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Abstract: Acetylsalicylic acid (ASA; Aspirin) has a neuroprotective potential by its anti-excitotoxic and anti-inflammatory effects. A temporary middle cerebral artery occlusion (tMCAO) model was used in 80 Wistar rats to evaluate whether a high dose of Aspirin (40 mg/kg) applied with different initiation time points after stroke onset (30 min, 3 h, 6 h, 12 h, 20 rats for each time group) and followed by repeated administration (1, 2 and 3 days) is neuroprotective. Neurological score and brain infarct volume were analyzed and indicated that postischemic therapy initiation at 30 min and as late as 6 h led to better neurological recovery (6 h, p =0.0046) and significant smaller infarct size (6 h, 57±9 mm3, n =10, p =0.0043) compared to the saline control group (110±13 mm3, n =10). Thus, there may be a relatively wide time window for acute stroke therapy with high dose Aspirin. [Copyright &y& Elsevier]

Abstract: Since pravastatin, a HMG-CoA reductase inhibitor, has recently been shown to reduce infarct volumes and glutamate release in a rat model of ischemic stroke, the aim of the present study was to investigate whether this neuroprotective effect may be due to a modulation of excitatory and inhibitory neurotransmitter receptors. Therefore, Wistar rats were treated six times in 4 days with pravastatin or saline and allowed to survive for 6 hours or 5 days (n =10 per time point and group), respectively. Using quantitative receptor autoradiography, ligand binding densities of [3H]MK-801, [3H]AMPA, and [3H]muscimol for labeling of NMDA, AMPA, and GABAA receptors were analyzed in sensorimotor cortices Par1 and Par2, the striatum, and the hippocampus. Statin therapy induced complex alterations of ligand binding densities in different brain regions. Labeling of NMDA receptors was significantly increased in Par2, both after 6 hours and 5 days, respectively. Within the striatum, AMPA as well as GABAA receptor binding values were significantly increased on day 5. Furthermore, a marked and significant increase of [3H]muscimol ligand binding to GABAA receptors throughout all hippocampal subfields was seen after 6 hours. This complexity could easily be unraveled when focusing on the balance between excitatory glutamate and inhibitory GABAA receptors, in which case only the increase of hippocampal [3H]muscimol ligand binding 6 hours after the first application of pravastatin was accompanied by a net shift towards inhibition. Consequently, our data suggest an additional regulatory pathway induced by statins, namely modification of the abundance of excitatory and inhibitory neurotransmitter receptors. [Copyright &y& Elsevier]

Abstract: The endocannabinoids anandamide (AEA) and palmitoylethanolamide (PEA) act as endogenous protective factors of the brain, using different pathways of neuroprotection against neuronal damage. Although several in vivo and in vitro studies confirmed the neuroprotective efficacy of endocannabinoids, no experimental settings compare and explore the neuroprotective potential of AEA and PEA in an acute stroke model. In this study, we investigated the neuroprotective potential by infarct measurement after high (30 mg/kg body weight) and low dosage administration (10 mg/kg body weight) of the endocannabinoid PEA in 49 male Wistar rats. In additions we studied infarct volumes of 22 male Wistar rats receiving the endocannabinoid AEA with a dosage of 10 mg/kg body weight or placebo. The neurological outcome was assessed 24 h after ischemia. Endocannabinoids were given intraperitoneally 30 min after initiation of transient middle cerebral artery occlusion (tMCAO). Infarct volume was calculated on the basis of 2.3.5-triphenyltetrazolium chloride staining. In the PEA high-dose group a significant total infarct reduction of 35% compared to the control group could be observed. AEA-treated rats presented a total infarct reducing effect of 26% compared to controls. Neurological scores, evaluated 24 h after tMCAO and physiological parameters, obtained 45 and 90 min after onset of ischemia showed no significant differences among the groups. As shown here, the endocannabinoids AEA and PEA achieved a significant neuroprotective effect by reducing size of infarcted tissue after tMCAO. Both endocannabinoids may have the potential to treat acute stroke and exert neuroprotection through a variety of mechanisms. [Copyright &y& Elsevier]

Abstract: Background and purpose: The timing and mechanisms of protection by hyperbaric oxygen (HBO) in cerebral ischemia have only been partially elucidated. We monitored the early in vivo effects of HBO after 2 h transient focal ischemia using repetitive MRI. Methods: Wistar rats underwent filament occlusion of the middle cerebral artery (MCAO). 40 min after MCAO, rats were placed in a HBO chamber and breathed either 100% O2 at 3.0 atmospheres absolute (ata; n = 24) or at 1.0 ata (control; n = 24) for 1 h. Diffusion, perfusion and T2-weighted MR-images were obtained after 15 min and 3, 6 and 24 h of reperfusion. In 6 axial MR slices, volume of abnormal diffusion and T2w signals were measured in the ischemic hemisphere. Furthermore, hemispheric mean apparent diffusion coefficient- (ADC) and T2 values were calculated for statistical analysis. Results: HBO significantly reduced volume of abnormal DWI signal beginning immediately after reperfusion (control: 92 ± 28 mm3; HBO: 64 ± 17) and lesion size on T2w (control: 375 ± 91 mm3; HBO: 225 ± 39) after 24 h. Correspondingly, mean ADC levels were lower and T2 values higher in the ischemic hemisphere in the control group. HBO reduced histological infarct size at 24 h. Conclusion: High-dose intraischemic HBO therapy has an immediate protective on the brain which is superior to normobaric oxygen. [Copyright &y& Elsevier]

Acetylsalicylic acid (ASA) is neuroprotective through various pharmacological action sites. We used a temporary middle cerebral artery occlusion (tMCAO) model in 56 Wistar rats to assess whether repeated ASA injections at 30 min, 6 h, 1, 2, 3, and 4 days after stroke onset are neuroprotective. Animals were sacrificed 5 days after MCAO; infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride staining. As compared to saline (164±13 mm3, n=14), only repeated injections of 40 mg/kg ASA (79±18 mm3, n=14, P=0.0029), but not of 20 mg/kg ASA (129±19 mm3, n=15), reduced infarct volume significantly. No significant change was noted with 40 mg/kg ASA injected only once at 30 min after MCAO (117±16 mm3, n=13). [Copyright &y& Elsevier]

To test the hypothesis that presence of metalloproteases (MMPs), their inhibitors (TIMPs) and their substrate laminin-5 differs between the ischemic core and the surrounding tissue, we examined the impact of middle cerebral artery occlusion/reperfusion (MCA:O/R) on these molecules in different regions of the infarct. We also investigated the influence of hypothermia on the progression of the ischemic lesion and MMP activity. Brain sections from 64 Wistar rats subjected to MCA:O/R were examined by means of cytohistochemistry and zymography. The artery was occluded for 2 h followed by 3, 5, 8 and 12 h of reperfusion. Well characterized antibodies against laminin-5, MMPs and TIMP-2 were used. A total of 32 rats were treated with hypothermia. The presence of each antigen was related to the following regions of interest: ischemic core with BBB breakdown (Ic), surrounding ischemic tissue without BBB breakdown (Ir), and the contralateral non-ischemic region (N). Regions of interest were defined by MRI. The Ic increased over time at the cost of the Ir. BBB breakdown occurred early in the ischemic core and increased over time. Hypothermia reduced the BBB breakdown at all time points. A graded decreased presence of laminin-5 was observed with 16.5±3.7(N)>10±2.8(Ir)>4±1.4(Ic) immunopositive microvessels/mm2 at 3 h of reperfusion. MMP-9 showed a reverse pattern with 0 (N)<4±0.8(Ir)<10±1.5(Ic) immunopositive microvessels/mm2. Hypothermia decreased the MMP activity measured by zymography. Laminin-5 and MMP presence relate directly to the degree of postischemic injury. Hypothermia reduces the conversion from the Ir to ischemic core and the degree of BBB as well as MMP abundance. [Copyright &y& Elsevier]