Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies

Loane, David J.; Faden, Alan I.

doi:10.1016/j.tips.2010.09.005

Cited by 508 publications

(420 citation statements)

References 117 publications

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“…The primary injury comprises direct and mechanical damage to brain tissue, including neurons, axons, glia, blood vessels, and skull, whereas the secondary injury encompasses diverse and reversible molecular, cellular, metabolic, and structural changes at and around the primary injured site. 3 The primary injury of mTBI is usually mild and is healed naturally in most of the cases and thus neurologic impairments occurring after mTBI in a proportion of the victims are most likely attributed to secondary brain injury. Secondary brain injury usually takes days to evolve from the primary injury, which offers a golden window of a time for intervention or prevention against postconcussion syndrome development.…”

Section: Traumatic Brain Injury (Tbi) Represents a Serious Public Healthmentioning

confidence: 99%

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

Zhang

Zhou

Hamblin

et al. 2014

J Cereb Blood Flow Metab

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A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1b and IL-6 but upregulated TNF-a. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT.

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Section: Traumatic Brain Injury (Tbi) Represents a Serious Public Healthmentioning

confidence: 99%

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

Zhang

Zhou

Hamblin

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

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“…Traumatic brain injury results from mechanical or acceleration-deceleration injury to the brain and is usually divided into primary and secondary mechanisms. The pathophysiology specific to TBI includes a hemorrhagic component and differences in the degree of metabolic changes, extent of focal versus diffuse injury, nonneuronal cell contributions, and white matter damage (Bramlett and Dietrich, 2004;Loane and Faden, 2010;Royo et al, 2003). Secondary damage is delayed and features prominent activation of cell death pathways due to deinnervation (Liou et al, 2003;Loane and Faden, 2010;Raghupathi et al, 2000).…”

Section: Neuronal Death After Cerebral Ischemia and Traumatic Brain Imentioning

confidence: 99%

“…The pathophysiology specific to TBI includes a hemorrhagic component and differences in the degree of metabolic changes, extent of focal versus diffuse injury, nonneuronal cell contributions, and white matter damage (Bramlett and Dietrich, 2004;Loane and Faden, 2010;Royo et al, 2003). Secondary damage is delayed and features prominent activation of cell death pathways due to deinnervation (Liou et al, 2003;Loane and Faden, 2010;Raghupathi et al, 2000). Microscopic and biochemical evidence supports apoptosis in cells undergoing secondary cell death and inhibitors of caspases can prevent TBI-induced neuronal death (Raghupathi et al, 2000;Royo et al, 2003).…”

Section: Neuronal Death After Cerebral Ischemia and Traumatic Brain Imentioning

confidence: 99%

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Engel

Plesnila

Prehn

et al. 2011

J Cereb Blood Flow Metab

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The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.

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“…At present, there are no satisfactory therapies to protect TBI patients against either gray matter injury or WMI. Furthermore, most preclinical TBI studies greatly emphasize gray matter over white matter, which may contribute to the many disappointing results in clinical trials to date (5).…”

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confidence: 99%

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Wang

Shi

Jiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

327

292

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Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/ macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.T raumatic brain injury (TBI) often leads to catastrophic neurological disabilities and sometimes ends in death (1). TBI results not only in gray matter damage, but also in severe white matter injury (WMI), thereby disrupting signal transmission and eliciting poor functional outcomes (2, 3). WMI in TBI patients is strongly correlated with neurological deficits, and diffusion tensor imaging of white matter offers prognostic value for neurological status (2-4). At present, there are no satisfactory therapies to protect TBI patients against either gray matter injury or WMI. Furthermore, most preclinical TBI studies greatly emphasize gray matter over white matter, which may contribute to the many disappointing results in clinical trials to date (5).Previous studies have shown that histone deacetylase (HDAC) inhibitors mitigate WMI after ischemia (6, 7). HDACs allow DNA to be wrapped more tightly around histones, thereby blocking gene transcription and acting in opposition to histone acetyltransferases that promote gene transcription (8, 9). Some HDAC inhibitors preferentially promote the transcription of neuroprotective genes. We...

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Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies

Cited by 508 publications

References 117 publications

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

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