Aspects Of Neuroprotection Research Articles

Announcement of the 2006 Special Issue: Behavioural Aspects of Neurodegeneration and Neuroprotection

Announcement of the 2006 Special Issue: Behavioural Aspects of Neurodegeneration and Neuroprotection

Region-specific phosphorylation of ERK5–MEF2C in the rat frontal cortex and hippocampus after electroconvulsive shock

ERK5–MEF2C has been implicated in many aspects of neuronal survival and neuroprotection. Neurotrophic effects have been considered as one of the mechanisms in therapeutic electroconvulsive shock (ECS). To investigate whether ECS activates ERK5–MEF2C, we examined the phosphorylation of ERK5, along with its downstream molecule MEF2C, after ECS in the rat frontal cortex and hippocampus. Increased phosphorylation of ERK5 was observed immediately after ECS, but was barely detectable from 2 min after ECS in both the frontal cortex and the hippocampus. The level of MEF2C phosphorylation was decreased immediately after ECS in both regions. It was increased from 2 min and maintained until 10 min after ECS in the frontal cortex, but it returned to the basal level from 2 min after ECS in the hippocampus. Taken together, these results suggest that ECS can regulate the region-specific activity of ERK5–MEF2C pathways in the rat brain.

S013 Clinical aspects of neuroprotection

S013 Clinical aspects of neuroprotection

Vascular aspects of neuroprotection

It is being increasingly suggested that the microcirculation, which is known to be in a large part responsible for maintaining an adequate and constant microenvironment for function of the central nervous system, functions as part of a neurovascular unit. The neurovascular unit includes neurons, astrocytes and elements of capillaries. The cerebral circulation exhibits unique functional characteristics and critical elements for the pathogenesis of cerebrovascular disease. For example, the blood–brain barrier formed by epithelial-like high resistance tight junctions within the endothelium is a key feature of microvessels of the central nervous system. Alterations in the microcirculation after ischemia/reperfusion include disruption of the blood–brain barrier, edema and swelling of perivascular astrocyte foot processes, decrease in arteriole endothelium-dependent relaxation and reduced inwardly-rectifying potassium channel function, altered expression of proteases and matrix metalloproteinases, increased inflammatory mediators and inflammation. Experiments studying the microcirculation in ischemia are few compared with those examining neuroprotection, although the two overlap because protection of the microcirculation might achieve some degree of neuroprotection and both processes may be mediated by at least some mechanisms in common.

Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, May 5-10, 2002.

Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, May 5-10, 2002.

Functional aspects of estrogen neuroprotection.

Evidence that estrogen protects neurons against toxic/ ischemic insults or degenerative/aging processes is evident in a variety of in vitro and in vivo systems. However, a critical remaining question is: Does the demonstrated morphologic and neurochemical protection by estrogen lead to a preservation of brain function or an enhanced ability to recover? To date, little basic research is available on this issue. Cognition is a critical function that might provide a sensitive way to examine this question. As a first step, we present results showing that two chronic environmental insults, psychoactive drugs and stress, produce gender-specific responses in cognitive abilities. Specifically, females appear less sensitive than males to cognitive impairments following chronic exposure to these factors. Results are presented in male and female rats utilizing cognitive tests that assess visual (object recognition) and spatial memory (object placement and radial arm maze) following chronic amphetamine, methamphetamine, or daily restraint stress. Following regimes of chronic stress or amphetamine, males were impaired on these tasks while females were either unaffected, less affected, or enhanced in performance. These observations suggest that differences in circulating gonadal hormone levels between the sexes may contribute to the differential sensitivity of the sexes and provide endogenous neuroprotection for females. Surprisingly, ovariectomized females were still not impaired following a stress regimen that impaired males (21 d of daily restraint). These data taken together with neurochemical data on estrogen neuroprotective effects indicate that it is possible that neuroprotection by estrogen may result from hormone action both during sexual differentiation (organizational effect) and in adulthood (activational effect). These considerations and possible unwanted/untoward effects of chronic estrogen use are discussed in relation to the use of selective estrogen receptor modulators for chronic treatment of both males and females. In conclusion, although compelling evidence for neuroprotection by estrogen has been presented in anatomic and neurochemical studies, it is clear that the functional/ behavioral aspects need further investigation.

Hibernation, a Model of Neuroprotection

Hibernation, a natural model of tolerance to cerebral ischemia, represents a state of pronounced fluctuation in cerebral blood flow where no brain damage occurs. Numerous neuroprotective aspects may contribute in concert to such tolerance. The purpose of this study was to determine whether hibernating brain tissue is tolerant to penetrating brain injury modeled by insertion of microdialysis probes. Guide cannulae were surgically implanted in striatum of Arctic ground squirrels before any of the animals began to hibernate. Microdialysis probes were then inserted in some animals after they entered hibernation and in others while they remained euthermic. The brain tissue from hibernating and euthermic animals was examined 3 days after implantation of microdialysis probes. Tissue response, indicated by examination of hematoxylin and eosin-stained tissue sections and immunocytochemical identification of activated microglia, astrocytes, and hemeoxygenase-1 immunoreactivity, was dramatically attenuated around probe tracks in hibernating animals compared to euthermic controls. No difference in tissue response around guide cannulae was observed between groups. Further study of the mechanisms underlying neuroprotective aspects of hibernation may lead to novel therapeutic strategies for stroke and traumatic brain injury.

Neuroprotection, excitotoxicity and NMDA antagonists.

To analyze the main aspects of neuroprotection and excitotoxicity. This is a significant theory on the pathophysiology of cerebral ischemia; it is based on the release of excitatory aminoacid (EAA), mainly glutamate. The sequence starts with a decrease of the blood flow and ends in neuronal death. The main stages of this reaction are herein presented and discussed. An in depth study of the effects of the excessive intracellular calcium is undertaken. Neuroprotectors (NP) are a group of drugs that reduce the excitotoxicity, opposing the excessive release of EAA and its intracellular effects. Neuroprotectors represent a rational approach to stroke treatment and offer a number of potential advantages. They prevent or limit ischemia-induced damage. There are many experimental and clinical NP trials. A minimum of 800 trials are currently under study worldwide. The most important NP subgroups are: N-methyl D-aspartate (NMDA) antagonists, gamma-amino butyric acid (GABA) agonists, amino-hydroxy-methyl-isoxalone propionic acid (AMPA) antagonists, reducers of intracellular Ca++ inhibitors of nitric oxide modulation pathway free radicals scavengers, sodium channel antagonists, glutamate release inhibitor, growth factors, hypothermia and potassium channel activators.

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Theoretical Aspects of Neuroprotection in Acute Ischaemic Stroke. I: Basic Mechanisms

Theoretical Aspects of Neuroprotection in Acute Ischaemic Stroke. I: Basic Mechanisms