Chronic Upregulation of Cleaved-Caspase-3 Associated with Chronic Myelin Pathology and Microvascular Reorganization in the Thalamus after Traumatic Brain Injury in Rats

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Glushakov, Andriy O.Univ S Florida, Dept Neurosurg, Coll Med, Tampa, FL 33612 USA (author)

Chronic Upregulation of Cleaved-Caspase-3 Associated with Chronic Myelin Pathology and Microvascular Reorganization in the Thalamus after Traumatic Brain Injury in Rats

Article/chapterEnglish2018

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2018-10-13
MDPI,2018
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-369759
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-369759URI
https://doi.org/10.3390/ijms19103151DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Traumatic brain injury (TBI) is associated with long-term disabilities and devastating chronic neurological complications including problems with cognition, motor function, sensory processing, as well as behavioral deficits and mental health problems such as anxiety, depression, personality change and social unsuitability. Clinical data suggest that disruption of the thalamo-cortical system including anatomical and metabolic changes in the thalamus following TBI might be responsible for some chronic neurological deficits following brain trauma. Detailed mechanisms of these pathological processes are not completely understood. The goal of this study was to evaluate changes in the thalamus following TBI focusing on cleaved-caspase-3, a specific effector of caspase pathway activation and myelin and microvascular pathologies using immuno- and histochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) in adult Sprague-Dawley rats. Significant increases in cleaved-caspase-3 immunoreactivity in the thalamus were observed starting one month and persisting for at least three months following experimental TBI. Further, the study demonstrated an association of cleaved-caspase-3 with the demyelination of neuronal processes and tissue degeneration in the gray matter in the thalamus, as reflected in alterations of myelinated fiber integrity (luxol fast blue) and decreases in myelin basic protein (MBP) immunoreactivity. The immunofluorescent counterstaining of cleaved-caspase-3 with endothelial barrier antigen (EBA), a marker of blood-brain barrier, revealed limited direct and indirect associations of cleaved caspase-3 with blood-brain barrier damage. These results demonstrate for the first time a significant chronic upregulation of cleaved-caspase-3 in selected thalamic regions associated with cortical regions directly affected by CCI injury. Further, our study is also the first to report that significant upregulation of cleaved-caspase-3 in selected ipsilateral thalamic regions is associated with microvascular reorganization reflected in the significant increases in the number of microvessels with blood-brain barrier alterations detected by EBA staining. These findings provide new insights into potential mechanisms of TBI cell death involving chronic activation of caspase-3 associated with disrupted cortico-thalamic and thalamo-cortical connectivity. Moreover, this study offers the initial evidence that this upregulation of activated caspase-3, delayed degeneration of myelinated nerve fibers and microvascular reorganization with impaired blood-brain barrier integrity in the thalamus might represent reciprocal pathological processes affecting neuronal networks and brain function at the chronic stages of TBI.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
chronic TBI
cleaved-caspase-3
thalamus
blood-brain barrier
microvascular reorganization
myelin pathology

Added entries (persons, corporate bodies, meetings, titles ...)

Glushakova, Olena Y.Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA (author)
Korol, Tetyana Y.Uppsala universitet,Institutionen för psykologi (author)
Acosta, Sandra A.Univ S Florida, Dept Neurosurg, Coll Med, Tampa, FL 33612 USA (author)
Borlongan, Cesar V.Univ S Florida, Dept Neurosurg, Coll Med, Tampa, FL 33612 USA (author)
Valadka, Alex B.Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA (author)
Hayes, Ronald L.Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA;Banyan Biomarkers Inc, Alachua, FL 32615 USA (author)
Glushakov, Alexander V.Single Breath Inc, Midlothian, VA 23113 USA (author)
Univ S Florida, Dept Neurosurg, Coll Med, Tampa, FL 33612 USAVirginia Commonwealth Univ, Dept Neurosurg, Richmond, VA 23298 USA (creator_code:org_t)

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In:International Journal of Molecular Sciences: MDPI19:101661-65961422-0067

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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