Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects

2019 ◽  
Vol 30 (8) ◽  
pp. 839-855 ◽  
Author(s):  
Mahasweta Das ◽  
Karthick Mayilsamy ◽  
Shyam S. Mohapatra ◽  
Subhra Mohapatra
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Tumor Formation ◽  
Functional Improvement ◽  
Preclinical Research ◽  
Mortality And Morbidity ◽  
Mesenchymal Stem Cell Therapy ◽  
Beneficial Effects

Abstract Traumatic brain injury (TBI) is a major cause of injury-related mortality and morbidity in the USA and around the world. The survivors may suffer from cognitive and memory deficits, vision and hearing loss, movement disorders, and different psychological problems. The primary insult causes neuronal damage and activates astrocytes and microglia which evokes immune responses causing further damage to the brain. Clinical trials of drugs to recover the neuronal loss are not very successful. Regenerative approaches for TBI using mesenchymal stem cells (MSCs) seem promising. Results of preclinical research have shown that transplantation of MSCs reduced secondary neurodegeneration and neuroinflammation, promoted neurogenesis and angiogenesis, and improved functional outcome in the experimental animals. The functional improvement is not necessarily related to cell engraftment; rather, immunomodulation by molecular factors secreted by MSCs is responsible for the beneficial effects of this therapy. However, MSC therapy has a few drawbacks including tumor formation, which can be avoided by the use of MSC-derived exosomes. This review has focused on the research works published in the field of regenerative therapy using MSCs after TBI and its future direction.

scholarly journals Moderately Elevated Intracranial Pressure after Diffuse Traumatic Brain Injury is Associated with Exacerbated Neuronal Pathology and Behavioral Morbidity in the Rat

2014 ◽  
Vol 34 (10) ◽  
pp. 1628-1636 ◽  
Author(s):  
Audrey D Lafrenaye ◽  
Thomas E Krahe ◽  
John T Povlishock
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracranial Pressure ◽  
Perfusion Pressure ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Global Ischemia ◽  
Neuronal Membrane ◽  
Elevated Intracranial Pressure ◽  
Membrane Perturbation

Traumatic brain injury (TBI)-induced elevated intracranial pressure (ICP) is correlated with ensuing morbidity/mortality in humans. This relationship is assumed to rely mostly on the recognition that extremely elevated ICP either indicates hematoma/contusions capable of precipitating herniation or alters cerebral perfusion pressure (CPP), which precipitates global ischemia. However, whether subischemic levels of elevated ICP without hematoma/contusion contribute to increased morbidity/mortality remains unknown. To address this knowledge gap, we utilized a model of moderate diffuse TBI in rats followed by either intraventricular ICP monitoring or manual ICP elevation to 20 mm Hg, in which CPP was above ischemic levels. The effects of ICP elevation after TBI on acute and chronic histopathology, as well as on behavioral morbidity, were evaluated. ICP elevation after TBI resulted in increased acute neuronal membrane perturbation and was also associated with reduced neuronal density at 4 weeks after injury. Somatosensory hypersensitivity was exacerbated by ICP elevation and was correlated to the observed neuronal loss. In conclusion, this study indicates that morbidity and increased neuronal damage/death associated with elevated ICP can occur without concurrent global ischemia. Therefore, understanding the pathologies associated with subischemic levels of elevated ICP could lead to the development of better therapeutic strategies for the treatment and management of TBI patients.

scholarly journals DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood–Brain Barrier Permeability

2020 ◽  
Vol 21 (17) ◽  
pp. 6291
Author(s):  
Zhuo-Hao Liu ◽  
Nan-Yu Chen ◽  
Po-hsun Tu ◽  
Chen-Te Wu ◽  
Shao-Chieh Chiu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Temporal Analysis ◽  
Brain Barrier ◽  
Functional Improvement ◽  
Post Injury ◽  
Edema Formation ◽  
Mortality And Morbidity ◽  
Blood Brain

Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood–brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

Oxidative Stress: Major Threat in Traumatic Brain Injury

2018 ◽  
Vol 17 (9) ◽  
pp. 689-695 ◽  
Author(s):  
Nidhi Khatri ◽  
Manisha Thakur ◽  
Vikas Pareek ◽  
Sandeep Kumar ◽  
Sunil Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Calcium Influx ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Physical Assault ◽  
Mortality And Morbidity ◽  
Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

FGF10 Attenuates Experimental Traumatic Brain Injury through TLR4/MyD88/NF-κB Pathway

2021 ◽  
pp. 1-9
Author(s):  
Qinhan Hou ◽  
Hongmou Chen ◽  
Quan Liu ◽  
Xianlei Yan
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Protein Expression ◽  
Water Content ◽  
Neurological Deficit ◽  
Neuronal Apoptosis ◽  
Neuronal Damage ◽  
Intraventricular Injection ◽  
Brain Water Content ◽  
Brain Water

Traumatic brain injury (TBI) can induce neuronal apoptosis and neuroinflammation, resulting in substantial neuronal damage and behavioral disorders. Fibroblast growth factors (FGFs) have been shown to be critical mediators in tissue repair. However, the role of FGF10 in experimental TBI remains unknown. In this study, mice with TBI were established via weight-loss model and validated by increase of modified neurological severity scores (mNSS) and brain water content. Secondly, FGF10 levels were elevated in mice after TBI, whereas intraventricular injection of Ad-FGF10 decreased mNSS score and brain water content, indicating the remittance of neurological deficit and cerebral edema in TBI mice. In addition, neuronal damage could also be ameliorated by stereotactic injection of Ad-FGF10. Overexpression of FGF10 increased protein expression of Bcl-2, while it decreased Bax and cleaved caspase-3/PARP, and improved neuronal apoptosis in TBI mice. In addition, Ad-FGF10 relieved neuroinflammation induced by TBI and significantly reduced the level of interleukin 1β/6, tumor necrosis factor α, and monocyte chemoattractant protein-1. Moreover, Ad-FGF10 injection decreased the protein expression level of Toll-like receptor 4 (TLR4), MyD88, and phosphorylation of NF-κB (p-NF-κB), suggesting the inactivation of the TLR4/MyD88/NF-κB pathway. In conclusion, overexpression of FGF10 could ameliorate neurological deficit, neuronal apoptosis, and neuroinflammation through inhibition of the TLR4/MyD88/NF-κB pathway, providing a potential therapeutic strategy for brain injury in the future.

scholarly journals Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

2010 ◽  
Vol 31 (1) ◽  
pp. 17-35 ◽  
Author(s):  
Martin Lauritzen ◽  
Jens Peter Dreier ◽  
Martin Fabricius ◽  
Jed A Hartings ◽  
Rudolf Graf ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Disorders ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Neuronal Damage ◽  
Ion Homeostasis ◽  
Large Body ◽  
Treatment Strategies ◽  
Pathophysiological Mechanism

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

NEURONAL LOSS AND CYTOSKELETAL PERTURBATION AFTER TRAUMATIC BRAIN INJURY (TBI) IN THE NFH/LacZ TRANSGENIC MOUSE

1998 ◽  
Vol 57 (5) ◽  
pp. 475
Author(s):  
J. E. Galvin ◽  
V. M. -Y. Lee ◽  
M. Nakamura ◽  
K. E. Saatman ◽  
R. Raghupathi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Transgenic Mouse ◽  
Neuronal Loss

scholarly journals Pengelolaan Central Diabetes Insipidus Pasca Cedera Kepala Berat

2019 ◽  
Vol 8 (2) ◽  
pp. 99-104
Author(s):  
Bona Akhmad Fithrah ◽  
Marsudi Rasman ◽  
Siti Chasnak Saleh
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Central Diabetes Insipidus ◽  
Young Generation ◽  
Posterior Pituitary ◽  
Challenging Problem ◽  
Mortality And Morbidity ◽  
Post Traumatic

Cedera otak traumatika adalah salah satu penyebab kematian dan kesakitan tersering pada kelompok masyarakat muda. Hasil akhir dari cedera kepala berat dapat menyebabkan gangguan kognitif, perilaku, psikologi dan sosial. Salah satu konsekuensi dari cedera kepala berat adalah terjadinya disfungsi hormonal baik dari hipofise anterior maupun posterior. Angka kejadian disfungsi hormonal ini sekitar 20-50%. Salah satu yang paling menantang dan sering terjadi adalah diabetes insipidus (DI) dan Syndrome inappropriate antidiuretic hormone (SIADH). Angka kejadian diabetes insipidus pasca cedera kepala diduga sebesar 1-2,9% dengan berbagai tingkatannya. Pada beberapa kasus bersifat sementara tapi beberapa kasus terjadi bersifat menetap. Pada laporan kasus ini akan dibawakan sebuah kasus diabetes insipidus pasca cedera kepala berat. Pasien mengalami cedera kepala berat, hingga dilakukan decompressive craniectomi dan trakeostomi. Untuk perawatan lanjutan pasien dirujuk ke Jakarta. Saat menjalani terapi lanjutan ini pasien terdiagnosis diabetes insipidus Pada kasus ini diabetes insipidus tidak timbul langsung setelah cedera kepala tetapi baru timbul lebih kurang satu bulan setelah cedera kepala. Diabetes insipidus dikelola dengan menggunakan desmopressin spray dan oral disamping mengganti cairan yang hilang. Pada kasus ini desmopressin sempat di stop sebelum akhirnya diberikan terus menerus dan pasien diterapi sebagai diabetes insipidus yang menetap. Managing Central Diabetes Insipidus in Post Severe Head Injury PatientAbstractTraumatic brain injury is the cause of mortality and morbidity in society mostly in male-young generation. The last outcome of traumatic brain injury might be deficit in cognitive, behavioral, psychological and social. the consequences of traumatic brain injury might be hormonal disfunction from anterior and posterior pituitary. The incidence around 20-50%. The most challenging problem is diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone (SIADH). The incident of post traumatic diabetes insipidus around 1-2,9% with several degree. In certain case its only occurred transiently but some report it could be permanent. In this case report will find one case post traumatic diabetes insipidus. This pasien had severe traumatic brain injury and underwent decompressive craniectomy and tracheostomy. For further therapy patient was referred to Jakarta. In this further treatment patient diagnosed with diabetes insipidus. Diabetes insipidus doesn’t occurred since the first day of injury but occurred almost one month after. Diabetes insipidus managed with desmopressin spray and oral beside replace water loss. For a few days desmopressin stop but diabetes insipidus occurred again so desmopressin given daily both spray and oral and the patient had therapy as diabetes insipidus permanent. 

scholarly journals Enhancement of Neurogenesis and Memory by a Neurotrophic Peptide in Mild to Moderate Traumatic Brain Injury

Neurosurgery ◽  
2014 ◽  
Vol 76 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Muhammad Omar Chohan ◽  
Olga Bragina ◽  
Syed Faraz Kazim ◽  
Gloria Statom ◽  
Narjes Baazaoui ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Parietal Cortex ◽  
Saline Solution ◽  
Neuronal Loss ◽  
Synaptic Density ◽  
Moderate Traumatic Brain Injury ◽  
Long Term Treatment ◽  
Newborn Neurons

ABSTRACT BACKGROUND: Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome. OBJECTIVE: To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6. METHODS: TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed. RESULTS: Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-β were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing. CONCLUSION: Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.

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