Cerebral Palsy

No effective therapy is currently available to promote recovery following ischemic stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. We undertook a detailed review of data from recent basic science and preclinical studies to investigate the potential application of endogenous and exogenous stem cell therapies for treatment of cerebral ischemia. To date, spontaneous endogenous neurogenesis has been observed in response to ischemic injury, and can be enhanced via infusion of appropriate cytokines. Exogenous stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells from multiple sources cells also exhibit neuroprotective properties that may ameliorate stroke deficits. In many cases, functional benefits observed are likely independent of neural differentiation, although the exact mechanisms remain poorly understood. Future studies of neuroregeneration will require the demonstration of function in endogenously born neurons following focal ischemia. Further, methods are currently lacking to demonstrate definitively the therapeutic effect of newly introduced neural cells. Increased plasticity following stroke may facilitate the functional integration of new neurons, but the loss of appropriate guidance cues and supporting architecture in the infarct cavity will likely impede the restoration of lost circuitry. Thus careful investigation of the mechanisms underlying trophic benefits will be essential. Evidence to date suggests that continued development of stem cell therapies may ultimately lead to viable treatment options for ischemic brain injury. J. Comp. Neurol. 515:125-144, 2009. (c) 2009 Wiley-Liss, Inc.

Hypothermia is an effective method for reducing the neuronal damage induced by hypoxia-ischemia (HI) but the underlying mechanism remains unclear. To investigate the effects of post-HI hypothermia on the developing brain, 7-day-old rats were subjected to left carotid artery ligation followed by 8% oxygen for 2hours. They were divided into a hypothermia group (rectal temperature 32-33 degrees C for 24h) and a normothermia group (36-37 degrees C for 24h) immediately after hypoxia-ischemia. Animals were sacrificed at 12, 24 and 72h for gene analysis and 0, 1, 3 and 7 days for protein analysis after HI. There was a significant decrease in infarct volume in the hypothermia group at 7 days after HI compared with that in the normothermia group. The hypothermia group had more Neuronal Nuclei (NeuN) positive neurons and lower levels of glial fibrillary acidic protein (GFAP) mRNA and immunoreactivity in the hippocampus CA1 region than the normothermia group. Real-time PCR showed no significant difference in glial cell line-derived neurotrophic factor (GDNF) mRNA expression in the hippocampus in the two groups at various time points after HI. However, GDNF protein level was significantly increased in the hypothermia group. On the other hand, mRNA and protein levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were dramatically decreased in the hypothermia compared with the normothermia group. The present findings highlight an apparent association between inhibition of hippocampal neuron loss by hypothermia and decreased astrocytosis and inflammatory cytokine release after hypoxia-ischemia in the developing brain.

Hypoxia-inducible transcription factors (HIF)-1 and HIF-2, composed of an oxygen-dependent alpha-subunit and a constitutive beta-subunit, have been characterized as the most important regulators of oxygen homeostasis during physiological and pathological conditions. During embryonic, fetal and postnatal brain development, HIFs and specific HIF target genes are involved in early and highly active maturational processes by modulating cell differentiation, vascular development, angiogenesis and metabolic homeostasis. Under hypoxic conditions, activation of the HIF system reflects an immediate and cell-specific response to acute brain hypoxia. In a complementary fashion, both HIF-1 and HIF-2 modulate cerebral hypoxic stress responses and activate endogenous neuroprotective systems during acute and late stages of hypoxic/ischemic (HI) damage of the developing brain. Therefore, HIFs and their specific target genes that are expressed during brain injury are of particular interest for future diagnostic and therapeutic options in HI injury of the developing nervous system.

AIM: To assess the regional vulnerability to ischemic damage and perfusion/metabolism mismatch of reperfused brain following restoration of spontaneous circulation (ROSC) after cardiac arrest. METHOD: We used positron emission tomography (PET) to map cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in brain of young pigs at intervals after resuscitation from cardiac arrest. After obtaining baseline PET recordings, ventricular fibrillation of 10min duration was induced, followed by mechanical closed-chest cardiopulmonary resuscitation (CPR) in conjunction with i.v. administration of 0.4U/kg of vasopressin. After CPR, external defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). CBF and CMRO(2) were mapped and voxelwise maps of OEF were calculated at times of 60, 180, and 300min after ROSC. RESULTS: There was hypoperfusion throughout the telencephalon at 60min, with a return towards baseline values at 300min. In contrast, there was progressively increasing CBF in cerebellum throughout the observation period. The magnitude of CMRO(2) decreased globally after ROSC, especially in cerebral cortex. The magnitude of OEF in cerebral cortex was 60% at baseline, tended to increase at 60min after ROSC, and declined to 50% thereafter, thus suggesting transition to an ischemic state. CONCLUSION: The cortical regions tended most vulnerable to the ischemic insult with an oligaemic pattern and a low CMRO(2) whereas the cerebellum instead showed a pattern of luxury perfusion.