Authors: Lyeth, Bruce G. | Jenkins, Larry W. | Hayes, Ronald L.
Article Type: Research Article
Abstract: Traumatic brain injury can produce neurochemical alterations in the brain that are of sufficient magnitude to cause neurological and cognitive deficits. These alterations are associated with a period of excessive neurotransmitter-receptor stimulation involving the N-Methyl-D-aspartate (NMDA) glutamate receptor, as well as other receptors. This abnormal stimulation can produce lasting disruption of neuronal signaling and functional deficits. A number of laboratory studies suggest that NMDA receptor antagonists administered before or soon after traumatic brain injury may provide some protection against pathophysiological effects. The likelihood that functional deficits associated with traumatic brain injury may be at least partly dependent on neurotransmitter-receptor interactions …suggests that this component of the injury process may be particularly amenable to pharmacologic treatment. Although a number of highly selective and potent NMDA receptor blockers are available, issues of dosing and toxicity need to be further examined before these agents are considered for human clinical trials. Show more
DOI: 10.3233/NRE-1991-1109
Citation: NeuroRehabilitation, vol. 1, no. 1, pp. 50-57, 1991
Authors: Di Giorgio, Anthony M. | Hou, Yongjin | Zhao, Xueren | Zhang, Bin | Lyeth, Bruce G. | Russell, Michael J.
Article Type: Research Article
Abstract: Purpose: The objective of this study was to evaluate the neuroprotective potential of the antioxidant, curcumin compared to α-tocopherol in a rat model of traumatic brain injury (TBI). Methods: Male Sprague-Dawley rats were administered curcumin (3, 30, 300 mg/kg), α-tocopherol (100 mg/kg), DMSO vehicle, or saline, 30 min prior to and 30 and 90 min after moderate lateral fluid percussion TBI. Rats were euthanized at 24 hours after injury and coronal brain sections were stained with Fluoro-Jade to identify degenerating neurons. Degenerating neurons in the CA2-3 sector of the dorsal hippocampus were quantified in 10 sections spaced 300 μm apart …in each rat. Results: One way ANOVA revealed a significant difference (p = 0.01) between groups. The curcumin, α-tocopherol, and DMSO groups had significantly reduced numbers of degenerating neurons compared to the saline-treated group. No significant differences were observed between any of the drug treatment groups or the DMSO group. Conclusions: Since protection in the DMSO vehicle group was equal to that of the experimental groups, no conclusions about neuroprotection regarding α-tocopherol or curcumin can be made from this study. The results suggest that DMSO may be acting as an overriding neuroprotectant in this experiment. We conclude that DMSO is a viable neuroprotective agent against secondary cell death in TBI. Show more
Keywords: DMSO, curcumin, traumatic brain injury, antioxidant, neuroprotection
Citation: Restorative Neurology and Neuroscience, vol. 26, no. 6, pp. 501-507, 2008
Authors: Beller, Justin A. | Gurkoff, Gene G. | Berman, Robert F. | Lyeth, Bruce G.
Article Type: Research Article
Abstract: Purpose: Glutamate transporters are responsible for removing glutamate from the extracellular space and have the potential to protect neurons from excitotoxicity. In the present study, the effects of ceftriaxone and (2R, 4R)-APDC (APDC) on the protein expression of GLAST and GLT-1, the rate of glutamate uptake, and neuroprotection were evaluated in a cell culture model of glutamate excitotoxicity. Methods: Mixed neuron/astrocyte cultures were prepared from 1 day old rat pups. Protein levels of GLAST and GLT-1 glutamate transporters were quantified using In-Cell Western techniques after acute or 5-day treatment with either ceftriaxone or APDC. Glutamate uptake was measured using Michaelis-Menten …kinetics to evaluate the effects of 5-day treatment with ceftriaxone or APDC. Neuronal cell death in response to a 10-minute 1 mM glutamate challenge was measured following 5-day treatment with either ceftriaxone or APDC. Results: Five-day treatment with 100 μM ceftriaxone significantly increased both GLAST and GLT-1 protein levels 31.3% and 47.5% above control, respectively, increased the Vmax 29.3%, increased the Km of glutamate uptake 117.9%, and reduced neuronal death 22.0% after a 1 mM glutamate challenge. Five-day treatment with 1 mM APDC significantly increased GLAST protein levels 27.6%, increased the Vmax 92.4%, increased the Km of glutamate transport 118.9%, and decreased neuronal death 36.8% after a 1 mM glutamate challenge. Conclusions: Chronic treatment with ceftriaxone or APDC provided neuroprotection from glutamate excitotoxicity while increasing GLAST and GLT-1 protein levels and increasing glutamate uptake. These compounds may have therapeutic potential in chronic excitotoxic neurodegenerative diseases. Show more
Keywords: Pharmacology, neurodegeneration, ceftriaxone, group II mGluR
DOI: 10.3233/RNN-2011-603
Citation: Restorative Neurology and Neuroscience, vol. 29, no. 5, pp. 331-346, 2011
Authors: Shahlaie, Kiarash | Gurkoff, Gene G. | Lyeth, Bruce G. | Muizelaar, J. Paul | Berman, Robert F.
Article Type: Research Article
Abstract: Purpose: Second insults following traumatic brain injury (TBI), such as ischemia and hypoxia, significantly worsen outcome in patients and in experimental models of TBI. Following TBI there is a pathological increase in intracellular calcium, triggering cellular mechanisms of dysfunction and death. N-type specific voltage gated calcium channel (VGCC) blockers reduce cell death in both in vitro mechanical strain injury (MSI) and in vivo models of TBI, but they have not been previously explored in a model of TBI followed by a second insult. Methods: In the following studies, cortical neurons and astrocytes experienced MSI followed by incubation in 20% CO2 …. Cultures were treated with the N-type VGCC blocker, ω-conopeptide SNX-185 (1 μM), 5-minutes post-injury and intracellular calcium accumulation was assessed at 3, 6 and 24 h. Neuronal viability was assessed 24 h after MSI. Results: Increasing incubator CO2 to 20% significantly increased calcium accumulation and cell death regardless of MSI severity. Treatment with 1 μM of SNX-185 significantly reduced the accumulation of calcium 3 hours following injury and increased the number of viable neurons 24 h post-injury and incubation in 20% CO2 . Conclusions: In vitro models provide a critical tool for identifying roles of cell specific mechanisms involved in neuronal dysfunction and death following injury. These data demonstrate the potential of N-type VGCC blockers in reducing the damaging effects of TBI and second insults. Show more
Keywords: In Vitro, traumatic brain injury, ischemia, hypoxia, neuronal cell death, rat
DOI: 10.3233/RNN-120243
Citation: Restorative Neurology and Neuroscience, vol. 31, no. 2, pp. 141-153, 2013
Authors: Wang, Tao | Van, Ken C. | Gavitt, Brian J. | Grayson, J. Kevin | Lu, Yi-Cheng | Lyeth, Bruce G. | Pichakron, Kullada O.
Article Type: Research Article
Abstract: Purpose: Repetitive mild traumatic brain injury (TBI) is a major military and sports health concern. The purpose of this study was to determine if a diet rich in omega-3 fatty acids would reduce cognitive deficits and neuronal cell death in a novel fluid percussion rat model of repetitive mild TBIs. Methods: Thirty-two Sprague-Dawley rats were assigned to either an experimental rat chow enhanced with 6% fish oil (source of omega-3 fatty acids) or a control rat chow. Both rat chows contained equivalent quantities of calories, oil, and nutrients. After four weeks, both groups received mild repetitive bilateral fluid percussion TBIs …on two sequential days. Pre-injury diets were resumed, and the animals were monitored for two weeks. On post-injury days 10–14, Morris Water Maze testing was performed to assess spatial learning and cognitive function. Animals were euthanized at 14 days post-injury to obtain specimens for neurohistopathology. Results: There was no difference in pre-injury weight gain between groups. Post-injury, animals on the fish oil diet lost less weight and recovered their weight significantly faster. By 14 days, the fish oil diet group performed significantly better in the Morris Water Maze. Neurohistopathology identified a non-significant trend toward a higher density of hippocampal neurons in the fish oil diet group. Conclusions: Pre-injury dietary supplementation with fish oil improves recovery of body weight and provides a small improvement in cognitive performance in a rat model of multiple mild TBIs. Show more
Keywords: Mild traumatic brain injury, omega-3 fatty acids, dietary supplementation, hippocampus, morris water maze
DOI: 10.3233/RNN-130316
Citation: Restorative Neurology and Neuroscience, vol. 31, no. 5, pp. 647-659, 2013
