Brain injury experimental studies

Many head-injured patients experience fever, and recent data indicate that bladder temperature and rectal temperature often underrepresent brain temperature after TBI, particularly when the patient is hypo-or hyperthermic (21). In that study, brain temperature was usually greater than rectal or bladder temperature in adults with severe brain injury. In another study, the duration of fever was reported to be associated with poor outcome in patients with supratentorial hemorrhage (5). Taken together, these experimental and clinical findings (4,5) indicate that fever should be aggressively treated when core temperature is mildly elevated above normal levels (22,23). 

Based on experimental and clinical data, cerebral hypothermia appears to be a potent therapeutic approach to treating brain trauma. However, recent results from the Multicenter National Brain Injury Study Hypothermia (NABIS H) clinical trial appear to be disappointing, and more refinement of the clinical application of hypothermia is required (73). Additional clinical trials are now required to evaluate systematically the beneficial effects of clinical hypothermia in different populations of brain-injured patients. In addition, experimental data regarding the beneficial effects of combination therapy are required to evaluate whether hypothermia plus pharmacotherapy may provide a better outcome. Forexample, mildpostischemichypothermia(33-39°C) combined with the antiinflammatory cytokine IL-10 has recently been reported to produce long-term protection of the C Al hippocampus after transient global ischemia (74). Hypothermia or IL-10 treatment alone did not protect chronically. In contrast, Kline etal. (75) showed that acute systemic administration of IL-10 suppressed the beneficial effects of... 

Erb D. E. and Povlishock J. T. (1988) Axonal damage in severe traumatic brain injury an experimental study in cat. Acta Neuropathol. 76, 347-358. 

It is known from animal models with global ischemia and traumatic brain injury that moderate hypothermia attenuates secondary brain damage by reducing cerebral ischemia and postischemic brain edema and preserving the blood-brainbarrier. Even though hypothermia has potent cerebroprotective effects after experimental focal ischemia, clinical studies on hypothermic therapy after MCA infarction were not available until recently. We performed a pilot study investigating the efficacy, feasibility, and safety of induced moderate hypothermia in the therapy of patients with acute, severe MCA infarction and increased ICP. 

A number of experimental studies have shown that caspase inhibition reduces ischemic injury [51]. Caspase-3 inhibitors [52], gene deletions of Bid or caspase-3 [53], and the use of peptide inhibitors, viral vector-mediated gene transfer, and antisense oligonucleotides that suppress the expression and activity of apoptosis genes have all been found to be neuroprotective [51]. However, caspase inhibitors do not reduce infarct size in all brain ischemia models, perhaps related to the greater severity of ischemia, limited potency or inability of the agent to cross the blood-brain barrier, relatively minor impact of apoptosis on stroke outcome, and upregulation of caspase-independent or redundant cell-death pathways. Ultimately, it may be necessary to combine caspase inhibitors and other inhibitors of apoptosis with therapies directed toward other pathways, for successful neuroprotection. 

The concept of the ischemic penumbra has proven to be an extremely valuable construct for both experimental studies of ischemic stroke and for the development of tools for the management of patients with this disorder. Indeed, a major driver in the development of treatments for ischemic stroke is the belief that in many acute stroke patients, there is a region of salvageable brain that is threatened with permanent injury. This region of brain corresponds to the ischemic penumbra originally described in experimental stroke studies. The clinical condition does not strictly meet the criteria as originally defined by experimentalists. Nonetheless, the concept is clinically valuable, and a suitable modification of its definition applicable to the clinical condition is appropriate. 

It is well recognized that a head impact produces both translational and rotational motion as well as deformation of the skull. Resultant brain injury may occur from both absolute motion of the brain and its relative displacement with respect to the skull. At present, there are several physical parameters used in the evaluation of head injury, including translational and/or rotational acceleration levels of head impact, impact force, velocity and kinetic energy, impulse and impact duration, etc. These measures have been widely used for animal, human cadaver, and dummy experimental data to determine tolerable and survival thresholds for head impact in translation or rotation. Other parameters such as skull displacement and stresses, brain pressures and strains, as well as neck stretch/strain are usually related to analytical and experimental head model studies. 

Cellular therapy is the replacement of lost or dysfunctional tissues with new ones. Various cell types have been evaluated and considered for therapy. In the CNS, fetal neuronal tissue has been particularly evaluated for its merit in treating neurological diseases and injuries [1]. While numerous experimental and clinical transplantation studies showed that fetal neuronal transplants improve functional deficits in models of CNS diseases [2-5], others reported less positive outcomes [6, 7]. In addition, the rate of survival of fetal neuronal cells transplanted into the adult brain is relatively low, requiring large quantities of tissue, generally from several fetuses, for therapy. Researchers are looking at other opportunities for cellular therapy, particularly in the CNS. 

Here we investigate the neuroprotective potential of BEO in vivo by using an experimental model of focal brain ischemia in rats. Moreover, we evaluate whether neuroprotection is associated with altered levels of excitatory neurotransmitters and with a modulation of PI3-K/Akt pathway in the ischemic cortex. Our results indicate that BEO indeed protects against ischemic injury in an in vivo model of permanent focal brain ischemia in rat and that neuroprotection is associated with reduced excitatory amino acid efflux induced by MCAo in the ischemic cortex and elevation ofp-Akt and phospho-GSK-3/3 (p-GSK-3/3) levels in the ischemic penumbra. A preliminary account of this in vivo study has been communicated to the British Pharmacologic Society (Morrone et al., 2006). 

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