Gamma-Hydroxybutyrate Accelerates Functional Recovery after Focal Cerebral Ischemia

Gao, Bo; Kılıç, Ertuğrul; Baumann, Christian R.; Hermann, Dirk M.

doi:10.1159/000151683

Cited by 58 publications

(43 citation statements)

References 39 publications

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“…We analyzed the grip strength in individual paws to measure the severity of the pMCAo-induced asymmetry. We assessed the grip strength in the ipsilateral and contralateral front paw and hindpaw before and 3 and 5 d after surgery in TNF-KO and C57BL/6 mice using a grip strength tester (BIO-GT-3; Bioseb) (Gao et al, 2008). We also used the rotating pole test (Nygren and Wieloch, 2005) and footprint analysis (Fiore et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lambertsen¹,

Clausen²,

Babcock³

et al. 2009

J. Neurosci.

335

352

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Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial-not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglialderived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.

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Section: Methodsmentioning

confidence: 99%

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lambertsen¹,

Clausen²,

Babcock³

et al. 2009

J. Neurosci.

335

352

View full text Add to dashboard Cite

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“…Disruption of sleep during acute and subacute phase of stroke aggravated brain damage21 and impeded functional recovery in rats 22. On the contrary, administration of γ-hydroxybutyric acid (GHB), considered a sleep-promoting drug, immediately after reperfusion accelerated motor function recovery in mice 23. Furthermore, a physiological enhancement of sleep (following previous sleep deprivation) occurring immediately after stroke induction, was also associated with a reduction of brain damage 24.…”

Section: Introductionmentioning

confidence: 99%

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats

Hodor

Palchykova

Baracchi

et al. 2014

Ann Clin Transl Neurol

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ObjectiveSleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch).MethodsRats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep–wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining.ResultsRepeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group.ConclusionDelayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

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“…First, the GHB-induced concentration in the brain of treated animals must be high enough to provoke deep sleep in all of them, in order to mimic the main effect of GHB used therapeutically (narcoleptic patients or anesthetic purposes). The neuroprotective effects of GHB described in several models also required high GHB concentrations (25), while by contrast low concentrations seemed to possess neurotoxic properties (55). Second, we have recently shown (43) that a GHB dose of 1 g/kg in rats induced a concentration of this substance in brain of ϳ1-1.5 mM.…”

Section: Discussionmentioning

confidence: 88%

A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex

Kemmel¹,

Klein²,

Dembélé

et al. 2010

Physiological Genomics

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Nyagan AG, Maitre M. A single acute pharmacological dose of ␥-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex. Physiol Genomics 41: 146-160, 2010. First published January 26, 2010 doi:10.1152/physiolgenomics.00208.2009.-␥-Hydroxybutyrate (GHB) is a natural brain neuromodulator that has its own enzymatic machinery for synthesis and degradation, release, and transport systems and several receptors that belong to the G protein-coupled receptor (GPCR) family. Targeting of this system with exogenous GHB is used in therapy to induce sleep and anesthesia and to reduce alcohol withdrawal syndrome. GHB is also popular as a recreational drug for its anxiolytic and mild euphoric effects. However, in both cases, GHB must be administered at high doses in order to maintain GHB concentrations in brain of ϳ800 -1,000 M. These high concentrations are thought to be necessary for interactions with lowaffinity sites on GABA B receptor, but the molecular targets and cellular mechanisms modulated by GHB remain poorly characterized. Therefore, to provide new insights into the elucidation of GHB mechanisms of action and open new tracks for future investigations, we explored changes of GHB-induced transcriptomes in rat hippocampus and prefrontal cortex by using DNA microarray studies. We demonstrate that a single acute anesthetic dose of 1 g/kg GHB alters a large number of genes, 121 in hippocampus and 53 in prefrontal cortex; 16 genes were modified simultaneously in both brain regions. In terms of molecular functions, the majority of modified genes coded for proteins or nucleotide binding sites. In terms of Gene Ontology (GO) functional categories, the largest groups were involved in metabolic processing for hippocampal genes and in biological regulation for prefrontal cortex genes. The majority of genes modified in both structures were implicated in cell communication processes. Western blot and immunohistochemical studies carried out on eight selected proteins confirmed the microarray findings.potentiation of brain ␥-aminobutyric acid synapses; sleep and anesthesia; neuroprotection and cell signaling THE IDEA that ␥-hydroxybutyrate (GHB) possesses important functions as a neuromodulator in brain is now supported by numerous results (49). This endogenous compound is synthesized from GABA and is coreleased with it during GABA synaptic activity (51). Endogenous GHB concentrations in brain tissue range from 0.5-1 M to 10-25 M (22) but the fluctuations of GHB in the extracellular spaces, namely in the synapses, have never been measured. Successively, specific GHB binding was described in the brain of several animal species and in humans (6, 13, 31), and more recently GHB receptors have been cloned from both human and rat brain (2, 3). These GHB receptors appear to be heterogeneous with respect to their architecture and pharmacology, despite the fact they belong to G protein-coupled receptor (GPCR) classes. In particular, the GHB analog NCS-382 possesses antagonistic, partial agonist, or no...

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Gamma-Hydroxybutyrate Accelerates Functional Recovery after Focal Cerebral Ischemia

Cited by 58 publications

References 39 publications

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats

A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex

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