Effects of Voluntary Physical Exercise, Citicoline, and Combined Treatment on Object Recognition Memory, Neurogenesis, and Neuroprotection after Traumatic Brain Injury in Rats

Jacotte-Simancas, Alejandra; David, Cristhian; Coll-Andreu, Margalida; Torras-Garcia, Meritxell; Borlongan, Cesar V.; Portell-Cortès, Isabel

doi:10.1089/neu.2014.3502

Cited by 59 publications

(37 citation statements)

References 60 publications

(71 reference statements)

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“…Thus, strategies to counteract acute injurymediated effects have aimed to dampen the inflammatory response (43,44,52,54,55). We and others have shown that blocking the acute inflammatory responses within 24 h after injury prevented the development of TBI-induced cognitive deficits (34,39,40,45,50,56,57). However, attempts to translate the insights gleaned from acute TBI models have failed in preclinical studies.…”

Section: Discussionmentioning

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.

197

213

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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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Section: Discussionmentioning

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.

197

213

View full text Add to dashboard Cite

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“…Other animal researchers have identified beneficial effects of early exercise shortly after mTBI on various measures of brain neuroplasticity. [47][48][49][50] The bulk of the animal data suggests that uncontrolled or forced activity too soon after concussion is detrimental to recovery, but that voluntary exercise is not and may enhance recovery.…”

Section: Active Rehabilitation Of Concussionmentioning

confidence: 99%

Active Rehabilitation of Concussion and Post-concussion Syndrome

Leddy

Baker

Willer

2016

Physical Medicine and Rehabilitation Clinics of North America

111

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“…Examples include Cytidine-5'-diphosphocholine (CDP-choline) in TBI and stroke (Hurtado et al, 2007; Jacotte-Simancas et al, 2015; Secades and Frontera, 1995), quinacrine in middle cerebral artery occlusion (MCAO) (Estevez and Phillis, 1997), and arachidonyl trifluoromethyl ketone in SCI (Huang et al, 2009). CDP-choline is also investigated for its neuroprotective potential in clinical TBI (Adibhatla, 2013; Zafonte et al, 2009).…”

Section: Therapeutic Strategies Targeting Lipid Peroxidationmentioning

confidence: 99%

Therapies targeting lipid peroxidation in traumatic brain injury

2016

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Lipid peroxidation can be broadly defined as the process of inserting a hydroperoxy group into a lipid. Polyunsaturated fatty acids present in the phospholipids are often the targets for peroxidation. Phospholipids are indispensable for normal structure of membranes. The other important function of phospholipids stems from their role as a source of lipid mediators – oxygenated free fatty acids that are derived from lipid peroxidation. In the CNS, excessive accumulation of either oxidized phospholipids or oxygenated free fatty acids may be associated with damage occurring during acute brain injury and subsequent inflammatory responses. There is a growing body of evidence that lipid peroxidation occurs after severe traumatic brain injury in humans and correlates with the injury severity and mortality. Identification of the products and sources of lipid peroxidation and its enzymatic or non-enzymatic nature is essential for the design of mechanism-based therapies. Recent progress in mass spectrometry-based lipidomics/oxidative lipidomics offers remarkable opportunities for quantitative characterization of lipid peroxidation products, providing guidance for targeted development of specific therapeutic modalities. In this review, we critically evaluate previous attempts to use non-specific antioxidants as neuroprotectors and emphasize new approaches based on recent breakthroughs in understanding of enzymatic mechanisms of lipid peroxidation associated with specific death pathways, particularly apoptosis. We also emphasize the role of different phospholipases (calcium-dependent and -independent) in hydrolysis of peroxidized phospholipids and generation of pro- and anti-inflammatory lipid mediators.

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Effects of Voluntary Physical Exercise, Citicoline, and Combined Treatment on Object Recognition Memory, Neurogenesis, and Neuroprotection after Traumatic Brain Injury in Rats

Cited by 59 publications

References 60 publications

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

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

Active Rehabilitation of Concussion and Post-concussion Syndrome

Therapies targeting lipid peroxidation in traumatic brain injury

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