162 results on '"Ramesh Raghupathi"'
Search Results
2. Trajectory of Long-Term Outcome in Severe Pediatric Diffuse Axonal Injury: An Exploratory Study
- Author
-
Shih-Shan Lang, Todd Kilbaugh, Stuart Friess, Susan Sotardi, Chong Tae Kim, Vanessa Mazandi, Bingqing Zhang, Phillip B. Storm, Gregory G. Heuer, Alexander Tucker, Steve B. Ampah, Heather Griffis, Ramesh Raghupathi, and Jimmy W. Huh
- Subjects
diffuse axonal injury (DAI) ,outcome ,fever ,intracranial hypertension (IH) ,traumatic brain injury ,pediatric ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI.Methods: Pediatric patients (5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes.Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery.
- Published
- 2021
- Full Text
- View/download PDF
3. A Pro-social Pill? The Potential of Pharmacological Treatments to Improve Social Outcomes After Pediatric Traumatic Brain Injury
- Author
-
Bridgette D. Semple and Ramesh Raghupathi
- Subjects
immature ,neurotrauma ,brain development ,oxytocin ,neuroprotection ,behavior ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Traumatic brain injury (TBI) is a leading cause of injury-induced disability in young children worldwide, and social behavior impairments in this population are a significant challenge for affected patients and their families. The protracted trajectory of secondary injury processes triggered by a TBI during early life—alongside ongoing developmental maturation—offers an extended time window when therapeutic interventions may yield functional benefits. This mini-review explores the scarce but promising pre-clinical literature to date demonstrating that social behavior impairments after early life brain injuries can be modified by drug therapies. Compounds that provide broad neuroprotection, such as those targeting neuroinflammation, oxidative stress, axonal injury and/or myelination, may prevent social behavior impairments by reducing secondary neuropathology. Alternatively, targeted treatments that promote affiliative behaviors, exemplified by the neuropeptide oxytocin, may reduce the impact of social dysfunction after pediatric TBI. Complementary literature from other early life neurodevelopmental conditions such as hypoxic ischemic encephalopathy also provides avenues for future research in neurotrauma. Knowledge gaps in this emerging field are highlighted throughout, toward the goal of accelerating translational research to support optimal social functioning after a TBI during early childhood.
- Published
- 2021
- Full Text
- View/download PDF
4. A Role for the Amygdala in Impairments of Affective Behaviors Following Mild Traumatic Brain Injury
- Author
-
Taylor A. McCorkle, Jessica R. Barson, and Ramesh Raghupathi
- Subjects
mild TBI ,depression ,anxiety ,posttraumatic stress disorder ,basolateral amygdala ,central amygdala ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Mild traumatic brain injury (TBI) results in chronic affective disorders such as depression, anxiety, and fear that persist up to years following injury and significantly impair the quality of life for patients. Although a great deal of research has contributed to defining symptoms of mild TBI, there are no adequate drug therapies for brain-injured individuals. Preclinical studies have modeled these deficits in affective behaviors post-injury to understand the underlying mechanisms with a view to developing appropriate treatment strategies. These studies have also unveiled sex differences that contribute to the varying phenotypes associated with each behavior. Although clinical and preclinical studies have viewed these behavioral deficits as separate entities with unique neurobiological mechanisms, mechanistic similarities suggest that a novel approach is needed to advance research on drug therapy. This review will discuss the circuitry involved in the expression of deficits in affective behaviors following mild TBI in humans and animals and provide evidence that the manifestation of impairment in these behaviors stems from an amygdala-dependent emotional processing deficit. It will highlight mechanistic similarities between these different types of affective behaviors that can potentially advance mild TBI drug therapy by investigating treatments for the deficits in affective behaviors as one entity, requiring the same treatment.
- Published
- 2021
- Full Text
- View/download PDF
5. Stem Cell Therapy for Pediatric Traumatic Brain Injury
- Author
-
Dana Lengel, Cruz Sevilla, Zoe L. Romm, Jimmy W. Huh, and Ramesh Raghupathi
- Subjects
pediatric TBI ,stem cells ,progenitor cells ,transplantation ,behavior ,white matter injury ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
There has been a growing interest in the potential of stem cell transplantation as therapy for pediatric brain injuries. Studies in pre-clinical models of pediatric brain injury such as Traumatic Brain Injury (TBI) and neonatal hypoxia-ischemia (HI) have contributed to our understanding of the roles of endogenous stem cells in repair processes and functional recovery following brain injury, and the effects of exogenous stem cell transplantation on recovery from brain injury. Although only a handful of studies have evaluated these effects in models of pediatric TBI, many studies have evaluated stem cell transplantation therapy in models of neonatal HI which has a considerable overlap of injury pathology with pediatric TBI. In this review, we have summarized data on the effects of stem cell treatments on histopathological and functional outcomes in models of pediatric brain injury. Importantly, we have outlined evidence supporting the potential for stem cell transplantation to mitigate pathology of pediatric TBI including neuroinflammation and white matter injury, and challenges that will need to be addressed to incorporate these therapies to improve functional outcomes following pediatric TBI.
- Published
- 2020
- Full Text
- View/download PDF
6. Spinal cord concussion: studying the potential risks of repetitive injury
- Author
-
Itzhak Fischer, Christopher Haas, Ramesh Raghupathi, and Ying Jin
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2016
- Full Text
- View/download PDF
7. Age-at-injury effects of microglial activation following traumatic brain injury: implications for treatment strategies
- Author
-
Ramesh Raghupathi and Jimmy W Huh
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2017
- Full Text
- View/download PDF
8. Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology
- Author
-
Saori Shimizu, Muhammad Z. Khan, Randi L Hippensteel, Anjum Parkar,, Ramesh Raghupathi, and Olimpia Meucci
- Subjects
Neuronal death ,Cdc2 ,Cell cycle proteins ,Chemokines ,gp120 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
This study sought to determine the role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology. We studied the effect of the HIV envelope protein gp120 on the expression of E2F1-dependent apoptotic proteins in human and rodent neurons and examined the expression pattern of E2F1 in the brain of HIV-infected individuals. Our findings suggest that in cultured neurons gp120 increased E2F1 levels in the nucleus, stimulated its transcriptional activity and enhanced the expression of the E2F1 target proteins Cdc2 and Puma. Studies with neuronal cultures from E2F1 deficient mice demonstrated that the transcription factor is required for gp120-induced neurotoxicity and up-regulation of Cdc2 and Puma. Levels of E2F1 protein were greater in the nucleus of neurons in brains of HIV-infected patients exhibiting dementia when compared to HIV-negative subjects or HIV-positive neurologically normal patients. Overall, these studies indicate that E2F1 is primarily involved in CXCR4-mediated neurotoxicity and HIV neuropathogenesis.
- Published
- 2007
- Full Text
- View/download PDF
9. Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition
- Author
-
Michael N. DeRidder, Melissa J. Simon, Robert Siman, Yves P. Auberson, Ramesh Raghupathi, and David F. Meaney
- Subjects
Traumatic brain injury ,Organotypic ,Hippocampus ,Caspase-3 ,Calpain ,N-methyl-d-aspartate receptor ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Apoptotic or necrotic cell death in the hippocampus is a major factor underlying the cognitive impairments following traumatic brain injury. In this study, we examined if traumatic mechanical injury would produce regional activation of calpain and caspase-3 in the in vitro hippocampus and studied how the mechanically induced activation of NR2A and NR2B containing N-methyl-d-aspartate receptors (NMDARs) affects the activation of these proteases following mechanical injury. Following a 75% stretch, significant levels of activated caspase-3 and calpain-mediated spectrin breakdown products were evident only in cells within the dentate gyrus, and little co-localization of the markers was identified within individual cells. After 100% stretch, only calpain activation was observed, localized to the CA3 subregion 24 h after stretch. At moderate injury levels, both caspase-3 and calpain activation was attenuated by blocking NR2B containing NMDARs prior to stretch or by blocking all NMDARs prior to stretch injury. Treatment with an NR2A selective NMDAR antagonist had little effect on either activated caspase-3 or Ab38 immunoreactivity following moderate injury but resulted in the appearance of activated caspase-3 in the dentate gyrus following severe mechanical stretch. Together, these studies suggest that the injury induced activation of NR2A containing NMDARs functions as a pro-survival signal, while the activation of NR2B containing NMDARs is a competing, anti-survival, signal following mechanical injury to the hippocampus.
- Published
- 2006
- Full Text
- View/download PDF
10. Hyperthermia following traumatic brain injury: a critical evaluation
- Author
-
Hilaire J Thompson, Nancy C Tkacs, Kathryn E Saatman, Ramesh Raghupathi, and Tracy K McIntosh
- Subjects
Head injury ,Thermoregulation ,Fever ,Hypothalamus ,Cytokines ,Antipyretic therapy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Hyperthermia, frequently seen in patients following traumatic brain injury (TBI), may be due to posttraumatic cerebral inflammation, direct hypothalamic damage, or secondary infection resulting in fever. Regardless of the underlying cause, hyperthermia increases metabolic expenditure, glutamate release, and neutrophil activity to levels higher than those occurring in the normothermic brain-injured patient. This synergism may further compromise the injured brain, enhancing the vulnerability to secondary pathogenic events, thereby exacerbating neuronal damage. Although rigorous control of normal body temperature is the current standard of care for the brain-injured patient, patient management strategies currently available are often suboptimal and may be contraindicated. This article represents a compendium of published work regarding the state of knowledge of the relationship between hyperthermia and TBI, as well as a critical examination of current management strategies.
- Published
- 2003
- Full Text
- View/download PDF
11. Sedation and Analgesia in Children with Developmental Disabilities and Neurologic Disorders
- Author
-
Todd J. Kilbaugh, Stuart H. Friess, Ramesh Raghupathi, and Jimmy W. Huh
- Subjects
Pediatrics ,RJ1-570 - Abstract
Sedation and analgesia performed by the pediatrician and pediatric subspecialists are becoming increasingly common for diagnostic and therapeutic purposes in children with developmental disabilities and neurologic disorders (autism, epilepsy, stroke, obstructive hydrocephalus, traumatic brain injury, intracranial hemorrhage, and hypoxic-ischemic encephalopathy). The overall objectives of this paper are (1) to provide an overview on recent studies that highlight the increased risk for respiratory complications following sedation and analgesia in children with developmental disabilities and neurologic disorders, (2) to provide a better understanding of sedatives and analgesic medications which are commonly used in children with developmental disabilities and neurologic disorders on the central nervous system.
- Published
- 2010
- Full Text
- View/download PDF
12. Glucocorticoid Receptor Overexpression in the Dorsal Hippocampus Attenuates Spatial Learning and Synaptic Plasticity Deficits after Pediatric Traumatic Brain Injury
- Author
-
Dana Lengel, Zoe L. Romm, Anna Bostwick, Jimmy W. Huh, Nathaniel W. Snyder, George M. Smith, and Ramesh Raghupathi
- Subjects
Male ,Neuronal Plasticity ,Long-Term Potentiation ,Spatial Learning ,Original Articles ,Hippocampus ,Rats ,Receptors, Glucocorticoid ,Receptors, Glutamate ,Brain Injuries ,Brain Injuries, Traumatic ,Animals ,Humans ,Female ,Neurology (clinical) ,Child ,Maze Learning ,Glucocorticoids - Abstract
Traumatic brain injury (TBI) in children
- Published
- 2023
13. Combination products
- Author
-
Andrew L. DiMatteo, Jessica Barson, and Ramesh Raghupathi
- Published
- 2023
14. List of contributors
- Author
-
Arad Abadi, Sherwin Abdoli, Benjamin Acton, Alexandra M. Adams, Aderinsola A. Aderonmu, Rakesh Ahuja, Saleh Aiyash, Gabriel Akopian, Benjamin G. Allar, Michael F. Amendola, Taylor Anderson, Athena Andreadis, Darwin N. Ang, Ersilia Anghel, Favour Mfonobong Anthony, Precious Idorenyin Anthony, Jordan C. Apfeld, Youssef Aref, Fernando D. Arias, Margaret Arnold, Abbasali Badami, Jeffrey Alexander Bakal, Varun V. Bansal, J. Barney, Jessica Barson, Lauren L. Beck, Andrew R. Bender, Vivek Bhat, Saptarshi Biswas, David Blitzer, Tayt Boeckholt, John S. Bolton, Sourav K. Bose, Gerald M. Bowers, Mary E. Brindle, Matthew A. Brown, F. Charles Brunicardi, Richard A. Burkhart, Jennifer L. Byk, M. Campbell, Danilea M. Carmona Matos, Kenny J. Castro-Ochoa, Juan Cendan, Shane Charles, Angel D. Chavez-Rivera, Hao Wei Chen, Herbert Chen, Kevin Chen, Wendy Chen, Darren C. Cheng, Nicole B. Cherng, Christina Shree Chopra, G. Travis Clifton, Jason Crowner, Houston Curtis, Temilolaoluwa O. Daramola, Aria Darbandi, Serena Dasani, Kaci DeJarnette, Jeremiah Deneve, Karuna Dewan, Marcus Dial, Jody C. DiGiacomo, Andrew L. DiMatteo, Tsering Y. Dirkhipa, James M. Dittman, Ashley C. Dodd, Israel Dowlat, Hans E. Drawbert, Juan Duchesne, Omar Elfanagely, Yousef Elfanagely, Javed Khader Eliyas, Chukwuma N. Eruchalu, James C. Etheridge, Erfan Faridmoayer, Arjumand Faruqi, Jessica Dominique Feliz, Martin D. Fleming, Laura M. Fluke, Jason M. Flynn, Kathryn L. Fowler, Miguel Garcia, Tushar Garg, Patrick C. Gedeon, Ruby Gilmor, Julie Goldman, Christian Gonzalez, Rachael E. Guenter, Brian C. Gulack, Matthew Handmacher, Ivy N. Haskins, Carl Haupt, Kshipra Hemal, Matthew T. Hey, Perez Holguin, Christopher S. Hollenbeak, Andrew Holmes, Hyo Jung Hong, Nicholas Huerta, Mohamad A. Hussain, Yaritza Inostroza-Nieves, Marc J. Kahn, Sunil S. Karhadkar, Mohammed A. Kashem, Qingwen Kawaji, Syed Faraz Kazim, Kathryn C. Kelley, Monty U. Khajanchi, Shaarif Rauf Khan, Quynh Kieu, Charissa Kim, Roger Klein, Suzanne Kool, Jessica S. Kruger, Afif N. Kulaylat, Audrey S. Kulaylat, Elizabeth Laikhter, Samuel Lance, Megan LeBlanc, David Lee, Frank V. Lefevre, Jacob Levy, Deacon J. Lile, Carol A. Lin, Xinyi Luo, David A. Machado-Aranda, Kashif Majeed, Madhu Mamidala, Nizam Mamode, Abhishek Mane, Samuel M. Manstein, Jenna Maroney, Jessica Maxwell, Patrick M. McCarthy, Philip McCarthy, Hector Mejia, Pallavi Menon, Albert Moeller, Dennis Spalla Morris, Haley Nadone, Anil Nanda, Allison Nauta, Matthew Navarro, Daniel W. Nelson, Daniel C. Neubauer, Kaitlin A. Nguyen, Louis L. Nguyen, Katherine Nielson, Austin O. McCrea, Delia S. Ocaña Narváez, Peter Oro, Gezzer Ortega, Adena J. Osband, Ahmad Ozair, Rohan Palanki, Jaime Pardo Palau, Juliet Panichella, Panini Patankar, Aneri Patel, Nirmit Patel, Gehan A. Pendlebury, Christina Poa-Li, Sangeetha Prabhakaran, Hashir Qamar, Ramesh Raghupathi, Faique Rahman, Mohan Ramalingam, Syed S. Razi, Aminah Abdul Razzack, Abdul Razzaq, Amanda J. Reich, Christopher Reid, Clay Resweber, Mark Riddle, Mehida Rojas-Alexandre, Susan Rowell, Vanessa Roxo, Debosree Roy, Jacqueline L. Russell, Mala Sachdev, Ruben D. Salas-Parra, Ali Salim, John H. Sampson, Andrea Valquiria Sanchez, Tiffany R. Sanchez, Jane R. Schubart, C. Schwartz, Alexander Schwartzman, Erin M. Scott, Ali Seifi, Aditya Sekhani, Chan Shen, Eric Shiah, Jeffrey W. Shupp, Meaghan Sievers, Rachel E. Silver, Kirit Singh, Robert D. Sinyard, Kevin L. Smith, Tandis Soltani, Abhinav Arun Sonkar, Dallas J. Soyland, Mackinzie A. Stanley, David E. Stein, Sean C. Stuart, Linh Tran, Andrew Vierra, Vanessa M. Welten, Kate Whelihan, Brandon M. White, Rebecca L. Williams-Karnesky, Emily E. Witt, Heather X. Rhodes, Seiji Yamaguchi, Ravali Yenduri, Andrew Yiu, Benjamin R. Zambetti, Christa Zino, and Haley A. Zlomke
- Published
- 2023
15. Microglia in traumatic brain injury
- Author
-
Ramesh Raghupathi, Dana Lengel, and Jimmy W. Huh
- Published
- 2022
16. Sex and estrous-phase dependent alterations in depression-like behavior following mild traumatic brain injury in adolescent rats
- Author
-
Ramesh Raghupathi, Jimmy W. Huh, and Laura L. Giacometti
- Subjects
Male ,medicine.medical_specialty ,Elevated plus maze ,Traumatic brain injury ,Anxiety ,Lesion ,Cellular and Molecular Neuroscience ,Atrophy ,Estrus ,Internal medicine ,medicine ,Animals ,Brain Concussion ,Swimming ,Estrous cycle ,Behavior, Animal ,business.industry ,Depression ,Antagonist ,Mifepristone ,medicine.disease ,Rats ,Endocrinology ,Female ,medicine.symptom ,business ,human activities ,medicine.drug ,Behavioural despair test - Abstract
Following mild traumatic brain injury (TBI), high school and collegiate-aged females tend to report more emotional symptoms than males. Adolescent male and female rats (35 days old) were subjected to mild TBI and evaluated for anxiety- and depression-like behaviors using the elevated plus maze and forced swim test (FST), respectively, and cellular alterations. Injured brains did not exhibit an overt lesion, atrophy of tissue or astrocytic reactivity underneath the impact site at 6-week post-injury, suggestive of the mild nature of trauma. Neither male nor female brain-injured rats exhibited anxiety-like behavior at 2 or 6 weeks, regardless of estrous phase at the time of behavior testing. Brain-injured male rats did not exhibit any alterations in immobility, swimming and climbing times in the FST compared to sham-injured rats at either 2- or 6-week post-injury. Brain-injured female rats did, however, exhibit an increase in immobility (in the absence of changes in swimming and climbing times) in the FST at 6 weeks post-injury only during the estrus phase of the estrous cycle, suggestive of a depression-like phenotype. Combined administration of the estrogen receptor antagonist, tamoxifen, and the progesterone receptor antagonist, mifepristone, during proestrus was able to prevent the depression-like phenotype observed during estrus. Taken together, these data suggest that female rats may be more vulnerable to exhibiting behavioral deficits following mild TBI and that estrous phase may play a role in depression-like behavior.
- Published
- 2021
17. Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury
- Author
-
Ramesh Raghupathi, Avery Runyan, Jessica R. Barson, Jimmy W. Huh, and Dana Lengel
- Subjects
Adult ,Male ,Traumatic brain injury ,Postsynaptic Current ,Prefrontal Cortex ,Inhibitory postsynaptic potential ,Oxytocin ,intranasal administration ,social behavior ,excitability ,Brain Injuries, Traumatic ,Medicine ,pediatric TBI ,Animals ,Humans ,GABAergic neurotransmission ,Prefrontal cortex ,Child ,Administration, Intranasal ,business.industry ,General Neuroscience ,Novelty ,General Medicine ,medicine.disease ,Oxytocin receptor ,Rats ,nervous system ,Inhibitory Postsynaptic Potentials ,Hypothalamus ,Disorders of the Nervous System ,Female ,business ,Neuroscience ,Research Article: New Research ,medicine.drug - Abstract
Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the OXT receptor (OXTR) mRNAs in the hypothalamus and mPFC, respectively, intranasal administration of OXT before behavioral testing was found to reduce impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals. These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits.
- Published
- 2021
18. The Cellular and Physiological Basis of Behavioral Health After Mild Traumatic Brain Injury
- Author
-
Ramesh Raghupathi, Lauren A. Buck, and Laura L. Giacometti
- Subjects
business.industry ,Traumatic brain injury ,Cognition ,medicine.disease ,Bioinformatics ,Mental health ,Substance abuse ,chemistry.chemical_compound ,chemistry ,Medicine ,Anxiety ,medicine.symptom ,business ,Neurotransmitter ,Depression (differential diagnoses) ,Post-Traumatic Headache - Abstract
Depression and anxiety have been identified as the two common psychiatric symptoms of mild traumatic brain injury (TBI). These conditions are often comorbid with other symptoms such as post-traumatic headache and sleep disturbances, which can further exacerbate or be exacerbated by depression and anxiety. Although most preclinical investigations into the consequences of mild traumatic brain injury have focused on transient cognitive deficits, persistent changes in mental health have been receiving increasing attention. The research on cellular and physiological impact has primarily been conducted in adult male mice and rats; age and sex have been shown to be major factors in determining vulnerability to exhibiting these behavioral alterations. Cell death, axonal injury, inflammation, and neurotransmitter dysfunction have been proposed as potential mechanisms of behavioral dysfunction following TBI. As the cellular and molecular consequences of TBI are complex, these behavioral deficits most likely result as a combination of all of these changes. This chapter reviews the state of the literature on the establishment and utility of preclinical models of mild TBI to examine mechanisms of behavioral deficits in the chronic post-traumatic period.
- Published
- 2020
19. Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology
- Author
-
Jimmy W. Huh, Lauren A. Hanlon, and Ramesh Raghupathi
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Traumatic brain injury ,Article ,White matter ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Developmental Neuroscience ,Memory ,Head Injuries, Closed ,Brain Injuries, Traumatic ,medicine ,Animals ,Maze Learning ,Cerebral Cortex ,Neurons ,Microglia ,Behavior, Animal ,business.industry ,Neurodegeneration ,Subiculum ,Analgesics, Non-Narcotic ,medicine.disease ,White Matter ,Pathophysiology ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,nervous system ,Animals, Newborn ,Closed head injury ,Nerve Degeneration ,Female ,Clodronic Acid ,business ,030217 neurology & neurosurgery ,Psychomotor Performance - Abstract
The inflammatory response is a significant component of the pathophysiology of pediatric traumatic brain injury. High levels of inflammatory mediators have been found in the cerebrospinal fluid of brain-injured children which have been linked to poor prognosis. Targeting aspects of the inflammatory response in the hopes of finding a viable post-injury therapeutic option has gained attention. Microglia are largely responsible for perpetuating the injury-induced inflammatory response but in the developing brain they play beneficial roles in both normal and disease states. Following closed head injury in the neonate rat, depletion of microglia with intracerebral injections of liposomes containing clodronate was associated with an increase in neurodegeneration in the early post-injury period (3 days) relative to those injected with empty liposomes suggestive of a decrease in clearance of dying cells. In sham-injured animals, microglia repopulated the clodrosome-mediated depleted brain regions over a period of 2–4 weeks and exhibited morphology typical of a resting phenotype. In brain-injured animals, the repopulated microglia in clodrosome-injected animals exhibited rod-like and amoeboid morphologies. However, fluoro-Jade B reactivity in these brain regions was more extensive than in empty liposome-injected animals suggesting that the active microglia may be unable to clear dying neurons. This was accompanied by an induction of hyperexcitability in the local cortical circuitry. Depletion of microglia within the white matter tracts and the thalamus did not affect the extent of injury-induced traumatic axonal injury. Increased neurodegeneration in the dorsal subiculum was not accompanied by any changes to injury-induced deficits in spatial learning and memory. These data suggest that activation of microglia may be important for removal of dying neurons in the traumatically-injured immature brain.
- Published
- 2019
20. Animal Models of Pediatric Traumatic Brain Injury: Lessons Learned
- Author
-
Jimmy W. Huh, Lauren A. Hanlon, and Ramesh Raghupathi
- Subjects
medicine.medical_specialty ,Physical medicine and rehabilitation ,Traumatic brain injury ,business.industry ,medicine ,medicine.disease ,business - Abstract
A predominant focus of both clinical and preclinical pediatric traumatic brain injury (TBI) research is to combat secondary injury processes in the acute posttraumatic period that may contribute to pathologies that lead to long-term functional impairments. Identified therapeutic targets must undergo rigorous preclinical testing in relevant animal models of pediatric TBI. Animal models for pediatric TBI use injury mechanisms such as fluid-percussion, rotational-acceleration, weight-drop, and controlled cortical impact. These models span species (mice, rats, rabbits and pigs) and several age groups to encompass the developmental time points and utilize various injury severities to reproduce the pathologies such as atrophy, ventriculomegaly, white matter injury, and behavioral impairment. This review focuses on the validation of these preclinical models using clinical observations of structural and functional impairment in the acute and chronic period following TBI. In addition, the limitations of the current animal models are discussed within the context of strategies for further development of clinically relevant outcomes and therapeutic strategies.
- Published
- 2018
21. Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat
- Author
-
Argie Zoubroulis, Ole V. Mortensen, Andréia Cristina Karklin Fontana, Douglas Paul Fox, and Ramesh Raghupathi
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Traumatic brain injury ,Central nervous system ,Excitotoxicity ,medicine.disease_cause ,Neuroprotection ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Brain Injuries, Traumatic ,medicine ,Glutamate aspartate transporter ,Animals ,biology ,Chemistry ,Nicotinic Acids ,Glutamate receptor ,Transporter ,Original Articles ,medicine.disease ,Rats ,Excitatory Amino Acid Transporter 1 ,Disease Models, Animal ,Neuroprotective Agents ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Excitatory Amino Acid Transporter 2 ,Biochemistry ,biology.protein ,Neurology (clinical) ,NeuN ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) in humans and in animals leads to an acute and sustained increase in tissue glutamate concentrations within the brain, triggering glutamate-mediated excitotoxicity. Excitatory amino acid transporters (EAATs) are responsible for maintaining extracellular central nervous system glutamate concentrations below neurotoxic levels. Our results demonstrate that as early as 5 min and up to 2 h following brain trauma in brain-injured rats, the activity (Vmax) of EAAT2 in the cortex and the hippocampus was significantly decreased, compared with sham-injured animals. The affinity for glutamate (KM) and the expression of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) were not altered by the injury. Administration of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a GLT-1 activator, beginning immediately after injury and continuing for 24 h, significantly decreased neurodegeneration, loss of microtubule-associated protein 2 and NeuN (+) immunoreactivities, and attenuated calpain activation in both the cortex and the hippocampus at 24 h after the injury; the reduction in neurodegeneration remained evident up to 14 days post-injury. In synaptosomal uptake assays, MS-153 up-regulated GLT-1 activity in the naïve rat brain but did not reverse the reduced activity of GLT-1 in traumatically-injured brains. This study demonstrates that administration of MS-153 in the acute post-traumatic period provides acute and long-term neuroprotection for TBI and suggests that the neuroprotective effects of MS-153 are related to mechanisms other than GLT-1 activation, such as the inhibition of voltage-gated calcium channels.
- Published
- 2016
22. Progesterone treatment following traumatic brain injury in the 11-day-old rat attenuates cognitive deficits and neuronal hyperexcitability in adolescence
- Author
-
Dana Lengel, Ramesh Raghupathi, Jimmy W. Huh, and Jessica R. Barson
- Subjects
Male ,0301 basic medicine ,Elevated plus maze ,medicine.medical_specialty ,Traumatic brain injury ,Excitatory Amino Acid Transporter 3 ,Glutamate decarboxylase ,Prefrontal Cortex ,Inhibitory postsynaptic potential ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Internal medicine ,Brain Injuries, Traumatic ,medicine ,Animals ,Cognitive Dysfunction ,Prefrontal cortex ,Progesterone ,Neurons ,business.industry ,Excitatory Postsynaptic Potentials ,medicine.disease ,Rats ,030104 developmental biology ,Endocrinology ,Animals, Newborn ,Neurology ,Closed head injury ,Excitatory postsynaptic potential ,Female ,business ,030217 neurology & neurosurgery - Abstract
Traumatic brain injury (TBI) in children younger than 4 years old results in cognitive and psychosocial deficits in adolescence and adulthood. At 4 weeks following closed head injury on postnatal day 11, male and female rats exhibited impairment in novel object recognition memory (NOR) along with an increase in open arm time in the elevated plus maze (EPM), suggestive of risk-taking behaviors. This was accompanied by an increase in intrinsic excitability and frequency of spontaneous excitatory post-synaptic currents (EPSCs), and a decrease in the frequency of spontaneous inhibitory post-synaptic currents in layer 2/3 neurons within the medial prefrontal cortex (PFC), a region that is implicated in both object recognition and risk-taking behaviors. Treatment with progesterone for the first week after brain injury improved NOR memory at the 4-week time point in both sham and brain-injured rats and additionally attenuated the injury-induced increase in the excitability of neurons and the frequency of spontaneous EPSCs. The effect of progesterone on cellular excitability changes after injury may be related to its ability to decrease the mRNA expression of the β3 subunit of the voltage-gated sodium channel and increase the expression of the neuronal excitatory amino acid transporter 3 in the medial PFC in sham- and brain-injured animals and also increase glutamic acid decarboxylase mRNA expression in sham- but not brain-injured animals. Progesterone treatment did not affect injury-induced changes in the EPM test. These results demonstrate that administration of progesterone immediately after TBI in 11-day-old rats reduces cognitive deficits in adolescence, which may be mediated by progesterone-mediated regulation of excitatory signaling mechanisms within the medial PFC.
- Published
- 2020
23. Therapeutic strategies to target acute and long-term sequelae of pediatric traumatic brain injury
- Author
-
Ramesh Raghupathi and Jimmy W. Huh
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Traumatic brain injury ,Psychological intervention ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Brain Injuries, Traumatic ,medicine ,Animals ,Humans ,Dosing ,Intensive care medicine ,Child ,Pharmacology ,Developmental age ,business.industry ,Mortality rate ,Neurointensive care ,Cognition ,medicine.disease ,030104 developmental biology ,Traumatic injury ,Acute Disease ,Chronic Disease ,business ,030217 neurology & neurosurgery - Abstract
Pediatric traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in children. Experimental and clinical studies demonstrate that the developmental age, the type of injury (diffuse vs. focal) and sex may play important roles in the response of the developing brain to a traumatic injury. Advancements in acute neurosurgical interventions and neurocritical care have improved and led to a decrease in mortality rates over the past decades. However, survivors are left with life-long behavioral deficits underscoring the need to better define the cellular mechanisms underlying these functional changes. A better understanding of these mechanisms some of which begin in the acute post-traumatic period may likely lead to targeted treatment strategies. Key considerations in designing pre-clinical experiments to test therapeutic strategies in pediatric TBI include the use of age-appropriate and pathologically-relevant models, functional outcomes that are tested as animals age into adolescence and beyond, sex as a biological variable and the recognition that doses and dosing strategies that have been demonstrated to be effective in animal models of adult TBI may not be effective in the developing brain. This article is part of the Special Issue entitled “Novel Treatments for Traumatic Brain Injury”.
- Published
- 2018
24. Genetics and Pathology of Chronic Traumatic Encephalopathy
- Author
-
Laura L. Krafjack and Ramesh Raghupathi
- Subjects
Chronic traumatic encephalopathy ,Personality changes ,business.industry ,Traumatic brain injury ,Medicine ,sense organs ,General Medicine ,business ,medicine.disease ,Neuroscience ,Pathological ,Memory problems - Abstract
Chronic traumatic encephalopathy (CTE), characterized by the presence of neurofibrillary and astrocytic tangles composed of hyperphosphorylated tau, is believed to be one of the pathological consequences of repetitive traumatic brain injury (TBI). CTE has been diagnosed postmortem in numerous individuals, including professional boxers and American football players, with a history of repetitive TBI [1, 2••, 3–7]. Concomitant with the identification of these neurofibrillary and astrocytic tangles are retrospective reports from family members and friends of these individuals of memory problems and personality changes, suggesting that the observed pathological changes may underlie the reported behavioral changes. Multiple animal models have been developed to further explore how repetitive TBI results in these pathological findings and whether these alterations underlie behavioral changes. Defining CTE and Limitations of Diagnosis
- Published
- 2015
25. Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments
- Author
-
Rudolph E. Tanzi, Nianli Sang, Ramesh Raghupathi, Can Zhang, Haizhi Wang, and Aleister J. Saunders
- Subjects
Leupeptins ,Cathepsin L ,Proteolysis ,Protein degradation ,Biochemistry ,Article ,Amyloid beta-Protein Precursor ,Cell Line, Tumor ,medicine ,Amyloid precursor protein ,Animals ,Humans ,Cells, Cultured ,Cathepsin ,L-Lactate Dehydrogenase ,medicine.diagnostic_test ,biology ,Calpain ,Chemistry ,Ubiquitination ,Peptide Fragments ,Rats ,Alpha secretase ,biology.protein ,Cattle ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase - Abstract
Alzheimer's disease (AD) is characterized by the deposition of amyloid β (Aβ), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via α-, β-, and γ-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of several novel APP C-terminal fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kDa and can be observed across multiple cell types. The process was independent of cytotoxicity or protein synthesis. We further determine that the accumulation of the novel CTFs is not mediated by proteasome or calpain inhibition, but by cathepsin L inhibition. Moreover, these novel CTFs are not generated by an increased amount of BACE. Here, we name the CTF of 25 kDa as η-CTF (eta-CTF). Our data suggest that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kDa CTFs, and the η-CTFs aret rapidly degraded and/or processed via the protein degradation machinery, specifically, cathepsin L.
- Published
- 2015
26. Spinal cord concussion: studying the potential risks of repetitive injury
- Author
-
Ramesh Raghupathi, Ying Jin, Christopher Haas, and Itzhak Fischer
- Subjects
medicine.medical_specialty ,business.industry ,Neurapraxia ,030229 sport sciences ,medicine.disease ,Spinal cord ,lcsh:RC346-429 ,Highlights ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine.anatomical_structure ,Developmental Neuroscience ,Concussion ,medicine ,Whiplash ,Posterior longitudinal ligament ,Spinal canal ,Paraplegia ,business ,Spinal cord injury ,030217 neurology & neurosurgery ,lcsh:Neurology. Diseases of the nervous system - Abstract
What is spinal concussion? Spinal cord concussion is a variant of mild spinal cord injury, clinically designated as transient paraplegia or neurapraxia, and characterized by variable degrees of sensory impairment and motor weakness that typically resolve within 24–72 hours without permanent deficits (Del Bigio and Johnson, 1989; Zwimpfer and Bernstein, 1990; Torg et al., 1997). Accordingly, a grading system was developed based on the duration of symptoms, ranging from Grade I ( 24 hours) (Zwimpfer and Bernstein, 1990; Torg et al., 1997). Spinal cord concussion is predominantly a sport-related injury occurring in a wide variety of contact sports in adult and pediatric athletes including wrestling, hockey, gymnastics, and diving, but most commonly in American football, although spinal concussions can also occur after minor car accidents as “whiplash injuries” and falls (Zwimpfer and Bernstein, 1990). In contact sports, the cervical spine is particularly susceptible to injury because of axial loading forces to the head with the neck in flexion or extension. In these circumstances, injury may occur due to disc herniation, buckling of the ligamentum flavum or the posterior longitudinal ligament, or by compression of the spinal cord between vertebral bodies. There appears to be a mechanistic difference in the injury between adult and pediatric age groups. In the adult, a stenotic spinal canal or a diminished spinal canal to vertebral body diameter predispose patients to cervical concussion at the level of stenosis after hyperextension, hyperflexion, or axial loading. The pediatric spine, in contrast, has increased mobility, predisposing the spinal cord to contact with bony elements even in absence of focal stenosis (Clark et al., 2011). Guidelines regarding return to play have been developed based upon the duration of neurological symptoms, neurapraxia, and MRI analysis, but they are based on a limited number of small-scale retrospective studies (Tempel et al., 2015). Given the lack of randomized trials, medical clearance of athletes for resumption of activities is a highly controversial topic without consensus opinion (Cantu, 1998; Morganti, 2003; Mayers, 2008; Harmon et al., 2013). Furthermore, many individuals may experience multiple episodes of spinal cord concussion with recurrence of symptoms (Zwimpfer and Bernstein, 1990; Torreman et al., 1996; Clark et al., 2011). It has therefore been important to develop animal models of spinal cord concussion to elucidate the histological and functional deficits of single and repeated injuries. This perspective presents our recent efforts in developing such a model and the consequences of repetitive injury (Jin et al., 2014, 2015).
- Published
- 2016
27. Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat
- Author
-
Ramesh Raghupathi, Lauren A. Hanlon, and Jimmy W. Huh
- Subjects
0301 basic medicine ,Male ,Time Factors ,Traumatic brain injury ,Spatial Learning ,Antigens, Differentiation, Myelomonocytic ,Inflammation ,Minocycline ,Corpus callosum ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,Cerebrospinal fluid ,Atrophy ,Antigens, CD ,medicine ,Animals ,Microglia ,Macrophages ,Neurodegeneration ,Calcium-Binding Proteins ,Microfilament Proteins ,Brain ,General Medicine ,Original Articles ,medicine.disease ,Fluoresceins ,Anti-Bacterial Agents ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Animals, Newborn ,Brain Injuries ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology ,Cognition Disorders ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury.
- Published
- 2017
28. Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models
- Author
-
Ramesh Raghupathi, Lee Anne Cannella, Servio H. Ramirez, Steven F. Merkel, Roshanak Razmpour, Evan M. Lutton, and Scott M. Rawls
- Subjects
0301 basic medicine ,Risk ,Traumatic brain injury ,Substance-Related Disorders ,Cognitive Neuroscience ,Neuropathology ,Affect (psychology) ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Neurochemical ,Brain Injuries, Traumatic ,medicine ,Animals ,Humans ,Neuroinflammation ,Dopaminergic ,medicine.disease ,nervous system diseases ,Substance abuse ,030104 developmental biology ,Neuropsychology and Physiological Psychology ,Models, Animal ,Substance use ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Recent studies have helped identify multiple factors affecting increased risk for substance use disorders (SUDs) following traumatic brain injury (TBI). These factors include age at the time of injury, repetitive injury and TBI severity, neurocircuits, neurotransmitter systems, neuroinflammation, and sex differences. This review will address each of these factors by discussing 1) the clinical and preclinical data identifying patient populations at greatest risk for SUDs post-TBI, 2) TBI-related neuropathology in discrete brain regions heavily implicated in SUDs, and 3) the effects of TBI on molecular mechanisms that may drive substance abuse behavior, like dopaminergic and glutamatergic transmission or neuroimmune signaling in mesolimbic regions of the brain. Although these studies have laid the groundwork for identifying factors that affect risk of SUDs post-TBI, additional studies are required. Notably, preclinical models have been shown to recapitulate many of the behavioral, cellular, and neurochemical features of SUDs and TBI. Therefore, these models are well suited for answering important questions that remain in future investigations.
- Published
- 2017
29. Differential Effects of FK506 on Structural and Functional Axonal Deficits After Diffuse Brain Injury in the Immature Rat
- Author
-
Ann Mae DiLeonardi, Jimmy W. Huh, and Ramesh Raghupathi
- Subjects
Male ,Aging ,medicine.medical_specialty ,Retrograde Degeneration ,Neurofilament ,Traumatic brain injury ,animal diseases ,Corpus callosum ,Tacrolimus ,Article ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,business.industry ,Diffuse axonal injury ,virus diseases ,General Medicine ,medicine.disease ,Axons ,Rats ,Calcineurin ,Endocrinology ,nervous system ,Neurology ,Brain Injuries ,Closed head injury ,Axoplasmic transport ,Female ,Neurology (clinical) ,business ,Neuroscience ,Immunosuppressive Agents - Abstract
Diffuse axonal injury is a major component of traumatic brain injury in children and correlates with long-term cognitive impairment. Traumatic brain injury in adult rodents has been linked to a decrease in compound action potential (CAP) in the corpus callosum but information on trauma-associated diffuse axonal injury in immature rodents is limited. We investigated the effects of closed head injury on CAP in the corpus callosum of 17-day-old rats. The injury resulted in CAP deficits of both myelinated and unmyelinated fibers in the corpus callosum between 1 and 14 days post-injury (dpi). These deficits were accompanied by intra-axonal dephosphorylation of the 200-kDa neurofilament subunit (NF200) at 1 and 3 dpi, a decrease in total NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi. Although total phosphatase activity decreased at 1 dpi, calcineurin activity was unchanged. The calcineurin inhibitor, FK506, significantly attenuated the injury-induced NF200 dephosphorylation of NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi, but did not affect the decrease in NF200 protein levels or impaired axonal transport. FK506 had no effect on CAP deficits at 3 dpi, but exacerbated the deficit in only the myelinated fibers at 7 dpi. Thus, in contrast to adult animals, FK506 treatment did not improve axonal function in brain-injured immature animals, suggesting that calcineurin may not contribute to impaired axonal function.
- Published
- 2012
30. Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat
- Author
-
Jimmy W. Huh, Lauren A. Hanlon, and Ramesh Raghupathi
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Traumatic brain injury ,Spatial Learning ,Hippocampus ,Minocycline ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cerebellar Cortex ,0302 clinical medicine ,Cerebrospinal fluid ,Developmental Neuroscience ,Thalamus ,Head Injuries, Closed ,medicine ,Animals ,Memory Disorders ,Microglia ,business.industry ,Neurodegeneration ,medicine.disease ,White Matter ,Pathophysiology ,Axons ,Anti-Bacterial Agents ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Animals, Newborn ,Anesthesia ,Closed head injury ,Nerve Degeneration ,Female ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3 days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p
- Published
- 2016
31. Strong Correlation of Genome-Wide Expression after Traumatic Brain Injury In Vitro and In Vivo Implicates a Role for SORLA
- Author
-
Jennifer L Hammers, Benjamin S. Elkin, John F. Crary, Barclay Morrison, Jimmy W. Huh, Michael R. Lamprecht, Kartik Kesavabhotla, and Ramesh Raghupathi
- Subjects
0301 basic medicine ,Adult ,Male ,Traumatic brain injury ,Protein Array Analysis ,Genomics ,Biology ,Hippocampus ,Rats, Sprague-Dawley ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,In vivo ,Gene expression ,Brain Injuries, Traumatic ,Amyloid precursor protein ,medicine ,Animals ,Humans ,Receptor ,Gene ,Cells, Cultured ,LDL-Receptor Related Proteins ,Membrane Transport Proteins ,Original Articles ,Middle Aged ,medicine.disease ,In vitro ,Cell biology ,030104 developmental biology ,Animals, Newborn ,biology.protein ,Female ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
The utility of in vitro models of traumatic brain injury (TBI) depends on their ability to recapitulate the in vivo TBI cascade. In this study, we used a genome-wide approach to compare changes in gene expression at several time points post-injury in both an in vitro model and an in vivo model of TBI. We found a total of 2073 differentially expressed genes in our in vitro model and 877 differentially expressed genes in our in vivo model when compared to noninjured controls. We found a strong correlation in gene expression changes between the two models (r = 0.69), providing confidence that the in vitro model represented at least part of the in vivo injury cascade. From these data, we searched for genes with significant changes in expression over time (analysis of covariance) and identified sorting protein-related receptor with A-type repeats (SORLA). SORLA directs amyloid precursor protein to the recycling pathway by direct binding and away from amyloid-beta producing enzymes. Mutations of SORLA have been linked to Alzheimer's disease (AD). We confirmed downregulation of SORLA expression in organotypic hippocampal slice cultures by immunohistochemistry and Western blotting and present preliminary data from human tissue that is consistent with these experimental results. Together, these data suggest that the in vitro model of TBI used in this study strongly recapitulates the in vivo TBI pathobiology and is well suited for future mechanistic or therapeutic studies. The data also suggest the possible involvement of SORLA in the post-traumatic cascade linking TBI to AD.
- Published
- 2016
32. Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function
- Author
-
Jennifer A Creed, Alan Tessler, Douglas Paul Fox, Ann Mae DiLeonardi, and Ramesh Raghupathi
- Subjects
Male ,Traumatic brain injury ,Blotting, Western ,Action Potentials ,Poison control ,Hippocampus ,Axonal Transport ,Mice ,Cognition ,Cortex (anatomy) ,Concussion ,medicine ,Animals ,Maze Learning ,Brain Concussion ,Neurons ,Analysis of Variance ,Dentate gyrus ,Original Articles ,medicine.disease ,Axons ,Memory, Short-Term ,medicine.anatomical_structure ,nervous system ,Anesthesia ,Nerve Degeneration ,Closed head injury ,Neurology (clinical) ,Righting reflex ,Cognition Disorders ,Psychology - Abstract
Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p
- Published
- 2011
33. Differential Effects of Injury Severity on Cognition and Cellular Pathology after Contusive Brain Trauma in the Immature Rat
- Author
-
Jimmy W. Huh, Ashley G. Widing, and Ramesh Raghupathi
- Subjects
Male ,Aging ,Cellular pathology ,Pathology ,medicine.medical_specialty ,Time Factors ,Traumatic brain injury ,Thalamus ,Brain damage ,Corpus callosum ,Severity of Illness Index ,Rats, Sprague-Dawley ,White matter ,Cortex (anatomy) ,medicine ,Animals ,Brain ,Cell Differentiation ,Original Articles ,medicine.disease ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,Brain Injuries ,Nerve Degeneration ,Closed head injury ,Female ,Neurology (clinical) ,medicine.symptom ,Cognition Disorders ,Psychology - Abstract
Although diffuse brain damage has been suggested to be the predominant predictor of neurological morbidity following closed head injury in infants and children, the presence of contusions also predicts long-term neurobehavioral dysfunction. Contusive brain trauma in the 17-day-old rat resulted in neurodegeneration and caspase activation in the cortex at 1 day, and in the thalamus at 3 days post-injury, and to a greater extent following a deeper impact. Cortical tissue loss in the 4-mm impact group was significantly greater than that in the 3-mm impact group (p
- Published
- 2011
34. Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice
- Author
-
Tracy K. McIntosh, Ramesh Raghupathi, Uwe Scherbel, Gregor Tomasevic, and Tadeusz Wieloch
- Subjects
Pathology ,medicine.medical_specialty ,Programmed cell death ,Tumor suppressor gene ,Traumatic brain injury ,Thalamus ,Ischemia ,Hippocampus ,Context (language use) ,Biology ,medicine.disease ,Cellular and Molecular Neuroscience ,medicine ,Function (biology) - Abstract
Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests. By 7 days posttrauma, p53(-/-) mice exhibited significantly improved neuromotor function, in the composite neuroscore (P = 0.002) as well as in two of three individual tests, when compared with brain-injured p53(+/+) animals. CCI resulted in the formation of a cortical cavity (mean volume = 6.1 mm(3)) 7 days postinjury in p53(+/+) as well as p53(-/-) mice. No difference in lesion volume was detected between the two genotypes (P = 0.95). Although significant cell loss was detected in the ipsilateral hippocampus and thalamus of brain-injured animals, no differences between p53(+/+) and p53(-/-) mice were detected. Although our results suggest that lack of the p53 gene results in augmented recovery of neuromotor function following experimental brain trauma, they do not support a role for p53 acting as a mediator of neuronal death in this context, underscoring the complexity of its role in the injured brain.
- Published
- 2010
35. Calpain as a therapeutic target in traumatic brain injury
- Author
-
Kathryn E. Saatman, Ramesh Raghupathi, and Jennifer A Creed
- Subjects
Pharmacology ,Cell signaling ,Proteases ,Programmed cell death ,Calpain ,Traumatic brain injury ,Review Article ,Biology ,medicine.disease ,Neuroprotection ,nervous system ,Brain Injuries ,medicine ,biology.protein ,Animals ,Humans ,Pharmacology (medical) ,Spectrin ,Neurology (clinical) ,Neuron death ,Neuroscience ,Biomarkers - Abstract
The family of calcium-activated neutral proteases, calpains, appears to play a key role in neuropathologic events following traumatic brain injury (TBI). Neuronal calpain activation has been observed within minutes to hours after either contusive or diffuse brain trauma in animals, suggesting that calpains are an early mediator of neuronal damage. Whereas transient calpain activation triggers numerous cell signaling and remodeling events involved in normal physiological processes, the sustained calpain activation produced by trauma is associated with neuron death and axonal degeneration in multiple models of TBI. Nonetheless, the causal relationship between calpain activation and neuronal death is not fully understood. Much remains to be learned regarding the endogenous regulatory mechanisms for controlling calpain activity, the roles of different calpain isoforms, and the in vivo substrates affected by calpain. Detection of stable proteolytic fragments of the submembrane cytoskeletal protein alphaII-spectrin specific for cleavage by calpains has been the most widely used marker of calpain activation in models of TBI. More recently, these protein fragments have been detected in the cerebrospinal fluid after TBI, driving interest in their potential utility as TBI-associated biomarkers. Post-traumatic inhibition of calpains, either direct or indirect through targets related to intracellular calcium regulation, is associated with attenuation of functional and behavioral deficits, axonal pathology, and cell death in animal models of TBI. This review focuses on the current state of knowledge of the role of calpains in TBI-induced neuropathology and effectiveness of calpain as a therapeutic target in the acute post-traumatic period.
- Published
- 2010
36. Combination Therapies for Traumatic Brain Injury: Prospective Considerations
- Author
-
James R. Pauly, Stephen W. Scheff, Jimmy W. Huh, Philip E. Empey, Michael R. Hoane, Jerome Badaut, Mona Hicks, Fahim Atif, M. V. Guseva, Susan S. Margulies, Huiling Tang, Ramesh Raghupathi, Donald G. Stein, Gail D. Anderson, and Robert S. B. Clark
- Subjects
Research design ,medicine.medical_specialty ,business.industry ,Clinical study design ,Alternative medicine ,MEDLINE ,Poison control ,Clinical trial ,Editorial ,Intervention (counseling) ,medicine ,Physical therapy ,Neurology (clinical) ,Intensive care medicine ,business ,Veterans Affairs - Abstract
Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time. Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development. To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.
- Published
- 2009
37. New Concepts in Treatment of Pediatric Traumatic Brain Injury
- Author
-
Jimmy W. Huh and Ramesh Raghupathi
- Subjects
Pediatrics ,medicine.medical_specialty ,Adolescent ,Basic science ,Traumatic brain injury ,Apoptosis ,Brain Edema ,Physical examination ,Article ,Craniocerebral Trauma ,Homeostasis ,Humans ,Medicine ,Anesthesia ,Acute management ,Child ,Intensive care medicine ,Physical Examination ,medicine.diagnostic_test ,business.industry ,Brain edema ,Age Factors ,Infant, Newborn ,Infant ,General Medicine ,Decompression, Surgical ,medicine.disease ,Craniocerebral trauma ,Cerebrovascular Circulation ,Pediatric patient ,Anesthesiology and Pain Medicine ,Child, Preschool ,Practice Guidelines as Topic ,Drainage ,Emergencies ,Intracranial Hypertension ,business ,Algorithms - Abstract
Emerging evidence suggests unique age-dependent responses following pediatric traumatic brain injury. As the anesthesiologist plays a pivotal role in the acute treatment of the head-injured pediatric patient, this review will provide important updates on the pathophysiology, diagnosis, and age-appropriate acute management of infants and children with severe traumatic brain injury. In addition, areas of important clinical and basic science investigations germane to the anesthesiologist, such as the role of anesthetics and apoptosis in the developing brain, will be discussed.
- Published
- 2009
38. Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration
- Author
-
Jimmy W. Huh, Ashley G. Widing, and Ramesh Raghupathi
- Subjects
Male ,Aging ,Wallerian degeneration ,Time Factors ,Subarachnoid hemorrhage ,Thalamus ,Hippocampus ,Brain Edema ,Nerve Fibers, Myelinated ,Article ,Functional Laterality ,Rats, Sprague-Dawley ,White matter ,Developmental Neuroscience ,Cortex (anatomy) ,medicine ,Animals ,Gliosis ,Neurons ,Brain ,medicine.disease ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,nervous system ,Neurology ,Blood-Brain Barrier ,Brain Injuries ,Nerve Degeneration ,Closed head injury ,Disease Progression ,Female ,medicine.symptom ,Cognition Disorders ,Wallerian Degeneration ,Psychology ,Neuroscience - Abstract
Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3–15 seconds), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury (P
- Published
- 2008
39. DNase I disinhibition is predominantly associated with actin hyperpolymerization after traumatic brain injury
- Author
-
Florence M. Bareyre, Ramesh Raghupathi, Kathryn E. Saatman, and Tracy K. McIntosh
- Subjects
Cellular and Molecular Neuroscience ,Traumatic brain injury ,Disinhibition ,business.industry ,medicine ,medicine.symptom ,medicine.disease ,business ,Biochemistry ,Neuroscience ,Actin - Published
- 2008
40. Chronic Cognitive Deficits and Long-Term Histopathological Alterations following Contusive Brain Injury in the Immature Rat
- Author
-
Jimmy W. Huh and Ramesh Raghupathi
- Subjects
Pathology ,medicine.medical_specialty ,Traumatic brain injury ,Thalamus ,Hippocampus ,Diffuse Axonal Injury ,White matter ,Head Injuries, Closed ,Cortex (anatomy) ,medicine ,Animals ,Gliosis ,Maze Learning ,Diffuse axonal injury ,Head injury ,Age Factors ,medicine.disease ,Immunohistochemistry ,Axons ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,Brain Injuries ,Anesthesia ,Chronic Disease ,Closed head injury ,Neurology (clinical) ,Cognition Disorders ,Psychology - Abstract
Although diffuse axonal injury is the primary pathology in pediatric brain trauma, the additional presence of focal contusions may contribute to the poor prognosis in brain-injured children younger than 4 years of age. Because existing models of pediatric brain trauma focus on diffuse brain injury, a model of contusive brain trauma was developed using postnatal day (PND) 11 and 17 rats, ages that are neurologically equivalent to a human infant and toddler, respectively. Closed head injury was modeled by subjecting the intact skull over the left parietal cortex of the immature rat to an impact with a metal-tipped indenter. Brain trauma on PND11 or PND17 led to significant spatial learning deficits at 28 days post-injury, compared to age-matched control rats (p < 0.05). Although both groups of rats sustained skull fractures on impact, the histopathologic response of the brain was distinctly age-dependent. At 3 days post-injury in PND11 rats, the cortex below the impact site was contused and hemorrhagic, and contained reactive astrocytes, while the subcortical white matter and thalamus contained injured (swollen) axons. At 14 and 28 days post-injury, the cortex, white matter, and hippocampus were substantially atrophied, and the lateral ventricle was enlarged. In contrast, in PND17 rats, the contused cortex observed at 3 days post-injury matured into a pronounced cavity lined with a glia limitans at 14 days; reactive astrocytes were present in both the hippocampus and thalamus up to 28 days post-injury. No evidence of traumatic axonal injury was observed in any region of the brain-injured PND17 rat. These data suggest that contusive brain trauma in the immature rat is associated with chronic cognitive deficits, but underscore the effect of the age-at-injury on behavioral and histopathologic outcomes.
- Published
- 2007
41. Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology
- Author
-
Anjum Parkar, Ramesh Raghupathi, Randi L Hippensteel, Muhammad Z. Khan, Olimpia Meucci, and Saori Shimizu
- Subjects
Male ,AIDS Dementia Complex ,Apoptosis ,Electrophoretic Mobility Shift Assay ,HIV Infections ,HIV Envelope Protein gp120 ,Mice ,Puma ,E2F1 ,Luciferases ,Cells, Cultured ,Mice, Knockout ,Neurons ,Reverse Transcriptase Polymerase Chain Reaction ,Brain ,virus diseases ,E2F1 Transcription Factor ,Cell cycle proteins ,Middle Aged ,Immunohistochemistry ,Up-Regulation ,Neurology ,Female ,Neurotoxicity Syndromes ,Chemokines ,biological phenomena, cell phenomena, and immunity ,Adult ,Receptors, CXCR4 ,endocrine system ,Neurotoxicity Syndrome ,Blotting, Western ,Immunoblotting ,Neuronal death ,Cdc2 ,Neuropathology ,Environment ,Biology ,Transfection ,Article ,lcsh:RC321-571 ,medicine ,Animals ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Transcription factor ,Aged ,Cell Nucleus ,Neurotoxicity ,Receptor Cross-Talk ,HIV envelope protein ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Rats ,gp120 ,Microscopy, Fluorescence ,Immunology ,Cancer research - Abstract
This study sought to determine the role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology. We studied the effect of the HIV envelope protein gp120 on the expression of E2F1-dependent apoptotic proteins in human and rodent neurons and examined the expression pattern of E2F1 in the brain of HIV-infected individuals. Our findings suggest that in cultured neurons gp120 increased E2F1 levels in the nucleus, stimulated its transcriptional activity, and enhanced the expression of the E2F1 target proteins Cdc2 and Puma. Studies with neuronal cultures from E2F1 deficient mice demonstrated that the transcription factor is required for gp120-induced neurotoxicity and up-regulation of Cdc2 and Puma. Levels of E2F1 protein were greater in the nucleus of neurons in brains of HIV-infected patients exhibiting dementia when compared to HIV-negative subjects or HIV-positive neurologically normal patients. Overall, these studies indicate that E2F1 is primarily involved in CXCR4-mediated neurotoxicity and HIV neuropathogenesis.
- Published
- 2007
42. Pathophysiology of Mild TBI: Implications for Altered Signaling Pathways
- Author
-
Robert Laskowski, Jennifer Creed, and Ramesh Raghupathi
- Published
- 2015
43. Computational Studies of Strain Exposures in Neonate and Mature Rat Brains during Closed Head Impact
- Author
-
Eran Linder-Ganz, Amit Gefen, Ramesh Raghupathi, Anna Levchakov, and Susan S. Margulies
- Subjects
Child abuse ,Head impact ,Traumatic brain injury ,Finite Element Analysis ,Models, Neurological ,Physiology ,Strain (injury) ,Brain tissue ,Head trauma ,Head Injuries, Closed ,medicine ,Neonatal brain ,Animals ,business.industry ,Age Factors ,Brain ,medicine.disease ,Elasticity ,Rats ,Disease Models, Animal ,Animals, Newborn ,Closed head injury ,Stress, Mechanical ,Neurology (clinical) ,business ,Neuroscience - Abstract
Traumatic brain injury (TBI) is the most common cause of death in childhood, and the majority of fatal cases are due to motor vehicle accidents, falls, sport-related accidents, and child abuse. Rodents and particularly rats became a commonly used animal model of TBI in childhood as well as in adults, and different techniques are described in the literature to induce the brain injury. However, findings reported in the last decade regarding the increased stiffness of brain tissue in young animals, including rats, are not considered in experimental designs of TBI studies, and this may seriously bias the results when TBI effects are compared across different animal ages. In this study, we determined the strain and stress distributions in neonatal (post-natal-day [PND] 13-17) and mature (PND 43 and 90) rat brains during a closed head injury, using age-specific finite element (FE) models. The FE simulations indicated that for identical cortical displacements, the neonatal brain may be exposed to larger peak stress magnitudes compared with a mature brain due to stiffer tissue properties in the neonate, as well as larger strain magnitudes due to its smaller size. The brain volume subjected to a certain strain level was greater in the neonate brain compared with the adult models for all indentation depths greater than 1 mm. In conclusion, our present findings allow better design of closed head impact experiments which involve an age factor. Additionally, the larger peak stresses and larger strain volumetric exposures observed in the neonatal brain support the hypothesis that the smaller size and stiffer tissue of the infant brain makes it more susceptible to TBI.
- Published
- 2006
44. Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition
- Author
-
Melissa J. Simon, Yves Auberson, Ramesh Raghupathi, Robert Siman, David F. Meaney, and Michael N. DeRidder
- Subjects
Traumatic brain injury ,Hippocampus ,Glutamic Acid ,Caspase 3 ,Apoptosis ,Mechanotransduction, Cellular ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,lcsh:RC321-571 ,Necrosis ,Organ Culture Techniques ,Organotypic ,medicine ,Animals ,Receptor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neurons ,N-methyl-d-aspartate receptor ,biology ,Chemistry ,Calpain ,Dentate gyrus ,musculoskeletal, neural, and ocular physiology ,Spectrin ,medicine.disease ,Cell biology ,Rats ,Up-Regulation ,Protein Subunits ,Neurology ,Animals, Newborn ,nervous system ,Caspase-3 ,Brain Injuries ,Caspases ,Dentate Gyrus ,biology.protein ,NMDA receptor ,Neuroscience ,Excitatory Amino Acid Antagonists ,Biomarkers ,Signal Transduction - Abstract
Apoptotic or necrotic cell death in the hippocampus is a major factor underlying the cognitive impairments following traumatic brain injury. In this study, we examined if traumatic mechanical injury would produce regional activation of calpain and caspase-3 in the in vitro hippocampus and studied how the mechanically induced activation of NR2A and NR2B containing N-methyl-d-aspartate receptors (NMDARs) affects the activation of these proteases following mechanical injury. Following a 75% stretch, significant levels of activated caspase-3 and calpain-mediated spectrin breakdown products were evident only in cells within the dentate gyrus, and little co-localization of the markers was identified within individual cells. After 100% stretch, only calpain activation was observed, localized to the CA3 subregion 24 h after stretch. At moderate injury levels, both caspase-3 and calpain activation was attenuated by blocking NR2B containing NMDARs prior to stretch or by blocking all NMDARs prior to stretch injury. Treatment with an NR2A selective NMDAR antagonist had little effect on either activated caspase-3 or Ab38 immunoreactivity following moderate injury but resulted in the appearance of activated caspase-3 in the dentate gyrus following severe mechanical stretch. Together, these studies suggest that the injury induced activation of NR2A containing NMDARs functions as a pro-survival signal, while the activation of NR2B containing NMDARs is a competing, anti-survival, signal following mechanical injury to the hippocampus.
- Published
- 2006
45. Regionally Distinct Patterns of Calpain Activation and Traumatic Axonal Injury following Contusive Brain Injury in Immature Rats
- Author
-
Jimmy W. Huh, Ashley G. Widing, Michael A. Franklin, and Ramesh Raghupathi
- Subjects
Aging ,Pathology ,medicine.medical_specialty ,Thalamus ,Diffuse Axonal Injury ,Corpus callosum ,White matter ,Amyloid beta-Protein Precursor ,Developmental Neuroscience ,Cortex (anatomy) ,medicine ,Animals ,Cell Death ,biology ,Calpain ,business.industry ,Diffuse axonal injury ,Head injury ,Brain ,Cerebral Infarction ,Dendrites ,medicine.disease ,Axons ,Rats ,Up-Regulation ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,Neurology ,Brain Injuries ,Nerve Degeneration ,Closed head injury ,biology.protein ,business ,Neuroscience ,Biomarkers - Abstract
Impact-induced head injury in infants results in acute focal contusions and traumatic axonal injury (TAI) that are associated with chronic holohemispheric cortical and white matter atrophy and may contribute to poor outcome in brain-injured children less than 4 years of age. Contusive brain trauma in postnatal day (PND) 11 or PND 17 rat pups, ages neurologically equivalent to a human infant and toddler, respectively, leads to cortical tissue loss and white matter atrophy which are associated with cognitive deficits. In adult models of brain trauma and in brain-injured humans, acute and sustained activation of the calpain family of calcium-activated neutral proteases has been implicated in neuronal death and TAI. PND 11 or PND 17 rat pups were subjected to closed head injury over the left hemisphere using the controlled cortical impact device and sacrificed at 6 h, 24 h or 3 days. Hemorrhagic contusions and tissue tears in the cortex and white matter were visible at 6 h, and neuronal loss was evident by 3 days. Calpain activation was observed in cell soma and dendrites of injured neurons at 6 h, and in degenerating dendrites and atrophic neurons at 24 h after injury at both ages. Axonal accumulation of amyloid precursor protein, indicative of TAI, was observed in the corpus callosum and lateral aspects of the white matter below the site of impact, and in the thalamus in PND 11 rats only. Intra-axonal calpain activation was observed to a limited extent in the corpus callosum and subcortical white matter tracts in both brain-injured PND 11 and PND 17 rats. Collectively, these results provide evidence that calpain activation may participate in neuronal loss in the injured cortex, but may not contribute to the pathogenesis of TAI following contusive brain trauma in the immature rat.
- Published
- 2006
46. Experimental Traumatic Brain Injury Alters Ethanol Consumption and Sensitivity
- Author
-
Anthony M. Provenzano, Alana C. Conti, James P Caruso, Ramesh Raghupathi, Jennifer L. Lowing, and Laura L. Susick
- Subjects
Male ,medicine.medical_specialty ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,Alcohol Drinking ,Traumatic brain injury ,Poison control ,Nucleus accumbens ,White matter ,chemistry.chemical_compound ,Amyloid beta-Protein Precursor ,Mice ,Internal medicine ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Ethanol ,Glial fibrillary acidic protein ,biology ,Dopaminergic ,Brain ,Central Nervous System Depressants ,Original Articles ,medicine.disease ,Astrogliosis ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,chemistry ,nervous system ,Anesthesia ,Brain Injuries ,Immunoglobulin G ,biology.protein ,Neurology (clinical) ,Psychology - Abstract
Altered alcohol consumption patterns after traumatic brain injury (TBI) can lead to significant impairments in TBI recovery. Few preclinical models have been used to examine alcohol use across distinct phases of the post-injury period, leaving mechanistic questions unanswered. To address this, the aim of this study was to describe the histological and behavioral outcomes of a noncontusive closed-head TBI in the mouse, after which sensitivity to and consumption of alcohol were quantified, in addition to dopaminergic signaling markers. We hypothesized that TBI would alter alcohol consumption patterns and related signal transduction pathways that were congruent to clinical observations. After midline impact to the skull, latency to right after injury, motor deficits, traumatic axonal injury, and reactive astrogliosis were evaluated in C57BL/6J mice. Amyloid precursor protein (APP) accumulation was observed in white matter tracts at 6, 24, and 72 h post-TBI. Increased intensity of glial fibrillary acidic protein (GFAP) immunoreactivity was observed by 24 h, primarily under the impact site and in the nucleus accumbens, a striatal subregion, as early as 72 h, persisting to 7 days, after TBI. At 14 days post-TBI, when mice were tested for ethanol sensitivity after acute high-dose ethanol (4 g/kg, intraperitoneally), brain-injured mice exhibited increased sedation time compared with uninjured mice, which was accompanied by deficits in striatal dopamine- and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32) phosphorylation. At 17 days post-TBI, ethanol intake was assessed using the Drinking-in-the-Dark paradigm. Intake across 7 days of consumption was significantly reduced in TBI mice compared with sham controls, paralleling the reduction in alcohol consumption observed clinically in the initial post-injury period. These data demonstrate that TBI increases sensitivity to ethanol-induced sedation and affects downstream signaling mediators of striatal dopaminergic neurotransmission while altering ethanol consumption. Examining TBI effects on ethanol responsitivity will improve our understanding of alcohol use post-TBI in humans.
- Published
- 2014
47. Ex VivoGene Therapy Using Targeted Engraftment of NGF-Expressing Human NT2N Neurons Attenuates Cognitive Deficits Following Traumatic Brain Injury in Mice
- Author
-
John H. Wolfe, Luca Longhi, Deborah J Castelbuono, Kathryn E. Saatman, John Q. Trojanowski, Tracy K. McIntosh, Hilaire J. Thompson, Scott Fujimoto, Nicolas C. Royo, Chen Zhang, Virginia M.-Y. Lee, Deborah Watson, Nino Stocchetti, and Ramesh Raghupathi
- Subjects
Male ,medicine.medical_specialty ,Traumatic brain injury ,Morris water navigation task ,Motor Activity ,Neuroprotection ,Choline O-Acetyltransferase ,Mice ,Transduction, Genetic ,Cyclosporin a ,Internal medicine ,Nerve Growth Factor ,medicine ,Animals ,Humans ,Maze Learning ,Neurons ,Basal forebrain ,biology ,business.industry ,Genetic Therapy ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Nerve growth factor ,nervous system ,Brain Injuries ,biology.protein ,Neurology (clinical) ,business ,Neuroscience ,Ex vivo ,Neurotrophin - Abstract
Infusion of nerve growth factor (NGF) has been shown to be neuroprotective following traumatic brain injury (TBI). In this study, we tested the hypothesis that NGF-expressing human NT2N neurons transplanted into the basal forebrain of brain-injured mice can attenuate long-term cognitive dysfunction associated with TBI. Undifferentiated NT2 cells were transduced in vitro with a lentiviral vector to release NGF, differentiated into NT2N neurons by exposure to retinoic acid and transplanted into the medial septum of mice 24 h following controlled cortical impact (CCI) brain injury or sham injury. Adult mice (n = 78) were randomly assigned to one of four groups: (1) sham-injured and vehicle (serum-free medium)-treated, (2) brain-injured and vehicle-treated, (3) brain-injured engrafted with untransduced NT2N neurons, and (4) brain-injured engrafted with transduced NGF-NT2N neurons. All groups were immunosuppressed daily with cyclosporin A (CsA) for 4 weeks. At 1 month post-transplantation, animals engrafted with NGF-expressing NT2N neurons showed significantly improved learning ability (evaluated with the Morris water maze) compared to brain-injured mice receiving either vehicle (p < 0.05) or untransduced NT2N neurons (p < 0.01). No effect of NGF-secreting NT2N cells on motor function deficits at 1-4 weeks post-transplantation was observed. These data suggest that NGF gene therapy using transduced NT2N neurons (as a source of delivery) may selectively improve cognitive function following TBI.
- Published
- 2004
48. Cell Death Mechanisms Following Traumatic Brain Injury
- Author
-
Ramesh Raghupathi
- Subjects
Programmed cell death ,Pathology ,medicine.medical_specialty ,Traumatic brain injury ,Poison control ,Calcium in biology ,Pathology and Forensic Medicine ,medicine ,Animals ,Humans ,Caspase ,Neurons ,Cell Death ,biology ,Kinase ,business.industry ,General Neuroscience ,Calpain ,medicine.disease ,Symposium: Traumatic Brain Injury ,Apoptosis ,Brain Injuries ,Nerve Degeneration ,Cancer research ,biology.protein ,Neurology (clinical) ,business ,Neuroglia - Abstract
Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head‐injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post‐traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma‐induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro‐ and anti‐apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting‐proteins such as Bcl‐2, Bcl‐x(L), and extracellular signal‐regulated kinases, and death‐inducing proteins such as Bax, c‐Jun N‐terminal kinase, tumor‐suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.
- Published
- 2004
49. Neuron-Specific mRNA Complexity Responses during Hippocampal Apoptosis after Traumatic Brain Injury
- Author
-
Kathryn E. Saatman, Julia Brettschneider, Christian J. Stoeckert, Ramesh Raghupathi, Tracy K. McIntosh, Paolo G. Marciano, Elisabetta Manduchi, Terence P. Speed, Scott Eastman, Jason Davis, and James Eberwine
- Subjects
Male ,Cell type ,Apoptosis ,Caspase 3 ,Biology ,Hippocampal formation ,Hippocampus ,Mice ,Neurobiology of Disease ,Gene expression ,In Situ Nick-End Labeling ,medicine ,Animals ,PrPC Proteins ,RNA, Messenger ,Oligonucleotide Array Sequence Analysis ,Neurons ,Messenger RNA ,TUNEL assay ,General Neuroscience ,Immunohistochemistry ,Molecular biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Brain Injuries ,Son of Sevenless Proteins ,Dentate Gyrus ,Neuron - Abstract
In an effort to understand the complexity of genomic responses within selectively vulnerable regions after experimental brain injury, we examined whether single apoptotic neurons from both the CA3 and dentate differed from those in an uninjured brain. The mRNA from individual active caspase 3(+)/terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling [TUNEL(–)] and active caspase 3(+)/TUNEL(+) pyramidal and granule neurons in brain-injured mice were amplified and compared with those from nonlabeled neurons in uninjured brains. Gene analysis revealed that overall expression of mRNAs increased with activation of caspase 3 and decreased to below uninjured levels with TUNEL reactivity. Cell type specificity of the apoptotic response was observed with both regionally distinct expression of mRNAs and differences in those mRNAs that were maximally regulated. Immunohistochemical analysis for two of the most highly differentially expressed genes (prionandSos2) demonstrated a correlation between the observed differential gene expression after traumatic brain injury and corresponding protein translation.
- Published
- 2004
50. ContinuedIn SituDNA Fragmentation of Microglia/Macrophages in White Matter Weeks and Months after Traumatic Brain Injury
- Author
-
Stephen Wilson, David I. Graham, Ramesh Raghupathi, Mary-Anne MacKinnon, Tracy K. McIntosh, and Kathryn E. Saatman
- Subjects
Adult ,Male ,Wallerian degeneration ,Time Factors ,Adolescent ,Traumatic brain injury ,Diffuse Axonal Injury ,DNA Fragmentation ,Pallor ,White matter ,Pons ,In Situ Nick-End Labeling ,medicine ,Humans ,Aged ,Microglia ,business.industry ,Macrophages ,Anatomy ,Middle Aged ,medicine.disease ,Staining ,medicine.anatomical_structure ,Case-Control Studies ,Neuroglia ,Female ,Neurology (clinical) ,medicine.symptom ,Wallerian Degeneration ,business - Abstract
Paraffin-embedded material from the pons of head-injured patients whose disability could be attributed to diffuse traumatic axonal injury, and controls, was identified from the department's archive. The cases were divided into three groups based on survival, viz Group 1 (n = 5) who survived for between 4 and 8 weeks, Group 2 (n = 5) for between 3 and 9 months, and Group 3 (n = 5) who survived for more that 12 months. Sections were stained by the TUNEL (TdT-mediated UTP nick end labelling) technique, and by HE, LFB/CV and immunohistochemically for astrocytes (GFAP) and microglia/macrophages (CD68). Microscopic abnormalities were mapped onto line diagrams of two levels of the pons and quantitation of the response determined by an eye-piece graticule placed over the medial lemmisci, cortico-spinal and transverse fiber tracts. Data were pooled by region of interest. In the HE and LFB/CV stained sections, there was variable pallor of staining in ascending and descending fiber tracts due to loss of myelin: within these same tracts there was an astrocytosis and increased numbers of microglia/macrophages compared with controls. In the white matter tracts of the controls, there was on average 1-2 TUNEL+ cells per unit area. In contrast, there were on average 2-16 TUNEL+ cells in the cortico-spinal tracts and in the medial lemnisci of all groups of head-injured patients. CD68+ cells co-located with the TUNEL+, and their number mirrored the TUNEL + staining with on average 16-30 cells per unit area in Group 1, 14-27 cells per unit area in Group 2, and 12-14 cells per unit area in Group 3. There was a statistical association between the TUNEL+ and CD68+ cells. Few changes were seen in the transverse fiber tracts of the pons. These findings indicate that most of the in situ DNA fragmentation occurred in microglia/macrophages in ascending and descending fiber tracts of the brain stem in which by conventional light microscopy there is Wallerian degeneration. However, in addition, a few TUNEL+ oligodendrocyte-like cells were also seen.
- Published
- 2004
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.