Positive and negative modulation of the GABAA receptor and outcome after traumatic brain injury in rats

O’Dell, Dianne M.; Gibson, Cynthia J.; Wilson, Margaret S.; DeFord, S. Michelle; Hamm, Robert J.

doi:10.1016/s0006-8993(00)02055-2

Cited by 51 publications

(28 citation statements)

References 50 publications

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“…Benzodiazepines, for example, are known to protect the brain from excessive seizure activity while concurrently protecting neurons (Borromei et al, 1997;Sanchez-Izquierdo-Riera et al, 1998). However, giving benzodiazepines (a GABA A receptor agonist) chronically to injured rats will impair their behavioral performance, whereas the post-injury administration of bicuculline (a competitive GABA A receptor antagonist) has been shown to enhance behavioral performance (Schallert et al, 1986;O'Dell et al, 2000). The same can be said about ketamine and other similar drugs which are known to be neuroprotective, but tend to reduce the excitatory tone of brain activity (Barth et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

Hoffman

Virmani²,

Simkins³

et al. 2003

Journal of Neurotrauma

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The goal of the current study was to test the hypothesis that dehydroepiandrosterone-sulfate (DHEAS), a pro-excitatory neurosteroid, could facilitate recovery of function in male rats after delayed treatment following TBI. DHEAS has been found to play a major role in brain development and aging by influencing the migration of neurons, arborization of dendrites, and formation of new synapses. These characteristics make it suitable as a potential treatment to enhance neural repair in response to CNS injury. In our study, behavioral tests were conducted concurrently with DHEAS administration (0, 5, 10, or 20 mg/kg) starting seven days post-injury (PI). These assays included 10 days of Morris Water Maze testing (MWM; 7d PI), 10 days of Greek-Cross (GC; 21d PI), Tactile Adhesive Removal task (TAR; PI days: 6, 13, 20, 27, 34), and spontaneous motor behavior testing (SMB; PI days: 2, 4, 6, 12, 19, 26, 33). Brain-injured rats showed an improvement in performance in all tasks after 5, 10, or 20 mg/kg DHEAS. The most effective dose of DHEAS in the MWM was 10 mg/kg, while in the GC it was 20 mg/kg, in TAR 5 mg/kg, and all doses, except for vehicle, were effective at reducing injury-induced SMB hyperactivity. In no task did DHEAS-treated animals perform worse than the injured controls. In addition, DHEAS had no significant effects on behavioral performance in the sham-operates. These results can be interpreted to demonstrate that after a 7-day delay, the chronic administration of DHEAS to injured rats significantly improves behavioral recovery on both sensorimotor and cognitive tasks.

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Section: Discussionmentioning

confidence: 99%

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

Hoffman

Virmani²,

Simkins³

et al. 2003

Journal of Neurotrauma

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“…Our results are consistent with a previous observation that GABAergic neocortical neurons are resistant to NMDA receptor-mediated injury (Tecoma and Choi, 1989). Exogenous administration of diazepam, an allosteric GABA potentiator, also has been shown to reduce postischemic and traumatic neuronal death in vivo (Schwartz et al, 1995;O'Dell et al, 2000). Because generalized augmentation of GABAergic inhibition, whether pharmacologically or by gene targeting, may impair normal synaptic plasticity (Levkovitz et al, 1999), there may be a strong advantage for a regional rather than a general enhancement of inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental models of epilepsy, for example, demonstrate a decrease in hippocampal GABA A receptor expression (Friedman et al, 1994;Rice et al, 1996) and function (Gibbs et al, 1997), suggesting that loss of inhibitory control plays a pathogenic role (Mody, 1998). Postischemic and traumatic neuronal death is reduced by the GABA potentiator diazepam (Schwartz et al, 1995;O'Dell et al, 2000). Enhancement of the GABA effect at the receptor is a reasonable strategy for increasing inhibition; this is the mechanism of many clinically useful drugs including anticonvulsants, anxiolytics, and general anesthetics (Hevers and Luddens, 1998).…”

Section: Abstract: Gaba C Receptors; Hippocampal Neurons; Adenovirusmentioning

confidence: 99%

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

2001

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The excessive neuronal excitation underlying several clinically important diseases is often treated with GABA allosteric modulators in an attempt to enhance inhibition. An alternative strategy would be to enhance directly the sensitivity of postsynaptic neurons to GABA. The GABA C receptor, normally found only in the retina, is more sensitive to GABA and demonstrates little desensitization compared with the GABA A receptor. We constructed an adenovirus vector that expressed cDNA for both the GABA C receptor 1 subunit and a green fluorescent protein (GFP) reporter and used it to transduce cultured hippocampal neurons. Transduced neurons were identified by fluorescence, double immunocytochemistry proved colocalization of the 1 protein and the reporter, Western blot verified the expected molecular masses, and electrophysiological and pharmacological properties confirmed the presence of functional GABA C receptors. 1 -GFP transduction resulted in an increased density of GABA A receptors as well as expression of novel GABA C receptors. This effect was not reproduced by addition of TTX or Mg 2ϩ to the culture medium to reduce action potentials or synaptic activity. In a model of neuronal hyperexcitability induced by chronic blockade of glutamate receptors, expression of GABA C receptors abolished the hyperactivity and the consequent delayed neuronal death. Adenovirus-mediated neuronal GABA C receptor engineering, via its dual mechanism of inhibition, may offer a way of inhibiting only those hyperexcitable neurons responsible for clinical problems, avoiding the generalized nervous system depression associated with pharmacological therapy.

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“…Moreover, etomidate is highly selective for the GABA A receptor, exhibiting potent GABA-modulatory and GABA-mimetic effects at low micromolar concentrations (36) and, therefore, may attenuate injury by enhancing the inhibitory effects of GABA. The acute administration of diazepam, a positive modulator at the GABA A receptor, decreases mortality rate and cognitive deficits after TBI in rats (37). Furthermore, the administration of bicuculline, a GABA A antagonist, is reported to increase cognitive deficits compared with animals treated with saline (37).…”

Section: Discussionmentioning

confidence: 99%

Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury

Dixon

Kline

et al. 2003

Critical Care Medicine

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Administration of etomidate both before and after injury attenuates secondary injury resulting from traumatic brain injury, but the effect is more pronounced with pretreatment. The ineffectiveness of postinjury etomidate on motor and histologic tasks suggests a brief therapeutic treatment window in rats. However, the treatment window in humans is unknown. Lastly, postinjury etomidate did not exacerbate neurologic or histologic outcome.

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Positive and negative modulation of the GABAA receptor and outcome after traumatic brain injury in rats

Cited by 51 publications

References 50 publications

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury

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Positive and negative modulation of the GABAA receptor and outcome after traumatic brain injury in rats

Cited by 51 publications

References 50 publications

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

The Delayed Administration of Dehydroepiandrosterone Sulfate Improves Recovery of Function after Traumatic Brain Injury in Rats

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABACReceptors

Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury

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Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors