High Dose Baclofen Is Neuroprotective but Also Causes Intracerebral Hemorrhage: A Quantal Bioassay Study Using the Intraluminal Suture Occlusion Method

Jackson-Friedman, Catherine; Lyden, Patrick D.; Nunez, Sonia; Jin, Albert; Zweifler, Richard M.

doi:10.1006/exnr.1997.6637

Cited by 49 publications

(28 citation statements)

References 27 publications

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“…In other experimental models of ischemia in vivo, muscimol, alone or in combination with the NMDA receptor antagonist MK-801, can prevent brain ischemic damage (Lyden et al, 2000). Baclofen has also been shown to protect against ischemic neurodegeneration, although it also causes hemorrhage (Jackson-Friedman et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

Velasco

Tapia

2001

J of Neuroscience Research

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The glutamate uptake inhibitor L-trans-2,4-pyrrolidine-dicarboxylate (PDC) induces glutamate accumulation and neuronal damage in cultured cells. We have used dissociated cortical cells in culture to study whether the toxicity induced by inhibiting glutamate uptake with PDC could be blocked by the simultaneous inhibition of gamma-aminobutyric acid (GABA) uptake, because both types of transporters are affected during an ischemic event. After 6 hr of exposure to 100 microM GABA or to four different GABA uptake inhibitors, the concentration of extracellular GABA was augmented from the basal 2 microM value to about 25 microM and 5 microM, respectively. These increases, however, did not result in protection against the neuronal damage induced by the accumulation of extracellular glutamate because of the simultaneous exposure to PDC. In contrast, when 100 microM GABA and an inhibitor of GABA uptake were added, after 6 hr the concentrations of GABA reached 50 microM, and neurons were protected from PDC-induced toxicity. The addition of the GABA(A) and GABA(B) receptor agonists muscimol and baclofen also partially protected against PDC-induced damage. The results suggest that the excitotoxic damage resulting from chronic gradual elevation of extracellular glutamate may be prevented by high concentrations of extracellular GABA, an effect mediated by activation of GABA(A) and GABA(B) receptors.

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Section: Discussionmentioning

confidence: 99%

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

Velasco

Tapia

2001

J of Neuroscience Research

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“…In this study the main goal was to test the effects of pharmacological sleep promotion with Bac starting 24 h after stroke onset, in order to avoid the reported neuroprotective effects of this compound 39,40…”

Section: Discussionmentioning

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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“…All sutures were pre-blunted in a microforge (Narishige MF83, NY, USA) and only filaments between 280 and 305 mm in diameter were used for occlusion. The surgical exposure and occlusion conditions were performed as previously described (Jackson-Friedman et al, 1997).…”

Section: Methodsmentioning

confidence: 99%

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

Friedman

Cheng

et al. 2007

J Cereb Blood Flow Metab

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The role of angiogenesis after stroke is unclear; if angiogenesis supports long-term recovery of blood flow, then microvessel hyperdensity consequent to angiogenesis should persist in infarcted cortex. Here, we assess the long-term stability of ischemia-induced microvessels after 2-h transient rat middle cerebral artery occlusion (tMCAo) followed by 30, 90, or 165 days of reperfusion. Stereological measures of microvessel density were taken adjacent to and within cortical cysts. Vascular permeability was documented by extravasation of immunoglobulin (IgG) and of fluorescein-dextran. After 30 days reperfusion, a significantly increased microvessel volume density (V V ) was restricted to the inner margin of cystic infarcts as compared with the region external to the infarct or contralateral control cortex (F = 42.675, P < 0.001). The hyperdense ischemic vasculature was abnormally leaky to IgG and fluorescein-dextran. Between 30 and 90 days of reperfusion, this vessel hyperdensity regressed significantly and then regressed further but less drastically between 90 and 165 days. Phagocytic macrophages were restricted to the infarct and dynamic changes in their number correlated with microvessel regression. Additional ED-1 labeled inflammatory cells were widely distributed inside and external to the infarct, even after 165 days of reperfusion. These data show that ischemia evoked angiogenesis results, at least in part, in transient populations of leaky microvessels and phagocytic macrophages. This suggests that a major role of this angiogenesis is for the removal of necrotic brain tissue.

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High Dose Baclofen Is Neuroprotective but Also Causes Intracerebral Hemorrhage: A Quantal Bioassay Study Using the Intraluminal Suture Occlusion Method

Cited by 49 publications

References 27 publications

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

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

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

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