Background and Purpose: The aim of this study was to investigate the neurobehavioral consequences of focal ischemia in rats.Methods: We induced permanent occlusion of the left middle cerebral artery in 14 SpragueDawley rats, and used 13 sham-operated rats as controls. During surgery, brain temperature and body temperature were kept at normothermia. Neurobehavioral studies (neurological examination, passive avoidance task, Y maze test, and modified open-field test) were carried out 4 days after ischemia before killing the rats to evaluate histological damage.Results: Ischemia induced large infarcts in the cortex (138.6±8.5 mm
The time course of changes in extracellular glutamic acid levels and their Ca2+ dependency were studied in the rat striatum during focal cerebral ischaemia, using microdialysis. Ischaemia‐induced changes were compared with those produced by high K+‐evoked local depolarization. To optimize time resolution, glutamate was analysed continuously as the dialysate emerged from the microdialysis probe by either enzyme fluorimetry or biosensor. The Ca2+ dependency of glutamate changes was examined by perfusing the probe with Ca2+‐free medium. With normal artificial CSF, ischaemia produced a biphasic increase in extracellular glutamate, which started from the onset of ischaemia. During the first phase lasting ∼10 min, dialysate glutamate level increased from 5.8 ± 0.9 µM· min−1 to 35.8 ± 6.2 µM where it stabilized for ∼3 min. During the second phase dialysate glutamate increased progressively to its maximum (82 ± 8 µM), reached after 55 min of ischaemia, where it remained for as long as it was recorded (3 h). The overall changes in extracellular glutamate were similar when Ca2+ was omitted from the perfusion medium, except that the first phase was no longer detectable and, early in ischaemia, extracellular glutamate increased at a significantly slower rate than in the control group (2.2 ± 1 µM· min−1; p < 0.05). On the basis of these data, we propose that most of the glutamate released in the extracellular space in severe ischaemia is of metabolic origin, probably originating from both neurons and glia, and caused by altered glutamate uptake mechanisms. Comparison with high K+‐induced glutamate release did not suggest that glutamate “exocytosis,” early after middle cerebral artery occlusion, was markedly limited by deficient ATP levels.
Brain trauma is the main cause of morbidity and mortality in young adults. One delayed events that occurs after a head trauma and compromises the survival of patients is cerebral edema. The present study examined first the occurrence of cerebral edema after a traumatic brain injury (TBI) induced by moderate fluid percussion in rats. Brain water content was measured from 1 h to 7 days posttrauma, in the hippocampus and cortex, on both ipsi- and contralateral hemispheres. Second, the effects of mannitol, an osmotic agent frequently used in the clinic, and riluzole, a neuroprotective compound, were investigated on regional edema formation. After TBI, the ipsilateral edema began early at 1-6 h, was maximal at 48 h and was resorbed by 5-7 days. No edema was observed in the contralateral hemisphere. Mannitol at 1 g/kg or vehicle was administered iv 15 min, 2 h and 4 h postinjury. At this dose, mannitol significantly attenuated the ipsilateral injured cortex edema measured at 6 h (p < 0.05). Riluzole at 4 and 8 mg/kg or vehicle was administered 15 min (IV) and 6 h, 24 h, and 30 h (SC) post-TBI. Riluzole at 4 x 4 mg/kg significantly reduced edema measured at 48 h, in the ipsilateral hippocampus (p < 0.05), whereas at 4 x 8 mg/kg, the reduction was observed in the hippocampus (p < 0.01) and the injured cortex (p < 0.05). Our results demonstrate that (1) cerebral edema begins early after the injury and is resorbed over 1 week; (2) mannitol could attenuate cerebral edema; and (iii) riluzole in addition to its neuroprotective effects reduces the brain edema. Thus, riluzole could be useful in human TBI treatment.
The neuroprotective effects of Riluzole, a compound with several mechanisms of action including the inhibition of sodium channel activity and glutamate release, were evaluated in a rat model of parasagittal fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (350-400 g, n = 17) were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and subjected to parasagittal FP brain injury of moderate severity (2.3-2.5 atm). Fifteen min following injury, animals randomly received an i.v. bolus of either Riluzole (8 mg/kg, n = 8) or vehicle (n = 9), followed by subcutaneous injections (identical dose) at 6 hr and 24 hr. Two weeks after injury and drug treatment, animals were sacrificed and a series of brain sections, stained with Hematoxylin and Eosin (H&E) or cresyl violet, were evaluated for quantitative cortical lesion volume and cell counts of hippocampal CA3 neurons, respectively, using a computerized image analysis system. Administration of Riluzole significantly reduced FP-induced tissue loss in the temporal/occipital cortices ipsilateral to the site of impact by 46%, compared to vehicle-treated, brain-injured animals (P = 0.01). In contrast, the selective neuronal loss observed in the CA3 region of the ipsilateral hippocampus was unaffected by Riluzole treatment. The present study demonstrates that Riluzole can attenuate cortical lesion size following brain trauma. These neuroprotective effects may be related to the synergy of the different mechanisms of action of Riluzole.
The aim of our study was to assess polymorphonuclear neutrophil infiltration into the injured parenchyma after a traumatic brain injury (TBI). Myeloperoxidase (MPO) activity was assayed on the hippocampus, temporal and parietal cortex 6, 24, 48, 72, and 120 h post-trauma. MPO activity occurred in these structures from 6 h post-trauma and was maximum at 24-48 h. It was resolved by 72 h in the hippocampus and the parietal cortex, but persisted in the temporal cortex until 120 h after trauma. This suggests that neutrophil infiltration is a delayed phenomenon in the physiopathology of TBI. Considering that a large therapeutic window may be crucial in the management of TBI, inhibition of neutrophil infiltration needs to be further investigated following cerebral trauma.
The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) re-establishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti-excitotoxic or anti-inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2´1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5h after insult, reduced cortical lesion size in a dose-dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non-hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema-induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4´1 mg/kg s.c., was administered later than 30h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain their anti-ischemic effects in experimental models. Furthermore, unfractionated heparin and specifically enoxaparin, have, in addition to anticoagulant, many other pharmacological effects (i.e. reduction of intracellular Ca 2+ release; antioxidant effect; anti-inflammatory or neurotrophic effects) that could act in synergy to explain the neuroprotective activity of enoxaparin in acute neurodegenerative diseases. Finally, we demonstrated, that in different in vivo models of acute neurodegenerative diseases, enoxaparin reduces brain edema and lesion size and improves motor and cognitive functional recovery with a large therapeutic window of opportunity (compatible with a clinical application). Taking into account these experimental data in models of ischemia and brain trauma, the clinical use of enoxaparin in acute neurodegenerative diseases warrants serious consideration.
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