Experimental neurology
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Experimental neurology · Aug 2009
ReviewMitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury.
There are several forms of acute pediatric brain injury, including neonatal asphyxia, pediatric cardiac arrest with global ischemia, and head trauma, that result in devastating, lifelong neurologic impairment. The only clinical intervention that appears neuroprotective is hypothermia initiated soon after the initial injury. Evidence indicates that oxidative stress, mitochondrial dysfunction, and impaired cerebral energy metabolism contribute to the brain cell death that is responsible for much of the poor neurologic outcome from these events. ⋯ In addition, the relative abundance of pro-apoptotic proteins in immature brains and neurons, and particularly within their mitochondria, predisposes these cells to the intrinsic, mitochondrial pathway of apoptosis, mediated by Bax- or Bak-triggered release of proteins into the cytosol through the mitochondrial outer membrane. Based on these pathways of cell dysfunction and death, several approaches toward neuroprotection are being investigated that show promise toward clinical translation. These strategies include minimizing oxidative stress by avoiding unnecessary hyperoxia, promoting aerobic energy metabolism by repletion of NAD(+) and by providing alternative oxidative fuels, e.g., ketone bodies, directly interfering with apoptotic pathways at the mitochondrial level, and pharmacologic induction of antioxidant and anti-inflammatory gene expression.
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Mitochondrial dysfunction has been identified as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Thus, a broad variety of mutation in mitochondrial DNA or nuclear genes leading to the impairment of mitochondrial respiratory chain or of mitochondrial ATP synthesis has been associated with epileptic phenotypes. ⋯ Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant temporal lobe epilepsy. Therefore, mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.
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Experimental neurology · Aug 2009
ReviewThe role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI.
Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occurs. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determine patient outcome. For mild and moderate TBI, the pathomechanism is similar but much less frequent and ischemic cell death is unusual, except with mass lesions. ⋯ Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of mPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.
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Experimental neurology · Aug 2009
ReviewThe Alzheimer's disease mitochondrial cascade hypothesis: an update.
In 2004 we proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD). Our hypothesis assumed sporadic and autosomal dominant AD are not etiologically homogeneous, considered evidence that AD pathology is not brain-limited, and incorporated aging theory. ⋯ We now review the reasoning used to formulate the hypothesis, discuss pertinent interim data, and update its tenants. Readers are invited to consider the conceptual strengths and weaknesses of this hypothesis.
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Experimental neurology · Jul 2009
Ventricular dilation and elevated aqueductal pulsations in a new experimental model of communicating hydrocephalus.
In communicating hydrocephalus (CH), explanations for the symptoms and clear-cut effective treatments remain elusive. Pulsatile flow through the cerebral aqueduct is often significantly elevated, but a clear link between abnormal pulsations and ventriculomegaly has yet to be identified. We sought to demonstrate measurement of pulsatile aqueductal flow of CSF in the rat, and to characterize the temporal changes in CSF pulsations in a new model of CH. ⋯ These groups were associated with severe and mild ventriculomegaly respectively. Thus, aqueductal flow can be measured in the rat using high-field MRI and basal cistern-induced CH is associated with an immediate change in CSF pulsatility. At the same time, our results highlight the complex nature of aqueductal pulsation and its relationship to ventricular dilation.