (2016).
Verma, M., Lizama, B. N. & Chu, C. T. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl. Neurodegener. 11, 3 (2022).
Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).
Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).
Senatorov, V. V. et al. Blood–brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction. Sci. Transl. Med. 11, eaaw8283 (2019).
McKee, A. C., Stein, T. D., Kiernan, P. T. & Alvarez, V. E. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 25, 350–364 (2015).
McKee, A. C. et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 131, 75–86 (2016).
Goldstein, L. E. et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci. Transl. Med. 4, 134ra60 (2012).
Doherty, C. P. et al. Blood–brain barrier dysfunction as a hallmark pathology in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 75, 656–662 (2016).
Nation, D. A. et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).
Diaz-Arrastia, R. et al. Acute biomarkers of traumatic brain injury: relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J. Neurotrauma 31, 19–25 (2013).
US Food and Drug Administration. FDA Authorizes Marketing of First Blood Test to Aid in the Evaluation of Concussion in Adults. https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-first-blood-test-aid-evaluation-concussion-adults (2018).
Dreier, J. P. et al. Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study. Brain 145, 1264–1284 (2022).
Eriksen, N. et al. Neurostereologic lesion volumes and spreading depolarizations in severe traumatic brain injury patients: a pilot study. Neurocrit. Care 30, 557–568 (2019).
Hartings, J. A. et al. Improving neurotrauma by depolarization inhibition with combination therapy: a phase 2 randomized feasibility trial. Neurosurgery 93, 924–931 (2023).
Chamanzar, A., Elmer, J., Shutter, L., Hartings, J. & Grover, P. Noninvasive and reliable automated detection of spreading depolarization in severe traumatic brain injury using scalp EEG. Commun. Med. 3, 113 (2023).
Meinert, F. et al. Subdural placement of electrocorticographic electrode array through a burr hole exposure: 2-dimensional operative video. Oper. Neurosurg. 23, e169 (2022).
Meinert, F. et al. Less-invasive subdural electrocorticography for investigation of spreading depolarizations in patients with subarachnoid hemorrhage. Front. Neurol. 13, 1091987 (2023).
Bulstrode, H. et al. Mitochondrial DNA and traumatic brain injury. Ann. Neurol. 75, 186–195 (2014).
Kayhanian, S. et al. Cell-free mitochondrial DNA in acute brain injury. Neurotrauma Rep. 3, 415–420 (2022).
Kilbaugh, T. J. et al. Peripheral blood mitochondrial DNA as a biomarker of cerebral mitochondrial dysfunction following traumatic brain injury in a porcine model. PLoS One 10, e0130927 (2015).
Tang, T. Z. et al. Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model. iScience 27, 108932 (2024).
Visser, K. et al. Blood-based biomarkers of inflammation in mild traumatic brain injury: a systematic review. Neurosci. Biobehav. Rev. 132, 154–168 (2022).
Werhane, M. L. et al. Pathological vascular and inflammatory biomarkers of acute- and chronic-phase traumatic brain injury. Concussion 2, CNC30 (2017).
Hier, D. B. et al. Blood biomarkers for mild traumatic brain injury: a selective review of unresolved issues. Biomark. Res. 9, 70 (2021).
Ceyzériat, K. et al. Reactive astrocytes mediate TSPO overexpression in response to sustained CNTF exposure in the rat striatum. Mol. Brain 16, 57 (2023).
Coughlin, J. M. et al. Imaging of glial cell activation and white matter integrity in brains of active and recently retired national football league players. JAMA Neurol. 74, 67–74 (2017).
Coughlin, J. M. et al. Neuroinflammation and brain atrophy in former NFL players: an in vivo multimodal imaging pilot study. Neurobiol. Dis. 74, 58–65 (2015).
Ramlackhansingh, A. F. et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann. Neurol. 70, 374–383 (2011).
Mahmud, M. et al. Translocator protein PET imaging in temporal lobe epilepsy: a reliable test–retest study using asymmetry index. Front. Neuroimaging 2, 1142463 (2023).
Varlow, C., Knight, A. C., McQuade, P. & Vasdev, N. Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy. Brain Commun. 4, fcac019 (2022).
Czeiter, E. et al. Blood biomarkers on admission in acute traumatic brain injury: relations to severity, CT findings and care path in the CENTER-TBI study. eBioMedicine 56, 102785 (2020).
Helmrich, I. R. A. R. et al. Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI): an observational cohort study. Lancet Neurol. 21, 792–802 (2022).
Yue, J. K. et al. Neuroinflammatory biomarkers for traumatic brain injury diagnosis and prognosis: a TRACK-TBI pilot study. Neurotrauma Rep. 4, 171–183 (2023).
Kumar, R. G., Boles, J. A. & Wagner, A. K. Chronic inflammation after severe traumatic brain injury: characterization and associations with outcome at 6 and 12 months postinjury. J. Head Trauma Rehabil. 30, 369–381 (2015).
Johnson, N. H. et al. Inflammatory biomarkers of traumatic brain injury. Pharmaceuticals 15, 660 (2022).
Kerr, N. et al. Inflammasome proteins as biomarkers of traumatic brain injury. PLoS One 13, e0210128 (2019).
Duan, M., Liu, Y., Li, F., Lu, L. & Chen, Y.-C. Cerebral blood flow network differences correlated with cognitive impairment in mild traumatic brain injury. Front. Neurosci. 16, 969971 (2022).
Lin, C.-M. et al. Arterial spin labeling perfusion study in the patients with subacute mild traumatic brain injury. PLoS One 11, e0149109 (2016).
Barlow, K. M. et al. Cerebral blood flow predicts recovery in children with persistent post-concussion symptoms after mild traumatic brain injury. J. Neurotrauma 38, 2275–2283 (2021).
Gaggi, N. L. et al. Temporal dynamics of cerebral blood flow during the first year after moderate–severe traumatic brain injury: a longitudinal perfusion MRI study. NeuroImage Clin. 37, 103344 (2023).
Khalifa, F. et al. Models and methods for analyzing DCE-MRI: a review. Med. Phys. 41, 124301 (2014).
O’Keeffe, E. et al. Dynamic blood–brain barrier regulation in mild traumatic brain injury. J. Neurotrauma 37, 347–356 (2019).
Ware, J. B. et al. Dynamic contrast enhanced MRI for characterization of blood–brain-barrier dysfunction after traumatic brain injury. NeuroImage Clin. 36, 103236 (2022).
Greene, C. et al. Microvascular stabilization via blood–brain barrier regulation prevents seizure activity. Nat. Commun. 13, 2003 (2022).
Csuka, E. et al. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-α, TGF-β1 and blood–brain barrier function. J. Neuroimmunol. 101, 211–221 (1999).
Zetterberg, H. et al. Neurochemical aftermath of amateur boxing. Arch. Neurol. 63, 1277–1280 (2006).
Shahim, P. et al. Cerebrospinal fluid brain injury biomarkers in children: a multicenter study. Pediatr. Neurol. 49, 31–39.e2 (2013).
Lublinsky, S. et al. Early blood–brain barrier dysfunction predicts neurological outcome following aneurysmal subarachnoid hemorrhage. eBioMedicine 43, 460–472 (2019).
Jewell, S. et al. Development and evaluation of a method for automated detection of spreading depolarizations in the injured human brain. Neurocrit. Care 35, 160–175 (2021).
Klein, P. et al. Repurposed molecules for antiepileptogenesis: missing an opportunity to prevent epilepsy? Epilepsia 61, 359–386 (2020).
Sakowitz, O. W. et al. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke 40, e519–e522 (2009).
Carlson, A. P., Abbas, M., Alunday, R. L., Qeadan, F. & Shuttleworth, C. W. Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J. Neurosurg. 130, 1513–1519 (2019).
Hertle, D. N. et al. Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain 135, 2390–2398 (2012).
Santos, E. et al. Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study. Crit. Care 23, 427 (2019).
Reinhart, K. M., Humphrey, A., Brennan, K. C., Carlson, A. P. & Shuttleworth, C. W. Memantine improves recovery after spreading depolarization in brain slices and can be considered for future clinical trials. Neurocrit. Care 35, 135–145 (2021).
Khan, S., Ali, A. S., Kadir, B., Ahmed, Z. & Di Pietro, V. Effects of memantine in patients with traumatic brain injury: a systematic review. Trauma Care 1, 1–14 (2021).
Muir, K. W. Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr. Opin. Pharmacol. 6, 53–60 (2006).
Morris, G. F. et al. Failure of the competitive N-methyl-d-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. J. Neurosurg. 91, 737–743 (1999).
Maas, A. I. R. et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 5, 38–45 (2006).
Novorolsky, R. J. et al. The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury. J. Cereb. Blood Flow Metab. 40, 1172–1181 (2020).
Chitturi, J., Santhakumar, V. & Kannurpatti, S. S. Traumatic brain injury metabolome and mitochondrial impact after early stage Ru360 treatment. Mitochondrion 57, 192–204 (2021).
Yonutas, H. M. et al. Bioenergetic restoration and neuroprotection after therapeutic targeting of mitoNEET: new mechanism of pioglitazone following traumatic brain injury. Exp. Neurol. 327, 113243 (2020).
Chavez, J. D. et al. Mitochondrial protein interaction landscape of SS-31. Proc. Natl Acad. Sci. USA 117, 15363–15373 (2020).
Zhu, Y. et al. SS-31 provides neuroprotection by reversing mitochondrial dysfunction after traumatic brain injury. Oxid. Med. Cell. Longev. 2018, 4783602 (2018).
Tarantini, S. et al. Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17, e12731 (2018).
Kelsen, J. et al. Copenhagen Head Injury Ciclosporin Study: a phase IIa safety, pharmacokinetics, and biomarker study of ciclosporin in severe traumatic brain injury patients. J. Neurotrauma 36, 3253–3263 (2019).
Hansson, M. J. & Elmér, E. Cyclosporine as therapy for traumatic brain injury. Neurotherapeutics 20, 1482–1495 (2023).
Singh, A., Faccenda, D. & Campanella, M. Pharmacological advances in mitochondrial therapy. eBioMedicine https://doi.org/10.1016/j.ebiom.2021.103244 (2021).
Lassarén, P. et al. Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury. J. Neuroinflammation 18, 221 (2021).
Scott, G. et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain 141, 459–471 (2018).
Robertson, C. S. et al. Phase II clinical trial of atorvastatin in mild traumatic brain injury. J. Neurotrauma 34, 1394–1401 (2016).
Hong, S. et al. Losartan inhibits development of spontaneous recurrent seizures by preventing astrocyte activation and attenuating blood–brain barrier permeability following pilocarpine-induced status epilepticus. Brain Res. Bull. 149, 251–259 (2019).
Bar-Klein, G. et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann. Neurol. 75, 864–875 (2014).
Smyth, L. C. D. et al. Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer’s disease. Commun. Biol. 5, 235 (2022).
Arango-Lievano, M. et al. Topographic reorganization of cerebrovascular mural cells under seizure conditions. Cell Rep. 23, 1045–1059 (2018).
Dreier, J. P., Lemale, C. L., Kola, V., Friedman, A. & Schoknecht, K. Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology 134, 189–207 (2018).
Farkas, E., Pratt, R., Sengpiel, F. & Obrenovitch, T. P. Direct, live imaging of cortical spreading depression and anoxic depolarisation using a fluorescent, voltage-sensitive dye. J. Cereb. Blood Flow Metab. 28, 251–262 (2008).
Dreier, J. P. et al. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-l-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J. Cereb. Blood Flow Metab. 18, 978–990 (1998).
Schwab, N., Leung, E. & Hazrati, L.-N. Cellular senescence in traumatic brain injury: evidence and perspectives. Front. Aging Neurosci. 13, 742632 (2021).
Pertusa, M., García-Matas, S., Rodríguez-Farré, E., Sanfeliu, C. & Cristòfol, R. Astrocytes aged in vitro show a decreased neuroprotective capacity. J. Neurochem. 101, 794–805 (2007).
Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).
Schwab, N. et al. Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner. Front. Neurosci. 16, 1027116 (2022).
Ritzel, R. M. et al. Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice. Neurobiol. Aging 77, 194–206 (2019).
Yamazaki, Y. et al. Vascular cell senescence contributes to blood–brain barrier breakdown. Stroke 47, 1068–1077 (2016).
Preininger, M. K., Zaytseva, D., Lin, J. M. & Kaufer, D. Blood–brain barrier dysfunction promotes astrocyte senescence through albumin-induced TGFβ signaling activation. Aging Cell https://doi.org/10.1111/acel.13747 (2023).
Bitto, A. et al. Stress-induced senescence in human and rodent astrocytes. Exp. Cell Res. 316, 2961–2968 (2010).
Vallée, A., Lecarpentier, Y., Guillevin, R. & Vallée, J.-N. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget 8, 90579–90604 (2017).
Preininger, M. K. & Kaufer, D. Blood–brain barrier dysfunction and astrocyte senescence as reciprocal drivers of neuropathology in aging. Int. J. Mol. Sci. 23, 6217 (2022).
Acknowledgements
The authors thank C. Lemale, S. Mirloo and N. T. Pham for providing their recordings and figures. This work was supported by the Canadian Institutes of Health Research (PJT 180636 and 186067), the Israel Science Foundation (2254/20) and the US–Israel Binational Science Foundation (2021133). In addition, this work was funded by the Citizens United for Research in Epilepsy, doing business as CURE Epilepsy (957373) and the Deanship of the Scientific Research, Al-Balqa Applied University (DSR-2022#484). J.P.D. and A.F. report a grant from the Era-Net Neuron EBio2 with funds from BMBF 01EW2004 and CIHR Award No. NDD 168164. J.P.D. reports a grant from DFG DR 323/10-2.
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van Hameren, G., Aboghazleh, R., Parker, E. et al. From spreading depolarization to blood–brain barrier dysfunction: navigating traumatic brain injury for novel diagnosis and therapy. Nat Rev Neurol 20, 408–425 (2024). https://doi.org/10.1038/s41582-024-00973-9
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DOI: https://doi.org/10.1038/s41582-024-00973-9
