Power spectrum slope is related to motor function after focal cerebral ischemia in the rat.

Electroencephalography (EEG) changes across vigilance states have been observed after ischemic stroke in patients and experimental stroke models, but their relation to functional recovery remains unclear. Here, we evaluate motor function, as measured by single pellet reaching (SPR), as well as local EEG changes in nonrapid eye movement (NREM), rapid eye movement (REM), and wakefulness during a 30 day recovery period after middle cerebral artery occlusion or sham surgery in rats. Small cortical infarcts resulted in poor SPR performance and induced widespread changes in EEG spectra in the ipsilesional hemisphere in all vigilance states, without causing major changes in sleep-wake architecture. Ipsilesional 1-4 Hz power was increased after stroke, whereas power in higher frequencies was reduced, resulting in a steeper slope of the power spectrum. Microelectrode array analysis of ipsilesional M1 showed that these spectral changes were present on the microelectrode level throughout M1 and were not related to increased synchronization between electrodes. Spectrum slope was significantly correlated with poststroke motor function and may thus be a useful readout of recovery-related plasticity.

Fullerenols and glucosamine fullerenes reduce infarct volume and cerebral inflammation after ischemic stroke in normotensive and hypertensive rats.

Cerebral inflammation plays a crucial role in the pathophysiology of ischemic stroke and is involved in all stages of the ischemic cascade. Fullerene derivatives, such as fullerenol (OH-F) are radical scavengers acting as neuroprotective agents while glucosamine (GlcN) attenuates cerebral inflammation after stroke. We created novel glucosamine-fullerene conjugates (GlcN-F) to combine their protective effects and compared them to OH-F regarding stroke-induced cerebral inflammation and cellular damage. Fullerene derivatives or vehicle was administered intravenously in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) immediately after transient middle cerebral artery occlusion (tMCAO). Infarct size was determined at day 5 and neurological outcome at days 1 and 5 after tMCAO. CD68- and NeuN-staining were performed to determine immunoreactivity and neuronal survival respectively. Cytokine and toll like receptor 4 (TLR-4) expression was assessed using quantitative real-time PCR. Magnetic resonance imaging revealed a significant reduction of infarct volume in both, WKY and SHR that were treated with fullerene derivatives. Treated rats showed an amelioration of neurological symptoms as both OH-F and GlcN-F prevented neuronal loss in the perilesional area. Cerebral immunoreactivity was reduced in treated WKY and SHR. Expression of IL-1ß and TLR-4 was attenuated in OH-F-treated WKY rats. In conclusion, OH-F and GlcN-F lead to a reduction of cellular damage and inflammation after stroke, rendering these compounds attractive therapeutics for stroke.

Sleep disturbance impairs stroke recovery in the rat.

STUDY OBJECTIVES: There is a lack of experimental evidence to support the hypothesis that sleep may modulate stroke outcome as suggested by clinical observations. We have previously shown that sleep disturbance (SDis) over 3 days aggravates brain damage in a rat model of focal cerebral ischemia. The aim of this study is to further investigate effects of SDis on long-term stroke recovery and neuroplasticity as assessed by axonal sprouting, neurogenesis, and angiogenesis. DESIGN: Focal cerebral ischemia was induced by permanent occlusion of the distal branches of middle cerebral artery. Twelve hours after initiation of ischemia, SDis was performed over 3 consecutive days (deprivation of 80% sleep during the 12-h light phase). Weekly assessments on sensorimotor function by the single pellet reaching test (SPR) were performed for 5 weeks after surgery. Axonal sprouting was evaluated by anterograde tracing with biotinylated dextran amine (BDA) and neurogenesis/angiogenesis by bromodeoxyuridine (BrdU) labelling along with cell-type markers. Control groups included ischemia without SDis, sham with SDis, and sham without SDis. SETTING: Basic sleep research laboratory. MEASUREMENTS AND RESULTS: Rats subjected to SDis after ischemia showed significantly less recovery of forearm motor skills during the post-stroke period of 5 weeks. This effect was accompanied by a substantial reduction in axonal sprouting, expression of synaptophysin, and the ischemia-stimulated neural and vascular cell proliferation. CONCLUSION: SDis has detrimental effects on functional and morphological/structural outcomes after stroke, suggesting a role of sleep in the modulation of recovery processes and neuroplasticity.

Sleep disruption aggravates focal cerebral ischemia in the rat.

STUDY OBJECTIVES: Sleep changes are frequent in stroke patients and predict a poor outcome. It remains unclear how sleep influences stroke evolution and recovery. We assessed effects of sleep disruption on brain damage and on the expression of axon sprouting genes after focal cerebral ischemia in rats. DESIGN: 12 h after ischemia induced by occlusion of the middle cerebral artery, rats were subjected to sleep disruption including sleep deprivation for 12h (SDpv12h) and sleep disturbances (SDis) by SDpv12h for consecutive 3 days. Control groups included ischemia without SDpv12h or SDis, sham surgery plus SDis and sham surgery without SDis. Sleep changes were evaluated based on EEG and EMG recordings. MEASUREMENTS AND RESULTS: SDpv12h increased the infarct volume by 40% (SDpv12h 82.8 +/- 10.9 vs. control 59.2 +/- 13.9 mm3, P = 0.008) and SDis by 76% (SDis 58.8 +/- 20.4 vs. control 33.8 +/- 6.3 mm3, P = 0.017). SDpv12h also increased the number of damaged cells, visualized by TUNEL staining, by 137% (SDpv12h 46.8 +/- 15 vs. control 19.7 +/- 7.7/mm2, P < 0.001) and SDis by 219% (SDis 32.9 +/- 13.2 vs. control 10.3 +/- 2.5/mm2, P = 0.002). In addition, SDis significantly elevated the expression of the axonal extension inhibitory molecule neurocan (SDis 14.3 +/- 0.4 vs. control 6.2 +/- 0.1-fold of change, P < 0.001) in the injured hemisphere. CONCLUSIONS: These results provide the first direct evidence for a detrimental impact of sleep disruption on stroke evolution and suggest a potential role of sleep modulating treatments on stroke outcomes.

Chronic treatment with red wine polyphenol compounds mediates neuroprotection in a rat model of ischemic cerebral stroke.

In this study, we investigated the in vivo effects of red wine polyphenol compounds (RWPC) in rats that were submitted to middle cerebral occlusion as an experimental model of stroke. Male Wistar rats were given RWPC [30 mg/(kg x d) dissolved in drinking water] or water for 1 wk before being subjected to transient middle cerebral artery occlusion followed by reperfusion. Sham-operated rats were subjected to transient occlusion in which the filament was not completely introduced. The release of amino acids and energy metabolites were monitored by intracerebral microdialysis. The volume of the ischemic lesion was assessed 24 h after reperfusion. Proteomic analysis of brain tissue was performed to study the effects of ischemia and RWPC on specific protein expression. Treatment with RWPC completely prevented the burst of excitatory amino acids that occurred in response to ischemia in untreated rats and significantly reduced brain infarct volumes. Rats chronically treated with RWPC, however, had lower basal concentrations of energy metabolites, including glucose and lactate in the brain parenchyma, compared with untreated rats. Chronic RWPC treatment significantly enhanced the residual cerebral blood flow during occlusion and reperfusion in rats subjected to transient occlusion compared with untreated rats. This effect resulted from arterial vasodilatation, as the internal diameters of several arteries were significantly enlarged after RWPC treatment. Proteomic studies revealed the modulation by RWPC of the expression of proteins involved in the maintenance of neuronal caliber and axon formation, in the protection against oxidative stress, and in energy metabolism. These findings provide an experimental basis for the beneficial effects of RWPC on the neurovascular unit during stroke.

Buprenorphine does not aggravate ischemic neuronal injury in experimental focal cerebral ischemia.

Buprenorphine has been increasingly used as maintenance therapy in opioid dependence as an alternative to methadone and other pharmacological therapies. However, available data suggest increased risk of cerebrovascular events in opioid-dependent patients. Therefore, an opioid that provides safety with regard to neurological function should be considered by opioid-dependent patients. The evidence for the in vitro neurotoxic effects of buprenorphine is rapidly increasing. In order to clarify whether buprenorphine is also neurotoxic under the condition of cerebral ischemia in vivo, we applied an acute dose of buprenorphine in a transient model of focal cerebral ischemia in rats. Our study provides preclinical evidence for the usage of buprenorphine during the postoperative period following ischemic events as well as for the maintenance therapy of opioid-dependent patients wherein the risk of cerebrovascular events is increased.

Olanzapine attenuates brain damage after focal cerebral ischemia in vivo.

Atypical antipsychotic drugs are widely used in the treatment of schizophrenia. These agents are discovered to have some additional beneficial effects beyond their effectiveness as antipsychotic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of olanzapine after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Olanzapine (0.1 and 1 mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Olanzapine (0.1 and 1 mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia.