[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the effects of normobaric oxygen (NBO) therapy on T2*-weighted images of intracranial hemorrhages (ICHs).
Two common models of ICH were performed in mice, and longitudinal T2*-weighted images of the hematomas were acquired under normoxia or NBO. The effects of NBO were also investigated on perfusion-weighted imaging, susceptibility-weighted imaging, and molecular imaging of vascular cell adhesion molecule-1 after ICH. Last, we performed neurological testing, including neuroscore, actimetry, and gait analysis (Catwalk), to study the influence of NBO on neurological outcome of mice presenting ICH.
Our results demonstrated that NBO, even during a short period of time, dramatically reduces the sensitivity of T2*-weighted imaging to detect ICH. Moreover, we provide evidence that the disappearance of ICH on T2*-weighted imaging could be used to improve accuracy of perfusion-weighted imaging and to allow molecular imaging after ICH. Importantly, a 30-minute NBO preparation 24 hours after ICH onset does not influence neurological outcome.
We provide an experimental demonstration that NBO significantly affects T2*-weighted imaging in ICH. Although this phenomenon could lead to inaccurate assessment of ICH volume, it could also be safely used to allow perfusion-weighted imaging and molecular imaging.
[Show abstract][Hide abstract] ABSTRACT: When in 1947, Astrup and Permin reported that animal tissues contain fibrinokinase, a plasminogen activator, and when Pennica and colleagues (Pennica et al., 1983) cloned and expressed human tissue plasminogen activator (tPA) in Escherichia coli in 1983, they might did not realize how much their pioneer work would impact the life of millions of patients suffering from myocardial infarction or ischemic stroke. Some years after, accumulating evidence shows that tPA is not just a plasminogen activator of endothelial origin. Indeed, the main function of tPA released from the endothelium is to convert fibrin-bound plasminogen into active plasmin, thus dissolving the fibrin meshwork of blood clots. But this serine protease is also expressed by several cell types, and its beneficial and deleterious actions stand beyond fibrinolysis or even proteolysis. We will review here the reported effects and mechanisms of action of tPA in the course of three different pathologies of the central nervous system (CNS): spinal cord injury, ischemic stroke and multiple sclerosis. While these three disorders have distinct aetiologies, they share some pathogenic mechanisms. We will depict the main "good" and "bad" sides of tPA described to date during each of these pathological situations, as well as the proposed mechanisms explaining these effects. We speculate that due to common pathogenic pathways, tPA's actions described in one particular disease could in fact occur in the others. Finally, we will evaluate if tPA could be a therapeutic target for these pathologies. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
[Show abstract][Hide abstract] ABSTRACT: Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.
PLoS ONE 01/2011; 6(8):e23690. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute alcohol exposure in rats (8% ethanol in the liquid diet for a period of 24 h) is associated with a decrease in the levels of endocannabinoids (anandamide and 2-arachidonoyl-glycerol) as well as in various N-acylethanolamines, in different brain regions. In the present study, we wanted to further explore: (i) whether these decreases might be caused by an increase in fatty acid amide hydrolase (FAAH), the enzyme involved in the degradation of N-acylethanolamines including anandamide, and (ii) whether the changes in endocannabinoid levels are accompanied by parallel changes in the major cannabinoid receptor type, the CB(1) receptor, activated by these ligands in the brain. Our data proved that FAAH activity did not increase in any of the four regions analyzed, even it was reduced in the hypothalamus and the prefrontal cortex. Paradoxically, FAAH levels increased in the hypothalamus and, to a lesser extent, in the prefrontal cortex and the amygdala, but not in the caudate-putamen. By contrast, the levels of CB(1) receptors were markedly reduced in the amygdala and prefrontal cortex of these rats, although no changes were seen in the hypothalamus and the caudate-putamen. These results suggest that reductions in the levels of endocannabinoids and related N-acylethanolamines caused by acute alcohol exposure are not originated by an enhanced degradation by FAAH enzyme, but they are associated with low levels of the receptors activated by these ligands, although this parallelism did not occur in all brain regions analyzed. In any case, these observations would support the notion of a general reduction in the activity of the cannabinoid signaling system by acute alcohol exposure.
Drug and alcohol dependence 11/2008; 99(1-3):354-8. · 3.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1 receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1 receptor knockout mice. Here we have examined whether the CB1 receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10 days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.
[Show abstract][Hide abstract] ABSTRACT: Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB(1) receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data-synthetically reviewed in the present paper-suggest (a) the involvement of the cannabinoid CB(1) receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence.
[Show abstract][Hide abstract] ABSTRACT: Chronic alcohol exposure leads to significant changes in the levels of endocannabinoids and their receptors in the brains of humans and laboratory animals, as well as in cultured neuronal cells. However, little is known about the effects of short-term periods of alcohol exposure. In the present study, we examined the changes in endocannabinoid levels (anandamide and 2-arachidonoylglycerol), as well as four additional N-acylethanolamines, in four brain regions of rats exposed to alcohol through the liquid diet for a period of 24h. The levels of N-acylethanolamines were diminished 24h after the onset of alcohol exposure. This was particularly evident for anandamide in the hypothalamus, amygdala and caudate-putamen, for N-palmitoylethanolamine in the caudate-putamen, for N-oleoylethanolamine in the hypothalamus, caudate-putamen and prefrontal cortex, and for N-stearoylethanolamine in the amygdala. The only exception was N-linoleoylethanolamine for which the levels increased in the amygdala after the exposure to alcohol. The levels of the other major endocannabinoid, 2-arachidonoylglycerol, were also reduced with marked effects in the prefrontal cortex. These results support the notion that short-term alcohol exposure reduces endocannabinoid levels in the brain accompanied by a reduction in several related N-acylethanolamines.