Novel Pharmacologic Strategies in the Treatment of Experimental Traumatic Brain Injury: 1998

McIntosh, Tracy K.; Juhler, Marianne; Wieloch, Tadeusz

doi:10.1089/neu.1998.15.731

Cited by 290 publications

(151 citation statements)

References 474 publications

(255 reference statements)

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“…This is best exemplified in transgenic mice that overexpress SOD1, where there is reduced cerebral edema, tissue necrosis, and disruption of the blood-brain barrier along with an improvement in functional recovery after TBI as compared to wildtype controls. 74,75 Similar neuroprotection is seen in these adult transgenic mice when subjected to focal ischemic brain injury. 76 Despite these findings, there is currently no evidence that SOD1 overexpression confers neuroprotection in the immature brain after TBI.…”

Section: Oxidative Damagementioning

confidence: 69%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

138

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Summary: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBIinflammation, oxidative injury, and iron-induced damage -and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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Section: Oxidative Damagementioning

confidence: 69%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

138

View full text Add to dashboard Cite

show abstract

“…For example, there is significant dysfunction of catecholaminergic systems associated with TBI (16)(17)(18). There is also evidence of altered central cholinergic tone (19)(20)(21)(22)(23) following trauma.…”

Section: Relationship Of Profile Of Injury To Neurobehavioral Sequelaementioning

confidence: 99%

Neurobehavioral sequelae of traumatic brain injury: evaluation and management

2008

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Traumatic brain injury (TBI) is a universal public health problem. A recent review of epidemiological studies in Europe suggests an incidence of 235 hospitalized cases (including fatalities) per 100,000 population (1). In the US, the incidence is estimated at 150 per 100,000 population (2). Less data is available from other regions of the world, but TBI is acknowledged as a significant problem worldwide. Of note is that the incidence rates are calculated from hospitalized cases only, and do not include injured individuals who do not seek or have access to care. Thus, the actual incidence of injury is probably 3 to 4 fold larger than the quoted numbers. Most studies suggest that the incidence rates for TBI are greatest in the second and third decades of life, with a secondary increase in the elderly stemming from falls (2,3). Males are more likely to suffer a TBI than females (2,3).In developed countries, there has been a reduction in the mortality rates associated with TBI over the last several decades, generally attributed to improved systems of trauma care and improved motor vehicle safety design. Many individuals with mild traumatic brain injury and virtually all individuals who survive moderate and severe TBI are left with significant long-term neurobehavioral sequelae (4-6). Thus, the reduction in TBI-associated mortality rates (7) has led to a significant increase in the number of individuals with long-term neurobehavioral disorders related to TBI (8,9).Brain trauma can be caused in a number of ways, including mechanisms which penetrate the substance of the brain (e.g., projectiles) and those that do not. This paper focuses on non-penetrating injuries. Despite different contexts and instruments, the physics and biomechanics underlying damage to the brain from non-penetrating injuries have some common features. This results in certain brain regions being at greater risk for damage than others and allows for some general statements to be made about typical profiles of brain injury associated with trauma. The assessment and treatment of the neurobehavioral sequelae of TBI follow logically from an understanding of this injury profile. RELATIONSHIP OF PROFILE OF INJURY TO NEUROBEHAVIORAL SEQUELAEThere are two broad categories of forces that result in brain injury: contact (or impact) and inertial (acceleration or deceleration). Contact injuries result from the brain coming into contact with an object (which might include the skull, or some external object). Contact mechanisms often result in damage to scalp, skull, and brain surface (e.g., contusions, lacerations, hematomas) (10). Frequent sites of such injury are the anterior temporal poles, lateral and inferior temporal cortices, frontal poles, and orbital frontal cortices.Inertial injury results from rapid acceleration or deceleration of the brain that produces shear, tensile, and compression forces. These forces have maximum impact on axons and blood vessels, resulting in axonal injury, tissue tears, and intracerebral hematomas. These mechanisms also produc...

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“…In both human neurological diseases and animal models of brain injury, cytokines and/or oxidative stress are likely to be involved (107)(108)(109)(110)(111). That cytokines may cause significant brain damage has been clearly demonstrated by results obtained in transgenic mice expressing in astrocytes cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-3 (IL-3) or interferon-α (IFN-α) under the control of the glial fibrillary acidic protein (GFAP) gene promoter.…”

Section: Transgenic Mice Show That Metallothionein-1and2 Are Essential mentioning

confidence: 99%

Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

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In rodents, the metallothionein (MT) family is composed of four members, MT-1 to MT-4. MT-1&2 are expressed in virtually all tissues including those of the Central Nervous System (CNS), while MT-3 (also called Growth Inhibitory Factor) and MT-4 are expressed prominently in the brain and in keratinizing epithelia, respectively. For the understanding of the physiological functions of these proteins in the brain, the use of transgenic mice has provided essential information. Results obtained in MT-1&2-null mice and in MT-1-overexpressing mice strongly suggest that these MT isoforms are important antioxidant, anti-inflammatory and antiapoptotic proteins in the brain. Results in MT-3-null mice show a very different pattern, with no support for MT-1&2-like functions. Rather, MT-3 could be involved in neuronal sprouting and survival. Results obtained in a model of peripheral nervous system injury also suggest that MT-3 could be involved in the control of nerve growth.

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Novel Pharmacologic Strategies in the Treatment of Experimental Traumatic Brain Injury: 1998

Cited by 290 publications

References 474 publications

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Neurobehavioral sequelae of traumatic brain injury: evaluation and management

Metallothioneins and brain injury: What transgenic mice tell us

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