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Brain stroke occurs when blood supply to, or within, the brain region stops. A stroke can occur anywhere in the CNS and is caused either by a cerebral infarction, as a result of a blocked artery (ischemic stroke) or by an intracra-nial or cerebral haemorrhage as a result of weak arteries or an aneurism in the brain that ruptures (haemorrhagic stroke). The symptoms a stroke victim experiences depend on which areas of the brain are involved and can include, amongst other symptoms, an abrupt loss of vision, coordination, sensation, speech, paralysis and loss of consciousness. Brain stem strokes are especially devastating and life threatening because they can disrupt the involuntary vegetative functions essential to life. When blood supply is blocked, brain cells die as they are deprived from oxygen (ischemia), and they start to release toxic chemicals that threaten surrounding tissue (the ischemic penumbra). In ischemic stroke, the acute goal is to restore blood flow to the area and to prevent cell death in the penumbra. Thrombolytic drugs are nowadays applied as a "blood clot-buster" to restore blood flow (Pulsinelli et al. 1997). A variety of cytoprotective agents can be used in the post-acute phase for up to six hours (Endres et al. 1998), but their effectiveness is poor and the treatment window limits its application to only a small number of patients. In hemorrhagic stroke, however, thrombolytic drugs would actually have a detremental affect (Schellinger et al. 1997). If spontaneous clotting does not occur and hematoma increases in size, a rapid neu-

rosurgical intervention may be needed to stop bleeding. Depending on the site, the duration and the severity of the blocked or hampered blood supply, the patient usually recovers, but often a lasting defect remains due to a loss of brain tissue, which is also visible in brain scans. The brain can compensate for this damage to some extent. Some neurons may only have been temporarily damaged, not killed, and the plasticity of the brain allows it to reorganise neuronal networks so that other parallel brain areas can take over functions stimulated by physical, occupational, and speech and audiology rehabilitation programmes. However, large infarctions or chronic cases of small strokes require tissue repair. The ischemic penumbra is the target area for both restoration and the prevention of further neuronal degeneration.

The possibilities of neurotransplantation guided experimental studies in rodent early stroke models to either replace the lost neurons or place cells as a source of trophic factors to enhance plasticity phenomena for recovery of function. It proved to be effective in many studies (cf. Abe 2000; Nishino and Borlongan 2000). Fetal neurons (Netto et al. 1993) and cultured LBS neurons, grown and differentiated from a malignant human testicular carcinoma (Borlongan et al. 1998) were found to integrate with existing neurons in the stroke affected area in rats and to correct cognitive and motor skill problems. In addition, human neuroprogenitor cells (Kelly et al. 2004), human bone marrow stem cells (Zhao et al. 2002) appear to exhibit a similar effect, and these cells differentiate themselves to resemble the neighbouring cells in the site of the lesion. However, the observed functional improvements are possibly mediated more by proteins secreted from the implanted cells than by cell supplementation since the integration of implanted cells in the host brain is limited. Thus, an upregulated host brain plasticity may be the underlying mechanism. This trophic mechanism is also assumed to take place following implantation of human umbilical cord blood cells (Ven-drame et al. 2005) or porcine choroid plexus tissue (Borlongan et al. 2004), but concurrent angiogenesis may occur as well (Jiang et al. 2005).

The early positive and encouraging results with the LBS neurons in rat stroke models has led to clinical trials in patients with chronic motor defects resulting from an ischemic stroke. The cells were implanted with multiple injections around the area of the brain lesion in patients whose stroke occurred six months to six years previously and who had a fixed motor deficit that had remained stable for at least two months in order to evaluate any possible improvements resulting from the procedure. This phase I trial, including twelve patients, showed no adverse cell-related serologic or imag-ing-defined effects up to 18 months after surgery. There was also evidence of improved metabolism at the implant site in seven patients and some improvement on the European stroke scale score in six patients (Kondziolka et al. 2000). A positive correlation was found between glucose metabolic activity in the stroke area and motor performance (Meltzer et al. 2001) and cognitive function improved for those patients treated for basal ganglia stroke after six months (Stilley et al. 2004). The subsequent phase II trial with LBS neurons using pre- and postoperative, observer-blind evaluations and control patients for comparison, revealed no significant benefit in motor function, although several patients noted measurable improvements of their functional defects in daily life compared to pre-surgery state (Kondziolka et al. 2005). So again neuron implantation is feasible in patients with motor area infarction, but a genuine and reproducable therapy was not reached. Other types of transplants, such as fetal porcine cells (Savitz et al. 2005) and cell suspensions from immature human nervous and hemopoietic tissues (Rabinovich et al. 2005), were also applied in small pilot studies with partial success. However, these studies were not based on any preclinical animal studies.

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