Donna M. Wilder

Walter Reed Army Institute of Research

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Joseph B. Long

Walter Reed Army Institute of Research

Venkata Siva Sai Sujith Sajja

Walter Reed Army Institute of Research

Peethambaran Arun

Walter Reed Army Institute of Research

Irene D. Gist

Walter Reed Army Institute of Research

Andrew Batuure

Walter Reed Army Institute of Research

Rodrigo Urioste

Walter Reed Army Institute of Research

Kevin C. Maki

Indiana University Bloomington

Lanier Heyburn

Walter Reed Army Institute of Research

James C. DeMar

Walter Reed Army Institute of Research

Matthew S. Reeves

MB Clinical Research and Consulting (United States)

Cooperative Institutions

Walter Reed Army Institute of Research

National Institutes of Health

The Geneva Foundation

University of Maryland, Baltimore

Uniformed Services University of the Health Sciences

United States Army Medical Research and Development Command

National Institute on Deafness and Other Communication Disorders

United States Army

Johns Hopkins University

Center for Environmental Health

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Preferential retina horizontal cell loss in an animal model of mild traumatic brain injury

Mary A. Johnson James C. DeMar Gilbert Xue Donna M. Wilder Andrew C. Batuure

Animal model

Cell injury

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Citations (0)

Antibodies Against Lysophosphatidic Acid Protect Against Blast-Induced Ocular Injuries

Frontiers in Neurology (2020)

Peethambaran Arun Franco Rossetti James C. DeMar Ying Wang Andrew Batuure

Exposure to blast overpressure waves is implicated as the major cause of ocular injuries and resultant visual dysfunction in veterans involved in recent combat operations. No effective therapeutic strategies have been developed so far for blast-induced ocular dysfunction. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells, and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid have been reported to increase acutely in patients with traumatic brain injury (TBI) as well as in a controlled cortical impact (CCI) TBI model in mice. In the present study, we have evaluated the efficacy of a single intravenous administration of a monoclonal LPA antibody (25 mg/kg) given at 1 h post-blast for protection against injuries to the retina and associated ocular dysfunctions. Our results show that a single 19 psi blast exposure significantly increased the levels of several species of LPA in blood plasma at 1 and 4 h post-blast. The anti-LPA antibody treatment significantly decreased glial cell activation and preserved neuronal cell morphology in the retina on day 8 after blast exposure. Optokinetic measurements indicated that anti-LPA antibody treatment significantly improved visual acuity in both eyes on days 2 and 6 post-blast exposure. Anti-LPA antibody treatment significantly increased rod photoreceptor and bipolar neuronal cell signaling in both eyes on day 7 post-blast exposure. These results suggest that blast exposure triggers release of LPAs, which play a major role promoting blast-induced ocular injuries, and that a single early administration of anti-LPA antibodies provides significant protection.

Precursor cell

Blast injury

10.3389/fneur.2020.611816

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Citations (5)

Cerebrospinal Fluid Chemokine (C-C Motif) Ligand 2 Is an Early-Response Biomarker for Blast-Overpressure-Wave–Induced Neurotrauma in Rats

Journal of Neurotrauma (2016)

Ying Wang Yanling Wei Samuel Oguntayo Donna M. Wilder Lawrence Tong

Chemokines and their receptors are of great interest within the milieu of immune responses elicited in the central nervous system in response to trauma. Chemokine (C-C motif)) ligand 2 (CCL2), which is also known as monocyte chemotactic protein-1, has been implicated in the pathogenesis of traumatic brain injury (TBI), brain ischemia, Alzheimer's disease, and other neurodegenerative diseases. In this study, we investigated the time course of CCL2 accumulation in cerebrospinal fluid (CSF) after exposures to single and repeated blast overpressures of varied intensities along with the neuropathological changes and motor deficits resulting from these blast conditions. Significantly increased concentrations of CCL2 in CSF were evident by 1 h of blast exposure and persisted over 24 h with peak levels measured at 6 h post-injury. The increased levels of CCL2 in CSF corresponded with both the number and intensities of blast overpressure and were also commensurate with the extent of neuromotor impairment and neuropathological abnormalities resulting from these exposures. CCL2 levels in CSF and plasma were tightly correlated with levels of CCL2 messenger RNA in cerebellum, the brain region most consistently neuropathologically disrupted by blast. In view of the roles of CCL2 that have been implicated in multiple neurodegenerative disorders, it is likely that the sustained high levels of CCL2 and the increased expression of its main receptor, CCR2, in the brain after blast may similarly contribute to neurodegenerative processes after blast exposure. In addition, the markedly elevated concentration of CCL2 in CSF might be a candidate early-response biomarker for diagnosis and prognosis of blast-induced TBI.

CCR2

Brain damage

Pathogenesis

10.1089/neu.2016.4465

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Citations (20)

Long-Term Effects of Blast Exposure: A Functional Study in Rats Using an Advanced Blast Simulator

Journal of Neurotrauma (2019)

Peethambaran Arun Donna M. Wilder Ondine Eken Rodrigo Urioste Andrew Batuure

Anecdotal observations of blast victims indicate that significant neuropathological and neurobehavioral defects may develop at later stages of life. To pre-clinically model this phenomenon, we have examined neurobehavioral changes in rats up to 1 year after exposure to single and tightly coupled repeated blasts using an advanced blast simulator. Neurobehavioral changes were monitored at acute, sub-acute, and chronic time-points using Morris water maze test of spatial learning and memory, novel object recognition test of short-term memory, open field exploratory activity as a test of anxiety/depression, a rotating pole test for vestibulomotor function, and a rotarod balance test for motor coordination. Single and repeated blasts resulted in significant functional deficits at both acute and chronic time-points. In most functional tests, rats exposed to repeated blasts performed more poorly than rats exposed to single blast. Interestingly, several functional deficits post-blast were most pronounced at 6 months and beyond. Significant neuromotor impairments occurred at early stages after blast exposure and the severity increased with repeated exposures. The novel object recognition testing revealed short-term memory deficits at 6 and 12 months post-blast. The water maze test revealed impairments at acute and chronic stages after blast exposure. The most substantial changes in the blast-exposed rats were observed with the center time and margin time legacies in the open field exploration test at 6, 9, and 12 months post-blast. Notably, these two outcome measures were minimally altered acutely, recovered during sub-acute stages, and were markedly affected during the chronic stages after blast exposures and may implicate development of chronic anxiety and depressive-like behaviors.

Blast injury

Repeated measures design

Water maze

Elevated plus maze

Motor coordination

10.1089/neu.2019.6591

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Citations (41)

Glucose tolerance modifies the effects of high‐viscosity hydroxypropylmethylcellulose on postprandial glucose and insulin excursions

The FASEB Journal (2007)

Kevin C. Maki Michael L. Carson Marvin P. Miller Maciej Turowski Marjorie Bell

High-viscosity hydroxypropylmethylcellulose (HV-HPMC) is a dietary fiber that forms a viscous gel in the gastrointestinal tract after consumption. The aim of the present analysis was to evaluate the influence of glucose tolerance on postprandial responses to HV-HPMC. Subjects were classified into low (LPG) or high (HPG) subgroups based on the median peak glucose concentration (< or ≥147 mg/dL) after a control test meal containing 75 g of carbohydrate. Those with HPG (n=16) did not differ from the LPG subset (n=15) in demographic characteristics or fasting insulin, but had significantly higher fasting glucose (99 vs. 91 mg/dL, p=0.006). Postprandial glucose (7882 vs. 5122 min x mg/dL, p=0.023) and insulin (5184 vs. 2739 min x mU/L, p=0.019) incremental areas under the curves (IAUC, 0–120 min) were higher in the HPG subjects. Adding HV-HPMC (4 or 8 g) to the meal reduced glucose and insulin responses (p<0.001). The degree of blunting of the insulin IAUC did not differ between the HPG and LPG subsets (−47 vs. −43%, p=0.671), but the glucose IAUC was blunted to a larger degree in the HPG subjects (−41 vs. −26%, p=0.034). Thus, slowing the rate of glucose absorption with HV-HPMC had a larger impact on postprandial glycemia in subjects with HPG. These findings may have implications for understanding how slowing carbohydrate absorption may influence diabetes risk. Funding support provided by Dow Chemical Co.

10.1096/fasebj.21.5.a178

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Blast Exposure Causes Long-Term Degeneration of Neuronal Cytoskeletal Elements in the Cochlear Nucleus: A Potential Mechanism for Chronic Auditory Dysfunctions

Frontiers in Neurology (2021)

Peethambaran Arun Franco Rossetti Donna M. Wilder Ying Wang Irene D. Gist

Blast-induced auditory dysfunctions including tinnitus are the most prevalent disabilities in service members returning from recent combat operations. Most of the previous studies were focused on the effect of blast exposure on the peripheral auditory system and not much on the central auditory signal-processing regions in the brain. In the current study, we have exposed rats to single and tightly coupled repeated blasts and examined the degeneration of neuronal cytoskeletal elements using silver staining in the central auditory signal-processing regions in the brain at 24 h, 14 days, 1 month, 6 months, and 1 year. The brain regions evaluated include cochlear nucleus, lateral lemniscus, inferior colliculus, medial geniculate nucleus, and auditory cortex. The results obtained indicated that a significant increase in degeneration of neuronal cytoskeletal elements was observed only in the left and right cochlear nucleus. A significant increase in degeneration of neuronal cytoskeletal elements was observed in the cochlear nucleus at 24 h and persisted through 1 year, suggesting acute and chronic neuronal degeneration after blast exposure. No statistically significant differences were observed between single and repeated blasts. The localized degeneration of neuronal cytoskeletal elements in the cochlear nucleus suggests that the damage could be caused by transmission of blast shockwaves/noise through the ear canal and that use of suitable ear protection devices can protect against acute and chronic central auditory signal processing defects including tinnitus after blast exposure.

Degeneration (medical)

Lateral lemniscus

10.3389/fneur.2021.652190

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Citations (2)

Longitudinal Biochemical and Behavioral Alterations in a Gyrencephalic Model of Blast-Related Mild Traumatic Brain Injury

Neurotrauma Reports (2024)

Shiyu Tang Su Xu Donna M. Wilder Alexandre E. Medina Xin Li

Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N-acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure.

Blast injury

Diffuse axonal injury

10.1089/neur.2024.0002

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Citations (1)

microRNA Profile Changes in Brain, Cerebrospinal Fluid, and Blood Following Low-Level Repeated Blast Exposure in a Rat Model

Journal of Neurotrauma (2024)

Shataakshi Dahal RamaRao Venkata Kakulavarapu Lanier Heyburn Donna M. Wilder Raina Kumar

It is well documented that service members are exposed to repeated low-level blast overpressure during training with heavy weapons such as artillery, mortars and explosive breaching. Often, acute symptoms associated with these exposures are transient but cumulative effect of low-level repeated blast exposures (RBEs) can include persistent deficits in cognitive and behavioral health. Thus far, reliable diagnostic biomarkers which can guide countermeasure strategies have not been identified. In this study, rats were exposed to multiple field-relevant blast waves with 8.5 and 10 psi peak positive overpressures, applying one exposure per day for 14 consecutive days. micro-RNAs that can potentially be used as biomarkers for RBEs were assessed in blood, brain, and cerebrospinal fluid (CSF). RBE caused a differential pattern of changes in various miRNAs in blood, brain and CSF in an overpressure-dependent manner. Our key outcomes were decrease of mir-6215 and let-7 family miRNAs and increase of mir-6321 and mir-222-5p in brain, blood, and CSF. Expression pattern of these miRNAs is in concurrence with various neurological conditions such as upregulation of mir-6321 in focal ischemic injury and downregulation of mir-6215 in nerve injury model. Contrarily, Let-7 family miRNAs have neuroprotective role and their downregulation suggests progression of blast induced traumatic brain injury (bTBI) with RBE at 14× -8.5 psi. Repeated blast caused alterations in miRNAs that are likely involved in vascular integrity, inflammation, and cell death. These results indicate that miRNAs are differentially dysregulated in response to blast injuries and may represent better prognostic and diagnostic biomarkers than traditional molecules to identify blast-specific brain injury.

10.1089/neu.2024.0269

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Green Tea Catechin Consumption Enhances Exercise-Induced Abdominal Fat Loss in Overweight and Obese Adults

Journal of Nutrition (2008)

Kevin C. Maki Matthew S. Reeves Mildred V. Farmer Koichi Yasunaga Noboru Matsuo

Abdominal fat

10.3945/jn.108.098293

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Citations (236)

Hydroxypropylmethylcellulose and Methylcellulose Consumption Reduce Postprandial Insulinemia in Overweight and Obese Men and Women ,

Journal of Nutrition (2008)

Kevin C. Maki Michael L. Carson Marvin P. Miller Maciej Turowski Marjorie Bell

10.1093/jn/138.2.292

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Citations (37)