Some other stimulants, in appropriate doses, can however be neuroprotective. Selegiline: It has been shown to slow early progression of. We review the mechanisms by which hypothermia confers neuroprotection as .. Therapeutic hypothermia consists of 3 phases: induction, maintenance, and. Neuroprotective and disease-modifying effects of the ketogenic diet . A third variation on the diet, known as the Radcliffe Infirmary diet, represents a.
Neuroprotection 3 –
To explore this mechanism in further detail, we examined the protective activity of Dkk3 in primary cultures of astrocytes and in mixed cortical cultures containing both astrocytes and neurons. In cultures from wild-type mice, glucose deprivation substantially increased Dkk3 protein levels Figure 2C. We extended the analysis to molecules that lie downstream of VEGF receptor activation and likely contribute to cell protection.
VEGF receptor activation is known to stimulate the phosphatidylinositolkinase PI3K pathway, which has a widespread role in cell protection mechanisms. Interestingly, glucose deprivation in astrocytes lacking Dkk3 caused a substantial reduction in phospho-Akt levels, which was not observed in wild-type astrocytes Figure 2E. Activation of the PI3K pathway induces the expression of the antiapoptotic gene, Bcl-2 Pugazhenthi et al.
We found a significant reduction in Bcl-2 protein levels in response to glucose deprivation in astrocytes lacking Dkk3, but not in wild-type astrocytes Figure 2F. Moving from this finding, we wondered whether astrocyte cultures prepared from CD1 mice could be more sensitive to a cytotoxic insult. Neuronal death was assessed 20 h after the NMDA pulse.
These findings suggested that Dkk3 produced from astrocytes acted on neighbor neurons to attenuate excitotoxic death. However, the extent of neuronal death varied in different culture preparations, and the appropriate concentrations of NMDA were established from time to time on the basis of data obtained with concentration-response curves of NMDA in sister cultures performed the day before the experiment.
In another experiment, we could also demonstrate that application of hrVEGF 0. We have shown here that: This suggests that endogenous Dkk3 shapes the responsiveness of CNS cells to environmental insults.
Activation of the Wnt pathway is known to support neuronal survival, and induction of the Wnt inhibitor, Dkk-1, contributes to neuronal death in experimental animal models of cerebrovascular disorders Cappuccio et al.
Dkk3 differs from all other Dkk family members because its modulatory action on Wnt signaling is complex and context-dependent. In contrast, Dkk3 positively modulates the canonical Wnt signaling pathway in the heart and kidney Federico et al. On the basis of these findings, we hypothesized the following scenario that could be targeted by therapeutic intervention: While ischemic infarct was greater in mice lacking Dkk3, we have no evidence so far that endogenous Dkk3 is protective against ischemic neuronal damage by a mechanism mediated by VEGF.
Excessive VEGF might have detrimental effects in cerebrovascular disorders and age-related neurodegenerative disorders by disrupting endothelial barriers, thereby inducing oedema and inflammation. It will be interesting to investigate whether exogenous VEGF rescues the pro-ischemic phenotype of Dkk3 mice.
However, this task is difficult to achieve because of the pleiotropic effects of VEGF in CNS cells, which require the analysis of different doses of VEGF delivered in different territories of the ischemic damage in different time windows. Perhaps strategies aimed at enhancing Dkk3 levels might help to overcome these limitations by optimizing the amount of VEGF that is endogenously produced under pathological conditions.
As opposed to other members of the Dkk family see Zorn, , the identity of the receptor s that mediate s the biological action of Dkk3 is unknown. Which of these or other mechanisms mediates the induction of VEGF by Dkk3 in astrocytes remains to be determined. In conclusion, we offered the first evidence that Dkk3 protects cultured neurons and astrocytes through a mechanism that involves the induction of VEGF. A limitation of the study is that we specifically focused on the involvement of VEGF in the action of Dkk3 and other potential mechanisms have been neglected.
In both in vitro and in vivo models, endogenous Dkk3 behaved as a defensive molecule, raising the possibility that strategies aimed at enhancing Dkk3 production are protective. The analysis of how neurotransmitter receptors expressed by astrocytes control Dkk3 gene expression might be a starting point in the identification of these strategies. CB performed in vitro experiments of glucose deprivation, histological and immunohistochemical analyses, statistical analyses, designed experiments and wrote the manuscript.
FB performed in vitro experiments of oxidative stress in cultured astrocytes and western blot analysis. FM and GBo performed in vivo experiments using the model of permanent focal ischemia. This work was supported by the Italian Ministry of Health Project code: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer. Expression patterns of the Wnt pathway inhibitors dickkopf3 and secreted frizzled-related proteins 1 and 4 in endometrial endometrioid adenocarcinoma: Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis.
The hormetic functions of Wnt pathways in tubular injury. Possible involvement of VEGF signaling system in rescuing effect of endogenous acetylcholine on NMDA-induced long-lasting hippocampal cell damage in organotypic hippocampal slice cultures.
Secreted antagonists of the Wnt signalling pathway. Small interfering RNA targeting Dickkopf-1 contributes to neuroprotection after intracerebral hemorrhage in rats. Loss of Dickkopf-3 promotes the tumorigenesis of basal breast cancer.
Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway. Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia. Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage. Vascular endothelial growth factor counteracts NMDA-induced cell death of adult cholinergic neurons in rat basal nucleus of Meynert.
Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina. Quantitative assessment of early brain damage in a rat model of focal cerebral ischemia. PubMed Abstract Google Scholar. In Vitro Biological System eds C. Academic press , 1, 46— VEGF signaling in neurological disorders. Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism.
Focal cerebral ischaemia in the rat: The Dickkopf-homolog 3 is expressed in tumor endothelial cells and supports capillary formation. Targeting the Wnt pathway in cancer: ZM, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity. Overexpression of Dickkopf-3 induces apoptosis through mitochondrial pathway in human colon cancer.
Dickkopf-3 as a new potential marker for neoangiogenesis in colorectal cancer: The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Ferdinando Nicoletti, ferdinandonicoletti hotmail. Login Register Login using. You can login by using one of your existing accounts.
We will be provided with an authorization token please note: Apoptosis extends over several days, and the degree of energy failure and apoptosis is proportional to the severity of adverse neurodevelopmental outcomes seen later at one and four years of age. It is this phase of HIE that hypothermia attempts to ameliorate. Fortunately, there is a brief recovery latency period between the two phases of injury that provides a therapeutic window for treatment.
After reperfusion but before secondary energy failure there is a brief period following resuscitation when brain oxidative metabolism and cellular pH recover before the second phase of injury. Initial studies performed in animal models showed that hypothermia during this period was neuroprotective. It was concluded that cooling should be initiated as early as possible after the initial injury preferably within 2, but no later than 6 hours and should continue for 48 to 72 hours.
The initial hypothermia trials with two separate devices were run concurrently Fig. Thus, inclusion criteria for use of both devices is very similar with the exception of the aEEG requirement. Major clinical trials have examined the outcomes in both selective head cooling and whole body cooling.
A meta-analysis of the three major trials examined the primary outcomes of death in infants and major neurodevelopmental disability after 18 months in infants.
The inclusion criteria for both devices are listed in Table 1. If the child meets the initial criteria items 1, 2, and 3 on Table 1 , the child is placed on an aEEG. Figure 5 shows an example of a moderately abnormal tracing bottom row as compared to the normal tracing on the top row. Our institution continues the aEEG throughout the 72 hour cooling process. Examples of aEEG tracings. Normal top tracing shows normal variability and sleep-wake cycle compared to moderately abnormal tracing on bottom.
Many of these children have systemic collapse associated with their HIE and close monitoring of injury to the heart, lungs, kidneys, and liver is critical. Ongoing laboratory measurements include blood gases, liver function tests, CPK, and electrolytes, as well as close monitoring of input and output.
Good cardiac output and blood pressure are maintained to optimize brain perfusion. Acidosis and electrolyte imbalances are corrected, and normal glucose levels are preserved. Many of these infants require ventilator support as well as pressor support in order to achieve good oxygenation and perfusion. Several of our infants have required advanced respiratory support, including inhaled nitric oxide and extracorporeal membrane oxygenation ECMO for support of their pulmonary and cardiovascular systems.
Nursing care for hypothermia therapy includes close monitoring of neurologic status, and observation for clinical or sub-clinical seizures on aEEG. The nursing staff observes the infants for pain as well as any complications due to skin exposure to the cap or blanket. Close monitoring of vital signs, and assessment of respiratory and cardiac stability is key the care of these infants.
After 72 hours, the infant is warmed slowly. Careful attention is given to the aEEG at this time, because seizures may occur during rewarming. After the course of hypothermia, an MRI is obtained for structural assessment and a traditional EEG is used to examine function.
Caspase 3 activation is essential for neuroprotection in preconditioning. BethAnn McLaughlin, Karen A. Hartnett, Joseph A. Erhardt, Jeffrey J. Legos, Ray F. Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. be reached within about 4 weeks. 8 Typically the increase in. Neuroprotection for the Warrior: Dietary Supplementation. With Omega-3 Fatty Acids. COL Michael.