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

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 hippocampal-dependent 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 trauma-induced chronic cognitive deficits.

Download Full-text

Abstract # 2056 Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Brain Behavior and Immunity ◽

10.1016/j.bbi.2018.11.184 ◽

2019 ◽

Vol 76 ◽

pp. e5

Author(s):

K. Krukowski ◽

A. Chou ◽

T. Jopson ◽

P. Jun Zhu ◽

M. Costa-Mattioli ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Stress Response ◽

Cognitive Deficits ◽

Integrated Stress Response

Download Full-text

Repetitive and Prolonged Omega-3 Fatty Acid Treatment after Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery

Cell Transplantation ◽

10.3727/096368916x693842 ◽

2017 ◽

Vol 26 (4) ◽

pp. 555-569 ◽

Cited By ~ 5

Author(s):

Hongjian Pu ◽

Xiaoyan Jiang ◽

Zhishuo Wei ◽

Dandan Hong ◽

Sulaiman Hassan ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Fish Oil ◽

Cognitive Deficits ◽

Combined Treatment ◽

Tissue Loss ◽

Sham Operation ◽

Omega 3 ◽

Cognitive Recovery

Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic.

Download Full-text

Traumatic Brain Injury by Weight-Drop Method Causes Transient Amyloid-β Deposition and Acute Cognitive Deficits in Mice

Behavioural Neurology ◽

10.1155/2019/3248519 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Hajime Shishido ◽

Masaki Ueno ◽

Kana Sato ◽

Masahisa Matsumura ◽

Yasunori Toyota ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cognitive Impairment ◽

Brain Injury ◽

Cognitive Deficits ◽

Amyloid Β ◽

Wild Type ◽

Long Term Effects ◽

Drop Method ◽

Weight Drop

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer’s disease (AD) later in life. It has been reported that TBI accelerated amyloid-β (Aβ) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-β pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-β (Aβ) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aβ deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-β deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.

Download Full-text

Donepezil in traumatic brain injury: Report of two cases

Indian Journal of Neurotrauma ◽

10.1016/s0973-0508(07)80030-x ◽

2007 ◽

Vol 04 (02) ◽

pp. 129-131

Author(s):

Arun Lata Agarwal ◽

Devdutta Biswas ◽

Sanjay Agarwal

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Behavioral Problems ◽

Cholinesterase Inhibitors ◽

Memory Deficits ◽

Acetyl Cholinesterase ◽

Behavioral Deficits ◽

Beneficial Impact ◽

And Behavior

AbstractAdults with traumatic brain injury (TBI) are often severely impaired and inadequately rehabilitated due to deficits in memory and behavioral problems like apathy, irritability and depression, and it has been suggested that an acetylcholine deficit could be contributory to these deficits. Central Acetyl cholinesterase Inhibitors (CAI) are being reported to have a beneficial impact in treatment of memory deficits in adults with TBI, with Donepezil studied most extensively. The authors present two patients with TBI with long term static dysfunction of memory and behavior who responded to Donepezil in terms of attention, memory and apathy. Donepezil appears to be a valuable pharmacological option for treatment of memory and behavioral deficits in TBI.

Download Full-text

Traumatic Brain Injury in Aged Mice Induces Chronic Microglia Activation, Synapse Loss, and Complement-Dependent Memory Deficits

International Journal of Molecular Sciences ◽

10.3390/ijms19123753 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3753 ◽

Cited By ~ 28

Author(s):

Karen Krukowski ◽

Austin Chou ◽

Xi Feng ◽

Brice Tiret ◽

Maria-Serena Paladini ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Deficits ◽

Brain Lesion ◽

Clinical Intervention ◽

Memory Deficits ◽

Cell Number ◽

Post Injury ◽

Synapse Loss ◽

Immune System Activation

Traumatic brain injury (TBI) is of particular concern for the aging community since there is both increased incidence of TBI and decreased functional recovery in this population. In addition, TBI is the strongest environmental risk factor for development of Alzheimer’s disease and other dementia-related neurodegenerative disorders. Critical changes that affect cognition take place over time following the initial insult. Our previous work identified immune system activation as a key contributor to cognitive deficits observed in aged animals. Using a focal contusion model in the current study, we demonstrate a brain lesion and cavitation formation, as well as prolonged blood–brain barrier breakdown. These changes were associated with a prolonged inflammatory response, characterized by increased microglial cell number and phagocytic activity 30 days post injury, corresponding to significant memory deficits. We next aimed to identify the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals, and measured increases in complement initiation components C1q, C3, and CR3, which are known to regulate microglial–synapse interactions. Specifically, we found significant accumulation of C1q on synapses within the hippocampus, which was paralleled by synapse loss 30 days post injury. We used genetic and pharmacological approaches to determine the mechanistic role of complement initiation on cognitive loss in aging animals after TBI. Notably, both genetic and pharmacological blockade of the complement pathway prevented memory deficits in aged injured animals. Thus, therapeutically targeting early components of the complement cascade represents a significant avenue for possible clinical intervention following TBI in the aging population.

Download Full-text

Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211028680 ◽

2021 ◽

pp. 0271678X2110286

Author(s):

Hongjian Pu ◽

Cheng Ma ◽

Yongfang Zhao ◽

Yangfan Wang ◽

Wenting Zhang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Deficits ◽

Cognitive Functions ◽

Diffusion Tensor ◽

Long Term Potentiation ◽

Interleukin 4 ◽

Intranasal Delivery ◽

Arginase 1

Traumatic brain injury (TBI) is commonly followed by long-term cognitive deficits that severely impact the quality of life in survivors. Recent studies suggest that microglial/macrophage (Mi/MΦ) polarization could have multidimensional impacts on post-TBI neurological outcomes. Here, we report that repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles for 4 weeks after controlled cortical impact improved hippocampus-dependent spatial and non-spatial cognitive functions in adult C57BL6 mice, as assessed by a battery of neurobehavioral tests for up to 5 weeks after TBI. IL-4-elicited enhancement of cognitive functions was associated with improvements in the integrity of the hippocampus at the functional ( e.g., long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, etc.). Mechanistically, IL-4 increased the expression of PPARγ and arginase-1 within Mi/MΦ, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/MΦ-specific PPARγ knockout (mKO) mice, indicating an obligatory role for PPARγ in IL-4-induced Mi/MΦ polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPARγ mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPARγ-dependent beneficial Mi/MΦ responses, and improves hippocampal function after TBI.

Download Full-text

Neuroplastic Changes Induced by Cognitive Rehabilitation in Traumatic Brain Injury: A Review

Neurorehabilitation and Neural Repair ◽

10.1177/1545968317723748 ◽

2017 ◽

Vol 31 (9) ◽

pp. 800-813 ◽

Cited By ~ 21

Author(s):

Valentina Galetto ◽

Katiuscia Sacco

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Training ◽

Cognitive Deficits ◽

Cognitive Rehabilitation ◽

Cerebral Activation ◽

Rehabilitation Programs ◽

Brain Changes ◽

The Impact

Background. Cognitive deficits are among the most disabling consequences of traumatic brain injury (TBI), leading to long-term outcomes and interfering with the individual’s recovery. One of the most effective ways to reduce the impact of cognitive disturbance in everyday life is cognitive rehabilitation, which is based on the principles of brain neuroplasticity and restoration. Although there are many studies in the literature focusing on the effectiveness of cognitive interventions in reducing cognitive deficits following TBI, only a few of them focus on neural modifications induced by cognitive treatment. The use of neuroimaging or neurophysiological measures to evaluate brain changes induced by cognitive rehabilitation may have relevant clinical implications, since they could add individualized elements to cognitive assessment. Nevertheless, there are no review studies in the literature investigating neuroplastic changes induced by cognitive training in TBI individuals. Objective. Due to lack of data, the goal of this article is to review what is currently known on the cerebral modifications following rehabilitation programs in chronic TBI. Methods. Studies investigating both the functional and structural neural modifications induced by cognitive training in TBI subjects were identified from the results of database searches. Forty-five published articles were initially selected. Of these, 34 were excluded because they did not meet the inclusion criteria. Results. Eleven studies were found that focused solely on the functional and neurophysiological changes induced by cognitive rehabilitation. Conclusions. Outcomes showed that cerebral activation may be significantly modified by cognitive rehabilitation, in spite of the severity of the injury.

Download Full-text