Experimental and Clinical Use of Therapeutic Hypothermia for Ischemic Stroke: Opportunities and Limitations

Stroke remains a disease with a serious impact on quality of life but few effective treatments exist. There is an urgent need to develop and/or improve neuroprotective strategies to combat this. Many drugs proven to be neuroprotective in experimental models fail to improve patient outcome in a clinical setting. An emerging treatment, therapeutic hypothermia (TH), is a promising neuroprotective therapy in stroke management. Several studies with TH in experimental models and small clinical trials have shown beneficial effects. Despite this, implementation into the clinical setting is still lacking due to methodological considerations as well as hypothermia-related complications. This paper discusses the possible opportunities and limitations of the use of TH in animal models and the translation into the clinic

The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection

Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia

Background: Stroke is an important cause of morbidity and mortality and few therapies exist thus far. Mild hypothermia (33 degrees C) is a promising neuroprotective strategy to improve outcome after ischemic stroke. However, its complete mechanism of action has not yet been fully elaborated. This study is the first to investigate whether this neuroprotection occurs through modulation of the neuroinflammatory response after stroke in a time-dependent manner. Methods: The Endothelin-1 (Et-1) model was used to elicit a transient focal cerebral ischemia in male Wistar rats. In this model, the core and penumbra of the insult are represented by the striatum and the cortex respectively. We assessed the effects of 2 hours of hypothermia, started 20 minutes after Et-1 injection on neurological outcome and infarct volume. Furthermore, pro-and anti-inflammatory cytokine expression was determined using ELISA. Microgliosis and astrogliosis were investigated using CD-68 and GFAP staining respectively. All parameters were determined 8, 24, 72 hours and 1 week after the administration of Et-1. Results: Et-1 infusion caused neurological deficit and a reproducible infarct size which increased up to 3 days after the insult. Both parameters were significantly reduced by hypothermia. The strongest reduction in infarct volume with hypothermia, at 3 days, corresponded with increased microglial activation. Reducing the brain temperature affected the stroke induced increase in interleukin-1 beta and tumor necrosis factor a in the striatum, 8 hours after its induction, but not at later time points. Transforming growth factor beta increased as a function of time after the Et-1-induced insult and was not influenced by cooling. Hypothermia reduced astrogliosis at 1 and 3 days after stroke onset. Conclusions: The beneficial effects of hypothermia after stroke on infarct volume and functional outcome coincide with a time-dependent modulation of the cytokine expression and gliosis

In vivo monitoring of endogenous hydrogen peroxide in rat model of stroke using amperometry on modified electrodes

info:eu-repo/semantics/nonPublishe

The neuroprotective action of candesartan is related to interference with the early stages of 6-hydroxydopamine-induced dopaminergic cell death.

Several studies have revealed that manipulation of the renin angiotensin system results in reduced progression of nigrostriatal damage in different animal models of Parkinson’s disease. In the present work, the effect of daily treatment of rats with the angiotensin II (Ang II) type 1 (AT1) receptor antagonist candesartan (3 mg/kg per day, s.c.) initiated 7 days before the intrastriatal injection of 6-hydroxydopamine (6-OHDA) was investigated by means of tyrosine hydroxylase-positive cell counts in the substantia nigra, and dopamine and 3,4-dihydroxyphenylacetic acid measurements in the striatum. In this experimental set-up, candesartan protected dopaminergic neurons of the nigrostriatal tract against the neurotoxin-induced cell death. However, the beneficial effects of AT1 receptor blockade were not confirmed when treatment was started 24 h after the lesion, suggesting that candesartan interferes with the early events of the 6-OHDA-induced cell death. Stimulation of the AT1 receptor with Ang II increased the formation of hydroxyl radicals in the striatum of intact rats as measured by the in vivo microdialysis salicylate trapping technique. This Ang II-induced production of reactive oxygen species was suppressed by candesartan perfusion. Furthermore, the Ang II-induced production of reactive oxygen species was nicotinamide adenine dinucleotide phosphate - oxidase and protein kinase C dependent as it could be blocked in the presence of apocynin, an nicotinamide adenine dinucleotide phosphate - oxidase inhibitor, and chelerythrine, an inhibitor of protein kinase C. Together, these data further support the hypothesis that Ang II might contribute in an early stage to the neurotoxicity of 6-OHDA by reinforcing the cascade of oxidative stress

Oxidative Stress in Genetic Mouse Models of Parkinson’s Disease

There is extensive evidence in Parkinson’s disease of a link between oxidative stress and some of the monogenically inherited Parkinson’s disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson’s disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson’s disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson’s disease, gene-environment interactions in genetically engineered mouse models of Parkinson’s disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson’s disease

Comparative study of an on-line system and an implantable modified platinum electrode for continuous monitoring of H2O2 in vivo

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sigma 1 receptor-mediated increase in hippocampal extracellular dopamine contributes to the mechanism of the anticonvulsant action of neuropeptide Y

The potent anticonvulsant properties of neuropeptide Y (NPY) are generally attributed to a Y-2 receptor-mediated inhibition of glutamatergic synaptic transmission. Independent studies have shown that NPY increases brain dopamine content, possibly via interaction with sigma 1 receptors. Recently, we showed that increased extracellular hippocampal dopamine attenuates pilocarpine-induced limbic seizures via activation of hippocampal D-2 receptors. Our aim in this study was to elucidate the role of increased hippocampal dopamine in the mechanism of the anticonvulsant action of NPY and to investigate the involvement of Y-2 and sigma 1 receptors in this process. Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. NPY was administered intracerebroventricularly, intrahippocampally via the microdialysis probe, or coadministered intrahippocampally with the D-2 receptor antagonist remoxipride, the Y-2 receptor antagonist BIIE0246 or the sigma 1 receptor antagonist BD1047. Changes in hippocampal extracellular dopamine were monitored, and behavioural changes indicative of seizure activity were scored. Intracerebroventricular (10 nmol/3 mu L) and intrahippocampal (20-50 mu M) NPY administration increased hippocampal dopamine and attenuated pilocarpine-induced seizures. Hippocampal D-2 receptor blockade (4 mu M remoxipride) reversed the anticonvulsant effect of NPY. Y-2 receptor blockade (1 mu M BIIE0246) reversed the anticonvulsant effect of NPY but did not prevent NPY-induced increases in hippocampal dopamine. Sigma 1 receptor blockade (10 mu M BD1047) abolished NPY-induced increases in hippocampal dopamine and reversed the anticonvulsant effect of NPY. Our results indicate that NPY-induced increases in hippocampal dopamine are mediated via sigma 1 receptors and contribute to the anticonvulsant effect of NPY via increased activation of hippocampal D-2 receptors. This novel mechanism of anticonvulsant action of NPY is separate from, and may be complementary to, the well established Y-2 receptor-mediated inhibition of hippocampal excitability