Skip to main content
NCBI home page
Neural Regeneration Research logoLink to Neural Regeneration Research
. 2014 Nov 1;9(21):1897–1901. doi: 10.4103/1673-5374.145357

Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury

Lei Cao 1,2,#, Xiaohua Bie 1,#, Su Huo 2, Jubao Du 2, Lin Liu 2, Weiqun Song 2,✉
PMCID: PMC4281428  PMID: 25558239

Abstract

The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.

Keywords: nerve regeneration, traumatic brain injury, fluid percussion injury, excitatory synaptic transmission, hippocampal CA1 pyramidal neurons, paired-pulse facilitation, miniature excitatory postsynaptic potential, gamma-aminobutyric acid, post-traumatic hyperactivity, intracellular recording, NSFC grant, neural regeneration

Introduction

Traumatic brain injury often results in persistent cognitive impairment, which severely reduces the quality of a patient's life (Azouvi et al., 2009; Risdall and Menon, 2011; Moreau et al., 2013). In addition to the risk of acute mortality, severe traumatic brain injury is a risk factor for the development of post-traumatic epilepsy (Liesemer et al., 2011; Lusardi et al., 2012; Yeh et al., 2013). Post-traumatic epilepsy is one of the major contributors to compromised functional outcome and quality-of-life in patients with traumatic brain injury (Andelic et al., 2009; Chen et al., 2013). Animal models provide an efficient way to study the pathophysiology of traumatic brain injury (O’Connor et al., 2011; Long et al., 2013; Xiong et al., 2013). Fluid percussion injury of the rat brain is one of the most extensively used and best characterized animal models of human traumatic brain injury (D’Ambrosio et al., 2004; Thompson et al., 2005; Kharatishvili et al., 2006). Fluid percussion injury produces hyperexcitability of hippocampal CA1 neurons by increasing the activity of the Schaffer collaterals of hippocampal CA3 neurons (Akasu et al., 2002; Dinocourt et al., 2011; Zhang et al., 2011).

Glutamate receptor antagonists have been shown to be neuroprotective (Bernert and Turski, 1996; Allen et al., 1999; Gasparini et al., 1999; Movsesyan and Faden, 2006). On the other hand, facilitating inhibitory synaptic transmission is another way to prevent excitotoxicity following traumatic brain injury (Luo et al., 2011). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, being found in 30–40% of all synapses (Noh et al., 2010; Ben-Ari et al., 2012). Diazepam, a benzodiazepine derivative drug, has an anxiolytic action, with sedative and hypnotic effects (Manna and Umathe, 2011; Liu et al., 2013). Diazepam enhances the efficacy of gamma-aminobutyric acid type A (GABAA) receptor-Cl− channels, which is beneficial for mortality and cognitive impairment following traumatic brain injury (O’Dell et al., 2000; Richter et al., 2012). Moreover, recent research has shown that diazepam attenuates the post-traumatic hyperactivity of rat hippocampal CA1 neurons (Ooba et al., 2008; Ma et al., 2014). In the present study, we sought to explore the effects of diazepam on excitatory synaptic transmission following brain trauma by intervention with the GABAA receptor antagonist dicentrine (Palombi and Caspary, 1992).

Materials and Methods

Animals

Twenty-four clean, healthy, 6-week-old male Wistar rats weighing 280–320 g were used in the experiments. All rats were obtained from Experimental Animal Laboratories of the Academy of Military Medical Sciences (Beijing, China) (license No. SCXK (Army) 2007-0004). Rats were maintained under a 12-hour light/dark cycle in the animal facility, and were allowed free access to food and water. All procedures in this study were approved by the Animal Care and Use Committee of Capital Medical University, China. All animals were equally and randomly divided into a control group (without any treatment), a diazepam group, a fluid percussion injury group, and a fluid percussion injury + diazepam group.

Establishment of fluid percussion injury model

A fluid percussion injury model was established as previously reported with some modifications (Smith et al., 2005). Briefly, animals were intraperitoneally anesthetized with pentobarbital sodium 50–60 mg/kg, placed in a stereotaxic frame (David Kopf Instruments, Tujunga, CA, USA). A scalp incision was made and the scalp and temporal muscles were exposed. A craniotomy (3 mm × 3 mm) was performed 3 mm caudal from the coronal suture and 3 mm lateral to the sagittal suture on the left parietal bone without impairing the dura. A connecting cap was placed over the craniotomy and connected with the fluid percussion injury device. Animals were subjected to a fluid percussion of 3.8–4.8 atm (385.0–486.4 kPa) onto the cerebral cortex of the left hemisphere.

Diazepam treatment post-injury

At 30 and 90 minutes following fluid percussion injury, animals in the fluid percussion injury + diazepam groups were intraperitoneally administered diazepam (C16D5H8ClN2O, molecular weight 284.76; 10 mg/kg, in 0.9% saline) (Product ID: D-910; Sigma, St. Louis, MO, USA). The rats in the control group received an equal volume of 0.9% saline at the corresponding time points.

Hippocampal brain slice preparations and intracellular recording

After a survival period of 7–8 days, the rats were decapitated and brains were harvested for slice preparation. Brain tissue including the hippocampal CA1 area was cut into 400-μm horizontal slices, which were immersed in a cooled artificial cerebrospinal fluid that was pre-bubbled with 95% O2–5% CO2 in a manner similar to that described previously[21]. Each slice was cut into two slices, one containing the left (ipsilateral to the impact) hippocampus and the other one containing the right (contralateral) hippocampus. Intracellular recording of hippocampal CA1 pyramidal neurons was conducted after 1 hour. Excitatory postsynaptic potentials were evoked through a concentric bipolar electrode (Nihon Kohden SEN-7103, Tokyo, Japan) placed on the Schaffer collaterals in the hippocampal CA2 region. Data were recorded when the resting membrane potential of the neuron had remained stable for more than 20 minutes. Input–output relationship curves were generated based on the stimulus intensity (input) and initial slopes of the excitatory postsynaptic potentials. With the greater stimulation intensities (10, 20 and 30 V, 200 μs duration), recordings of the numbers of spikes were conducted in the presence of 15 μmol/L bicuculline (Product ID: 285269; Sigma). Bicuculline (C20H17NO6, molecular weight 284.76) is a GABAA receptor antagonist (Palombi and Caspary, 1992). The consecutive excitatory postsynaptic potentials were evoked by paired-pulse stimuli with intervals from 50 to 160 ms repeated every 10 seconds in the presence of bicuculline (15 μmol/L), and the values for amplitude ratios of excitatory postsynaptic potentials (P2/P1) were recorded. Miniature excitatory postsynaptic potentials were recorded in the presence of 15 μmol/L bicuculline and 1 μmol/L tetrodotoxin (Product ID: T8024; C11H17N3O8, molecular weight 319.27; Sigma), and the numbers of miniature excitatory postsynaptic potentials during 300 seconds were analyzed by Mini-analysis software (Version 6; Synaptosoft, Decatur, GA, USA).

Statistical analysis

Quantitative data were expressed as the mean ± SD and analyzed by one-way analysis of variance using SPSS 16.0 (SPSS, Chicago, IL, USA). Student-Newman-Keuls tests were used for specific comparisons. Statistical significance was set at a level of P < 0.05.

Results

Diazepam decreased fluid percussion injury-induced hyperactivity in rat hippocampal CA1 pyramidal neurons

The slope of the input–output curve was greater in the ipsilateral hippocampus with the fluid percussion injury group than in the control group (P < 0.05). Compared with the fluid percussion injury group, the slope of the input–output was significantly lower in the fluid percussion injury + diazepam group (P < 0.05). However, no significant difference in slope was detected among the control, fluid percussion injury and fluid percussion injury + diazepam groups in the contralateral hippocampus (P > 0.05; Figure 1A). These observations suggested that the efficacy of excitatory synaptic transmission in the hippocampal CA1 area was enhanced at 1 week after fluid percussion injury; however, diazepam hampered this enhancement.

Figure 1.

Figure 1

Open in a new tab

Diazepam (DZ) decreases fluid percussion injury (FPI)-induced hyperactivity of rat hippocampal CA1 pyramidal neurons.

(A) Effect of DZ on the input–output (I–O) relationship of monosynaptic excitatory postsynaptic potentials obtained from FPI rat hippocampal CA1 pyramidal neurons induced by stimulating the Schaffer collaterals. The figure shows pooled values for slopes of the I–O curves of the four groups. The number in the brackets represents the number of rats. (B) Effect of DZ on the number of spikes induced by super-threshold orthodromic stimulation (stimulation intensity (10, 20 and 30 V, 200 μs duration)) of the Schaffer collaterals in the FPI rat hippocampal CA1 region. The figure shows pooled data for the relationship between the number of spikes and stimulus intensity in the FPI and FPI + DZ group in (bicuculline (+)) and without (bicuculline (−)) the presence of 15 µmol/L bicuculline. n: Number of rats. Quantitative data were expressed as the mean ± SD and analyzed by one-way analysis of variance. Student-Newman-Keuls tests were used for specific comparisons. *P < 0.05, vs. other groups.

To examine whether the fluid percussion injury-induced facilitation of synaptic transmission is due to functional damage of GABAergic inhibitory neurons in ipsilateral hippocampal slices, bicuculline (15 μmol/L), a selective blocker of GABAA receptors, was applied. In normal artificial cerebrospinal fluid, the numbers of spikes induced by different stimulus intensities (10, 20 and 30 V, 200 μs duration) were not significantly different between the fluid percussion injury group and the fluid percussion injury + diazepam group (P > 0.05). However, in the presence of 15 μmol/L bicuculline, diazepam significantly reduced the number of spikes (P < 0.05; Figure 1B). These results suggested that the inhibitory pathways are fully functional in the hippocampi of fluid percussion injury rats.

Taken together, these results indicated that diazepam significantly decreases the fluid percussion injury-induced hyperactivity of rat hippocampal CA1 pyramidal neurons in the ipsilateral hippocampus following fluid percussion injury.

Diazepam increased fluid percussion injury-induced paired-pulse facilitation in rat hippocampal CA1 pyramidal neurons

The results described above revealed the preservation of inhibitory pathways; therefore, we concluded that fluid percussion injury directly enhanced the function of the glutamatergic excitatory pathway in the hippocampal CA1 area. To test this, Schaffer collaterals were stimulated by a pair of electrical pulses at 50–160-ms intervals, repeated every 10 seconds. As shown in Figure 2, the paired-pulse facilitation ratio (P1/P2 ratio) decreased with prolonged stimulus interval. P2/P1 ratios were significantly increased in the fluid percussion injury + diazepam group compared with the fluid percussion injury group (P < 0.05), to a level that showed no significant difference from the control group (P > 0.05). These results suggested that diazepam effectively diminishes the probability of action-potential-dependent glutamine release from the terminals of Schaffer collateral terminals in the ipsilateral hippocampus CA1 area following fluid percussion injury.

Figure 2.

Figure 2

Open in a new tab

Effects of diazepam (DZ) on the excitatory postsynaptic potential paired-pulse facilitation of fluid percussion injury (FPI) rat hippocampal CA1 neurons.

The two consecutive excitatory postsynaptic potentials were evoked by paired-pulse stimuli with intervals from 50 to 160 ms repeated every 10 seconds in the presence of bicuculline (15 μmol/L). Sample records (average of six consecutive pairs) of excitatory postsynaptic potential pairs (stimulus interval is 60 ms) were obtained in the control, DZ, FPI and FPI + DZ groups. P1 and P2 indicate the first and second excitatory postsynaptic potentials, respectively. The figure shows pooled data for the effect of DZ on the P2/P1 ratio with stimulation intervals from 50 ms to 160 ms on the FPI ipsilateral side. n: Number of rats. Quantitative data were expressed as the mean ± SD and analyzed by one-way analysis of variance. Student-Newman-Keuls tests were used for specific comparisons. *P < 0.05, vs. other groups.

Diazepam diminished the number of miniature excitatory postsynaptic potentials in fluid percussion injury-induced rat hippocampal CA1 pyramidal neurons

To investigate a possible contribution of postsynaptic mechanisms in this enhancement, we analyzed the number of miniature excitatory postsynaptic potentials. Under the experimental conditions, the spontaneous miniature excitatory postsynaptic potentials were recorded as subliminal depolarization waveforms. During the recording time of 300 seconds, the number of miniature excitatory postsynaptic potentials recorded in the ipsilateral hippocampus following fluid percussion injury was significantly decreased by the application of diazepam (P < 0.05; Figure 3). These results showed that, in the ipsilateral rat hippocampus CA1 area following fluid percussion injury, diazepam effectively reversed the increase in spontaneous glutamate release from the Schaffer collateral terminals.

Figure 3.

Figure 3

Open in a new tab

Effect of diazepam (DZ) on the miniature excitatory postsynaptic potentials (mEPSPs) in rat hippocampal CA1 pyramidal neurons following fluid percussion injury (FPI).

The number in the brackets represents the number of rats. There were 19 and 12 pyramidal neurons in FPI and FPI + DZ groups, respectively. Quantitative data were expressed as the mean ± SD and analyzed by one-way analysis of variance. Student-Newman-Keuls tests were used for specific comparisons. *P < 0.05, vs. FPI group.

Discussion

Studying the mechanisms underlying post-traumatic epilepsy is complicated by its long latency, often occurring months or years after a traumatic event (Lusardi et al., 2012). Early pharmacological intervention following traumatic brain injury is especially important for preventing post-traumatic epilepsy. The present study was designed to evaluate the ability of diazepam to prevent the development of hyperexcitability in rats with traumatic brain injury. We found that diazepam could decrease fluid percussion injury-induced hyperactivity and increase fluid percussion injury-induced paired-pulse facilitation in rat hippocampal CA1 pyramidal neurons. Diazepam also diminished the number of miniature excitatory postsynaptic potentials.

Lateral fluid percussion injury is one of the most commonly used experimental models of human traumatic brain injury in rodents (Morales et al., 2005). Early electrophysiological studies using acute hippocampal slices demonstrated increased excitability at 1 week (Santhakumar et al., 2000) and as late as 15 weeks (Golarai et al., 2001) after brain injury. Based on a previous study (Cao et al., 2006), we used 1 week as the time point at which to study the change in excitabilities after fluid percussion injury. The present results show that diazepam markedly decreases fluid percussion injury-induced hyperactivity of rat hippocampal CA1 pyramidal neurons, which may be realized through effectively diminishing the probability of action potential-induced glutamate release from Schaffer collateral branches, and inhibiting spontaneous glutamate release in Schaffer collateral branches.

Diazepam is effective in treating chronic seizures (Han et al., 2011; Rossetti et al., 2012). Glutamatergic synaptic transmission in the hippocampal CA1 area is facilitated through presynaptic mechanisms after traumatic brain injury (Cao et al., 2006). Electrophysiological experiments have clarified that diazepam binds to an allosteric site for GABAA receptor chloride channels to enhance the efficacy of inhibitory synapses (Ooba et al., 2008). The present findings indicate that diazepam effectively attenuates fluid percussion injury-induced glutamatergic synaptic transmission in the hippocampal CA1 area, and also affects hyperexcitability after traumatic brain injury. This observation suggested that weakened glutamatergic synaptic transmission is the cause, rather than the result, of hyperexcitability after traumatic brain injury. Diazepam is a well-characterized and widely consumed drug; however, there has been little clinical research on using diazepam to treat post-traumatic epilepsy. Our findings indicate that diazepam has the potential to prevent post-traumatic epilepsy following traumatic brain injury and may reduce brain excitability long term, thus presenting a theoretical basis for the treatment and prevention of post-traumatic epilepsy after traumatic brain injury.

In summary, diazepam significantly decreased fluid percussion injury-induced hyperexcitability in the rat hippocampal CA1 area. The mechanism underlying this effect includes decreased probability of action potential-dependent and spontaneous release of glutamate from Schaffer collateral terminals.

Footnotes

Funding: This study was supported by the National Natural Science Foundation of China, No. 81201984; the Scientific Research Project of Shaanxi Provincial Health Department in China, No. 2010E03; and the Yulin Municipal Science and Technology Research and Development Project, No. Sf12-06.

Conflicts of interest: None declared.

Copyedited by McGowan D, Yajima W, Yu J, Qiu Y, Li CH, Song LP, Zhao M

References

  • 1.Akasu T, Muraoka N, Hasuo H. Hyperexcitability of hippocampal CA1 neurons after fluid percussion injury of the rat cerebral cortex. Neurosci Lett. 2002;329:305–308. doi: 10.1016/s0304-3940(02)00707-3. [DOI] [PubMed] [Google Scholar]
  • 2.Allen JW, Ivanova SA, Fan L, Espey MG, Basile AS, Faden AI. Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury. J Pharmacol Exp Ther. 1999;290:112–120. [PubMed] [Google Scholar]
  • 3.Andelic N, Hammergren N, Bautz-Holter E, Sveen U, Brunborg C, Røe C. Functional outcome and health-related quality of life 10 years after moderate-to-severe traumatic brain injury. Acta Neurol Scand. 2009;120:16–23. doi: 10.1111/j.1600-0404.2008.01116.x. [DOI] [PubMed] [Google Scholar]
  • 4.Azouvi P, Vallat-Azouvi C, Belmont A. Cognitive deficits after traumatic coma. Prog Brain Res. 2009;177:89–110. doi: 10.1016/S0079-6123(09)17708-7. [DOI] [PubMed] [Google Scholar]
  • 5.Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist. 2012;18:467–486. doi: 10.1177/1073858412438697. [DOI] [PubMed] [Google Scholar]
  • 6.Bernert H, Turski L. Proc Natl Acad Sci. Vol. 93. U S A: 1996. Traumatic brain damage prevented by the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f] quinoxaline; pp. 5235–5240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Cao R, Hasuo H, Ooba S, Akasu T, Zhang X. Facilitation of glutamatergic synaptic transmission in hippocampal CA1 area of rats with traumatic brain injury. Neurosci Lett. 2006;401:136–141. doi: 10.1016/j.neulet.2006.03.005. [DOI] [PubMed] [Google Scholar]
  • 8.Chen W, Gao Z, Ni Y, Dai Z. Carbenoxolone pretreatment and treatment of posttraumatic epilepsy. Neural Regen Res. 2013;8:169–176. doi: 10.3969/j.issn.1673-5374.2013.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.D’Ambrosio R, Fairbanks JP, Fender JS, Born DE, Doyle DL, Miller JW. Post-traumatic epilepsy following fluid percussion injury in the rat. Brain. 2004;127:304–314. doi: 10.1093/brain/awh038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dinocourt C, Aungst S, Yang K, Thompson SM. Homeostatic increase in excitability in area CA1 after Schaffer collateral transection in vivo. Epilepsia. 2011;52:1656–1665. doi: 10.1111/j.1528-1167.2011.03113.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Gasparini F, Bruno V, Battaglia G, Lukic S, Leonhardt T, Inderbitzin W, Laurie D, Sommer B, Varney MA, Hess SD, Johnson EC, Kuhn R, Urwyler S, Sauer D, Portet C, Schmutz M, Nicoletti F, Flor PJ. (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo. J Pharmacol Exp Ther. 1999;289:1678–1687. [PubMed] [Google Scholar]
  • 12.Golarai G, Greenwood AC, Feeney DM, Connor JA. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci. 2001;21:8523–8537. doi: 10.1523/JNEUROSCI.21-21-08523.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Han Y, Lin Y, Xie N, Xue Y, Tao H, Rui C, Xu J, Cao L, Liu X, Jiang H, Chi Z. Impaired mitochondrial biogenesis in hippocampi of rats with chronic seizures. Neuroscience. 2011;194:234–240. doi: 10.1016/j.neuroscience.2011.07.068. [DOI] [PubMed] [Google Scholar]
  • 14.Kharatishvili I, Nissinen JP, McIntosh TK, Pitkänen A. A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats. Neuroscience. 2006;140:685–697. doi: 10.1016/j.neuroscience.2006.03.012. [DOI] [PubMed] [Google Scholar]
  • 15.Liesemer K, Bratton SL, Zebrack CM, Brockmeyer D, Statler KD. Early post-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, and clinical features. J Neurotrauma. 2011;28:755–762. doi: 10.1089/neu.2010.1518. [DOI] [PubMed] [Google Scholar]
  • 16.Liu X, Yu Y, Li Y, Ning S, Liu T, Li F, Duan G. Restricted access magnetic core-mesoporous shell microspheres with C8-modified interior pore-walls for the determination of diazepam in rat plasma by LC-MS. Talanta. 2013;106:321–327. doi: 10.1016/j.talanta.2012.11.015. [DOI] [PubMed] [Google Scholar]
  • 17.Long J, Cai L, Li J, Zhang L, Yang H, Wang T. JNK3 involvement in nerve cell apoptosis and neurofunctional recovery after traumatic brain injury. Neural Regen Res. 2013;8:1491–1499. doi: 10.3969/j.issn.1673-5374.2013.16.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Luo P, Fei F, Zhang L, Qu Y, Fei Z. The role of glutamate receptors in traumatic brain injury: implications for postsynaptic density in pathophysiology. Brain Res Bull. 2011;85:313–320. doi: 10.1016/j.brainresbull.2011.05.004. [DOI] [PubMed] [Google Scholar]
  • 19.Lusardi TA, Lytle NK, Szybala C, Boison D. Caffeine prevents acute mortality after TBI in rats without increased morbidity. Exp Neurol. 2012;234:161–168. doi: 10.1016/j.expneurol.2011.12.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ma JY, Zhang SP, Guo LB, Li YM, Li Q, Wang SQ, Liu HM, Wang C. KCC2 expression changes in Diazepam-treated neonatal rats with hypoxia-ischaemia brain damage. Brain Res. 2014;1563:22–30. doi: 10.1016/j.brainres.2014.03.034. [DOI] [PubMed] [Google Scholar]
  • 21.Manna SS, Umathe SN. Transient receptor potential vanilloid 1 channels modulate the anxiolytic effect of diazepam. Brain Res. 2011;1425:75–82. doi: 10.1016/j.brainres.2011.09.049. [DOI] [PubMed] [Google Scholar]
  • 22.Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, Longhi L, Laurer H, Maegele M, Neugebauer E, Graham DI, Stocchetti N, McIntosh TK. Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience. 2005;136:971–989. doi: 10.1016/j.neuroscience.2005.08.030. [DOI] [PubMed] [Google Scholar]
  • 23.Moreau OK, Cortet-Rudelli C, Yollin E, Merlen E, Daveluy W, Rousseaux M. Growth hormone replacement therapy in patients with traumatic brain injury. J Neurotrauma. 2013;30:998–1006. doi: 10.1089/neu.2012.2705. [DOI] [PubMed] [Google Scholar]
  • 24.Movsesyan VA, Faden AI. Neuroprotective effects of selective group II mGluR activation in brain trauma and traumatic neuronal injury. J Neurotrauma. 2006;23:117–127. doi: 10.1089/neu.2006.23.117. [DOI] [PubMed] [Google Scholar]
  • 25.Noh J, Seal RP, Garver JA, Edwards RH, Kandler K. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci. 2010;13:232–238. doi: 10.1038/nn.2478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.O’Connor WT, Smyth A, Gilchrist MD. Animal models of traumatic brain injury: a critical evaluation. Pharmacol Ther. 2011;130:106–113. doi: 10.1016/j.pharmthera.2011.01.001. [DOI] [PubMed] [Google Scholar]
  • 27.O’Dell DM, Gibson CJ, Wilson MS, DeFord SM, Hamm RJ. Positive and negative modulation of the GABA A receptor and outcome after traumatic brain injury in rats. Brain Res. 2000;861:325–332. doi: 10.1016/s0006-8993(00)02055-2. [DOI] [PubMed] [Google Scholar]
  • 28.Ooba S, Hasuo H, Shigemori M, Akasu T. Diazepam attenuates the post-traumatic hyperactivity of excitatory synapses in rat hippocampal CA1 neurons. Neurosci Res. 2008;62:195–205. doi: 10.1016/j.neures.2008.08.005. [DOI] [PubMed] [Google Scholar]
  • 29.Palombi PS, Caspary DM. GABA A receptor antagonist bicuculline alters response properties of posteroventral cochlear nucleus neurons. J Neurophysiol. 1992;67:738–746. doi: 10.1152/jn.1992.67.3.738. [DOI] [PubMed] [Google Scholar]
  • 30.Richter L, de Graaf C, Sieghart W, Varagic Z, Mörzinger M, de Esch IJP, Ecker GF, Ernst M. Diazepam-bound GABA A receptor models identify new benzodiazepine binding-site ligands. Nat Chem Biol. 2012;8:455–464. doi: 10.1038/nchembio.917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Risdall JE, Menon DK. Traumatic brain injury. Philos Trans R Soc Lond B Biol Sci. 2011;366:241–250. doi: 10.1098/rstb.2010.0230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Rossetti F, de Araujo Furtado M, Pak T, Bailey K, Shields M, Chanda S, Addis M, Robertson BD, Moffett M, Lumley LA, Yourick DL. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology. 2012;33:500–511. doi: 10.1016/j.neuro.2012.02.010. [DOI] [PubMed] [Google Scholar]
  • 33.Santhakumar V, Bender R, Frotscher M, Ross ST, Hollrigel GS, Toth Z, Soltesz I. Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the ‘irritable mossy cell’ hypothesis. J Physiol. 2000;524:117–134. doi: 10.1111/j.1469-7793.2000.00117.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Smith DC, Modglin AA, Roosevelt RW, Neese SL, Jensen RA, Browning RA, Clough RW. Electrical stimulation of the vagus nerve enhances cognitive and motor recovery following moderate fluid percussion injury in the rat. J Neurotrauma. 2005;22:1485–1502. doi: 10.1089/neu.2005.22.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Thompson HJ, Lifshitz J, Marklund N, Grady MS, Graham DI, Hovda DA, McIntosh TK. Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma. 2005;22:42–75. doi: 10.1089/neu.2005.22.42. [DOI] [PubMed] [Google Scholar]
  • 36.Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci. 2013;14:128–142. doi: 10.1038/nrn3407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Yeh CC, Chen TL, Hu CJ, Chiu WT, Liao CC. Risk of epilepsy after traumatic brain injury: a retrospective population-based cohort study. J Neurol Neurosurg Psychiatry. 2013;84:441–445. doi: 10.1136/jnnp-2012-302547. [DOI] [PubMed] [Google Scholar]
  • 38.Zhang BL, Chen X, Tan T, Yang Z, Carlos D, Jiang RC, Zhang JN. Traumatic brain injury impairs synaptic plasticity in hippocampus in rats. Chin Med J (Engl) 2011;124:740–745. [PubMed] [Google Scholar]

Articles from Neural Regeneration Research are provided here courtesy of Wolters Kluwer -- Medknow Publications

RESOURCES