Journal of neurotrauma
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Journal of neurotrauma · Jul 1999
Sequential changes in glial fibrillary acidic protein and gene expression following parasagittal fluid-percussion brain injury in rats.
This study documents the regional and temporal patterns of glial fibrillary acidic protein (GFAP) RNA and protein expression after parasagittal fluid-percussion (F-P) brain injury (1.7 to 2.2 atm) in male Sprague-Dawley rats. In situ hybridization was conducted in 28 rats with a 35S-labeled antisense riboprobe to GFAP at 0.5, 2, and 6 hours and 1, 3, and 30 days after traumatic brain injury (TBI) or sham procedures. Immunocytochemical staining of GFAP was conducted in 20 rats at 1, 3, 7, and 30 days after TBI or sham procedures. ⋯ At 30 days, GFAP mRNA and protein expression were present within the deeper cortical layers of the lateral somatosensory cortex and lateral thalamus and throughout ipsilateral white matter tracts. These data demonstrate a complex pattern of GFAP mRNA and protein expression within gray and white matter tracts following F-P brain injury. Patterns of GFAP gene expression may be a sensitive molecular marker for evaluating the global response of the brain to focal injury in terms of progressive neurodegenerative as well as regenerative processes.
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Journal of neurotrauma · Jul 1999
Differential effects of traumatic brain injury on vesicular acetylcholine transporter and M2 muscarinic receptor mRNA and protein in rat.
Experimental traumatic brain injury (TBI) produces cholinergic neurotransmission deficits that may contribute to chronic spatial memory deficits. Cholinergic neurotransmission deficits may result from presynaptic alterations in the storage and release of acetylcholine (ACh) or from changes in the receptors for ACh. The vesicular ACh transporter (VAChT) mediates accumulation of ACh into secretory vesicles, and the M2 muscarinic receptor subtype can modulate cholinergic neurotransmission via a presynaptic inhibitory feedback mechanism. ⋯ An increase in VAChT mRNA was also observed. Immunohistochemistry demonstrated a loss of M2; however, there was no significant change in M2 mRNA levels in comparison with sham controls. These changes may represent a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission chronically after TBI through differential transcriptional regulation.
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Journal of neurotrauma · Jul 1999
Clinical TrialTGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function.
Traumatic brain injury (TBI) induces local and systemic immunologic changes, release of cytokines, and cell activation. Perpetuation of these cascades may contribute to secondary damage to the brain. Therefore, the ability of the antiinflammatory mediator transforming growth factor-beta (TGF-beta) to downregulate intrathecal immunoactivation may be of fundamental value for diminishing the incidence and extent of secondary insults. ⋯ Levels of TGF-beta could not be correlated with extent of initial injury by computed tomography (CT), CD4/CD8 ratios, acute lung injury, or clinical outcome as rated by the Glasgow Outcome Scale (GOS). Although increased levels of TGF-beta in CSF seem to parallel BBB function, a partial intrathecal production is suggested, possibly modulated by elevation of interleukin-6 (IL-6). Thus, TGF-beta may function as a factor in the complex cytokine network following TBI, acting as an antiinflammatory and neuroprotective mediator.
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Lubeluzole, a novel nitric oxide synthase (NOS) pathway modulator, was shown to be neuroprotective in cerebral ischemia as studied in animal models and clinical trials. The present study investigated the effect of lubeluzole on contusion volume and brain edema following traumatic brain injury. Sprague-Dawley rats (n = 36) were subjected to cortical impact injury. ⋯ T2-weighted MRI revealed a higher volume of edema at 90 minutes after trauma in treated rats. However, at 6 and 24 hours after trauma, no significant difference was discernible. Under these experimental conditions, lubeluzole fails to exert beneficial effects following experimental traumatic brain injury (TBI).
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Journal of neurotrauma · Jun 1999
Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury.
Recent observations concerning presumed calcium-induced mitochondrial damage and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. Studies from our laboratory demonstrated that cyclosporin A (CsA), a potent inhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal foci destined to undergo delayed disconnection. We attributed this neuroprotection to the inhibition by CsA of mitochondrial permeability transition (MPT). ⋯ These results once again suggest that the maintenance of the functional integrity of the mitochondria can prevent TAI, presumably via the preservation of the local energy homeostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the early posttraumatic period. Collectively, our findings suggest that a therapeutic window exists for the use of drugs targeting mitochondria and energy regulation in traumatic brain injury.