Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics

Pearn, Matthew L.; Niesman, Ingrid R.; Egawa, Junji; Sawada, Atsushi; Almenar-Queralt, Angels; Shah, Sameer B.; Duckworth, Josh; Head, Brian P.

doi:10.1007/s10571-016-0400-1

Cited by 241 publications

(182 citation statements)

References 132 publications

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“…The pathological changes associated with TBI mainly include mitochondrial dysfunction, ER stress, Ca 2+ homeostasis disruptions, oxidative stress, excitotoxicity and free-radical generation, all of which can induce inflammation and apoptosis (Faridar et al, 2011; Pearn et al, 2017). In this study, we focused our attention on the potential anti-apoptotic effects of TUDCA and its downstream signaling proteins and did not investigate its role in neuroinflammation following TBI.…”

Section: Discussionmentioning

confidence: 99%

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

Sun

Wang

et al. 2017

Front. Cell. Neurosci.

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Traumatic brain injury (TBI) is one of the leading causes of trauma-induced mortality and disability, and emerging studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of TBI. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been reported to act as an ER stress inhibitor and chemical chaperone and to have the potential to attenuate apoptosis and inflammation. To study the effects of TUDCA on brain injury, we subjected mice to TBI with a controlled cortical impact (CCI) device. Using western blotting, we first examined TBI-induced changes in the expression levels of GRP78, an ER stress marker, p-PERK, PERK, p-eIF2a, eIF2a, ATF4, p-Akt, Akt, Pten, Bax, Bcl-2, Caspase-12 and CHOP, as well as changes in the mRNA levels of Akt, GRP78, Caspase-12 and CHOP using RT-PCR. Neuronal cell death was assessed by a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and CHOP expression in neuronal cells was detected by double-immunofluorescence staining. Neurological and motor deficits were assessed by modified neurological severity scores (mNSS) and beam balance and beam walking tests, and brain water content was also assessed. Our results indicated that ER stress peaked at 72 h after TBI and that TUDCA abolished ER stress and inhibited p-PERK, p-eIF2a, ATF4, Pten, Caspase-12 and CHOP expression levels. Moreover, our results show that TUDCA also improved neurological function and alleviated brain oedema. Additionally, TUDCA increased p-Akt expression and the Bcl-2/Bax ratio. However, the administration of the Akt inhibitor MK2206 or siRNA targeting of Akt abolished the beneficial effects of TUDCA. Taken together, our results indicate that TUDCA may attenuate early brain injury via Akt pathway activation.

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Section: Discussionmentioning

confidence: 99%

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

Sun

Wang

et al. 2017

Front. Cell. Neurosci.

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“…While the primary injury at the moment of the impact (including hemorrhage, laceration, contusion, and primary axotomy) is not amenable to medical treatment, the complex cascade of molecular and cellular events (secondary injury) that follows the original damage can aggravate the initial harm. This cascade reduces the chances of functional recovery but could, at least theoretically, be counteracted (6, 7). …”

Section: Introductionmentioning

confidence: 99%

Rethinking Neuroprotection in Severe Traumatic Brain Injury: Toward Bedside Neuroprotection

et al. 2017

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Neuroprotection after traumatic brain injury (TBI) is an important goal pursued strenuously in the last 30 years. The acute cerebral injury triggers a cascade of biochemical events that may worsen the integrity, function, and connectivity of the brain cells and decrease the chance of functional recovery. A number of molecules acting against this deleterious cascade have been tested in the experimental setting, often with preliminary encouraging results. Unfortunately, clinical trials using those candidate neuroprotectants molecules have consistently produced disappointing results, highlighting the necessity of improving the research standards. Despite repeated failures in pharmacological neuroprotection, TBI treatment in neurointensive care units has achieved outcome improvement. It is likely that intensive treatment has contributed to this progress offering a different kind of neuroprotection, based on a careful prevention and limitations of intracranial and systemic threats. The natural course of acute brain damage, in fact, is often complicated by additional adverse events, like the development of intracranial hypertension, brain hypoxia, or hypoperfusion. All these events may lead to additional brain damage and worsen outcome. An approach designed for early identification and prompt correction of insults may, therefore, limit brain damage and improve results.

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“…Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5)(6)(7)(8)(9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10)(11)(12)(13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.…”

mentioning

confidence: 99%

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Chou

Krukowski

Jopson

et al. 2017

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

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Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

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Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics

Cited by 241 publications

References 132 publications

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation

Rethinking Neuroprotection in Severe Traumatic Brain Injury: Toward Bedside Neuroprotection

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

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