Current Neurovascular Research - Volume 1, Issue 5, 2004

For a body of work to eventually be designated as a “Landmark” article may require years of analysis, further investigative support, and frequent citations in future articles. In this issue of Current Neurovascular Research, we are introducing the publication of pioneering original articles in combination with “state-of the-art” review articles that may someday be considered significant building blocks for future lines of investigation. In several respects, the articles focus upon the ability of ischemic cell injury to not only lead to acute or chronic nervous system impairment in a variety of disorders, but also to actively generate reparative processes that may even result from activities considered as simple as physical exercise. Our original articles in this issue offer a unique perspective upon the central nervous system's ability to respond to hypoxicischemic injury. The initial article by He et al. demonstrates that even during periods of severe ischemia to regions of the brain that are exquisitely sensitive to injury, such as the hippocampus, progenitor stem cells are actively generated that may lead to a viable repair process. Furthermore, the severity of injury may be predicted by the analysis of postural changes that can be associated with the degree of stem cell induction. Work from Ding et al. in our second original article illustrates that in animals subjected to physical exercise prior to a focal ischemic insult, both cerebral infarct volume and neurological disability are significantly reduced. These observations support the premise that pre-ischemic exercise can reduce cellular injury. Further cellular analysis by this group of authors also suggests that the beneficial effects of exercise may be secondary to the induction of new vessel formation through angiogenesis. Our review articles in this issue form a perfect complement to the original manuscripts and begin with an article from Ronen Leker and Ron McKay that discusses the use and therapeutic potential of endogenous neural stem cells for disease entities such as stroke, Alzheimer's disease, and Parkinson's disease. Nakamichi et al. take us next into the cellular world of ischemic injury and consider the potential relationship between central nervous system ferrous ion metabolism and the modulation of the Nmethyl- D-aspartate receptor. The role of cerebral ischemic injury is further examined by Ryszard Pluta with an alternative hypothesis that proposes that repetitive ischemic-reperfusion insults may form the basis for development of chronic neurodegenerative disorders, such as Alzheimer's disease. This process may occur by increasing the sensitivity of neurons to amyloid formation, aberrant amyloid precursor protein processing, and presenilin expression. Lephart et al. follow suit in their article by revealing the unusual role that dietary phytoestrogens, primary components in a variety of soy foods, may play during vascular, neuroendocrine, and cognitive dysfunction. Given that phytoestrogens act as selective estrogen receptor modulators, these authors suggest that dietary phytoestrogens will have a substantial role in the etiology, pathophysiology, and treatment of cardiovascular and neurodegenerative diseases. Our final article in this issue by Sergio Rey and Rodrigo Iturriaga moves us from the cellular mechanisms that may determine vascular integrity to the level of the carotid body as the principal arterial chemoreceptor. They provide us with evidence that endothelins and free radicals, such as nitric oxide, can modulate carotid body chemoreception by modulating vascular tone, cerebral blood flow, and oxygen delivery to chemoreceptor cells to potentially influence a variety of nervous system functions. With the introduction of pioneering original articles to complement our cutting edge review manuscripts that together focus upon the components of activity, anoxia, angiogenesis, and Alzheimer's disease, we are proud to present this issue as our “Landmark” and hope that in the future the very articles that comprise this issue will themselves be considered “Landmark” pieces of work in their own right.

An 8-vessel-occlusion (8VO) method was developed to compare with the conventional 4-vessel-occlusion (4VO) in hippocampal ischemic damage and progenitor cell induction 10 days following ischemia in female rats. Eight posture-relevant tests were performed following ischemia to correlate grades of postural abnormality with the histological outcome. The total hippocampal living cell ratio including 7 hippocampal subregions in 8VO group (n=11) was much lower than that in 4VO group (n=10, 51±5% vs. 78±4, p<0.01). In 4VO group, BrdU positive cells were mainly located in the subgranular zone (SGZ) with a count of 54±20 / mm2 (7μ-thick slice), comparable to the maximal level following global ischemia in male gerbils and rats reported so far referring to slice-thickness differences (50-60μ-thick slices). Similarly, nestin-bearing cells were 29±11 / mm2. In 8VO group, BrdU and nestin positive cells increased by 10 times. Triple staining of BrdU, nestin and DAPI demonstrated that BrdU-immunoreactivity was extensively distributed in the hippocampal hilus while the nestin was mainly located along the SGZ. Most of nestin labeling was not co-localized with the BrdU, indicating that establishment of these cells might precede BrdU injections (8 and 9d post ischemia). Behavioral scores were much greater for 8VO group than for 4VO group and composite postural scores well correlated with the hippocampal cell loss. In conclusion, severe ischemia correlates with vigorous induction of the hippocampal progenitor cells in rats while behavioral profiling of posture changes permits prediction of severity of damage.

The purpose of this study was to determine if exercise could induce expression of vascular endothelial growth factor (VEGF) and angiopoietin 1 and 2, in association with angiogenesis; and if angiogenic changes correlated with reduced brain injury in stroke. Adult male Sprague Dawley rats (3 month old, n=44) were exercised on a treadmill 30 minutes each day for 1, 3 or 6 weeks, or housed as non-exercised controls for 3 weeks. Some 3 week-exercised rats were then housed for an additional 3 weeks. Exercise significantly (p<0.01) increased mRNA (determined by real-time reverse transcriptase-polymerase chain reaction) expression of angiopoietin 1 and 2 as early as 1 week, with further increases occurring at 3 weeks. A mild increase after 1 week and a robust increase after 3 weeks of exercise in four isoforms (120, 144, 164, 188) of VEGF mRNA levels were significantly (p<0.01) observed, with VEGF144 being more markedly upregulated. Overexpression of the mRNAs decreased upon withdrawal of exercise. A significant increase (p<0.01) in the density of microvessels (determined by laminin-immunocytochemistry) was found at 3 weeks of exercise and this continued after exercise was withdrawn. In exercising rats subjected to 2-h MCA occlusion followed by 48-h reperfusion, neurological deficits and infarct volume were significantly reduced. Neuroprotection continued after 3 weeks of rest. This study indicates that pre-ischemic exercise reduces brain injury in stroke. The reduced damage is associated with angiogenesis, possibly induced by angiogenic factors following exercise. Physical exercise up-regulates mRNA levels of the angiopoietin family and VEGF.

The use of cell-based therapy may be a valid therapeutic approach to ischemic brain injury. Stem cells have been proposed as a new form of cell based therapy in a variety of disorders, including acute and degenerative brain diseases. Up to date most efforts have concentrated on transplantation of embryonic stem cells (ESC) or neural stem cells (NSCs) obtained from immortalized cell lines into the diseased brain. These procedures require harvesting the appropriate stem cell, expansion in vitro and transplantation. Endogenous NSCs have been identified in the central nervous system where they reside largely in the subventricular zone and in the subgranular zone of the hippocampus. Endogenous NSCs may be capable of self-renewal and differentiation into functional glia and neurons. Manipulation of endogenous NSCs may bypass the need to use ESC as a form of therapy thus avoiding the complex ethical and biological issues involved with ES cells or immortalized cell lines. This review summarizes the evidence recently gathered in support of a therapeutic role for endogenous NSCs in acute experimental stroke.

Activation of the N-methyl-D-aspartate (NMDA) receptor would induce rapid opening of an ion channel permeable to Ca2+ ions across cell membranes, followed by an increase in the concentration of free Ca2+ ions in the cytoplasm and subsequent signaling cascade from the cytoplasm to the nucleus for consolidation of a transient extracellular signal carried by L-glutamate in the central nervous system. Both neuronal plasticity and cell death have been shown to involve intracellular free Ca2+ ions incorporated through this receptor-operated cation channel in the brain. On the other hand, iron is also abundant in the brain, with an essential role in mechanisms underlying maintenance of cellular integrity and function. Ferrous ions are believed to participate in neuronal cell death through generation of reactive oxygen species in ischemic brain injuries, for instance, while ferrous but not ferric ions are shown to block the influx of Ca2+ ions across NMDA receptor channels in cultured neurons. In this review article, we will summarize the possible relationship between iron and NMDA receptor channels in mechanisms associated with neuronal cell death in brains with ischemia.

Understanding of the molecular basis of dementias such as Alzheimer's disease has not improved greatly in recent years. In this situation the study of neurobiology of Alzheimer's disease, now more than ever, needs an infusion of new concept. Recent evidence suggests that the neuropathological picture of Alzheimer's disease comprises more than amyloid accumulation, neurofibrillary tangles and finally brain atrophy. At least one third of Alzheimer type of dementia cases exhibit different cerebrovascular diseases. In addition, micro- and macroinfarctions and ischemic white matter changes are also evident in brains of Alzheimer's disease patients. The presence of vascular abnormalities seems usually ignored and regarded by researchers as insignificant or considered incidental in Alzheimer's disease etiology. The “ischemia-reperfusion hypothesis” was primarily aimed at stimulating research and redirecting the focus of studies towards ischemic cellular mechanisms of Alzheimer's disease. Considerable progress has been made in recent years in understanding the role of ischemia in the aging process and in contributing to the development of Alzheimer's disease. To accommodate the recent ischemic progress of study in Alzheimer's disease there is a need to synthesize all the divergent pieces of data into a coherent story. In this review, current knowledge on the relation between cerebrovascular disease factors and Alzheimer's type dementia will be reviewed. We will summarize the results with a special focus on Alzheimer lesions in experimental brain ischemia.

The early discontinuation of the Women's Health Initiative trial evaluating the effects of estrogen plus progestin due to concerns about the risk-benefit ratio of this steroid combination therapy emphasizes the need to examine alternative methods of estrogen replacement. One such alternative is isoflavone consumption of soy-derived dietary phytoestrogens that have received prevalent usage due to their ability to decrease age related disease (cardiovascular and osteoporosis), hormone-dependent cancers (breast and prostate), and peri- and postmenopausal symptoms. Differences in dietary phytoestrogen consumption result in large variations in somatic phytoestrogen content. These molecules affect estrogen and estrogen receptor function in several ways, including having both agonist and antagonist effects on estrogen receptors, as well as functioning like natural selective estrogen receptor modulators. Similar to estrogens, dietary phytoestrogens appear to affect certain aspects of vascular, neuroendocrine, and cognitive function. This article reviews health effects of estrogen, isoflavones and their hormonal mechanism of action, brain penetration by isoflavones, heath effects of isoflavones, and effects of isoflavones on vascular, neuroendocrine, and cognitive function. Because of their diverse health effects and widespread availability in soy foods, dietary phytoestrogens merit continued research into their effects on human health and cognitive function.

The carotid body (CB) is the main arterial chemoreceptor that senses arterial PO2, PCO2 and pH. The structural unit of the CB is the glomoid, which is formed by clusters of chemoreceptor (glomus) cells located around the capillaries. The glomus cells are synaptically connected to nerve terminals of petrosal ganglion (PG) neurons and surrounded by sustentacular cells. The most accepted model of CB chemoreception states that glomus cells are the primary sensors. In response to hypoxia, hypercapnia and acidosis, glomus cells release one or more transmitters, which acting on the nerve terminals of sensory PG neurons, increase the chemosensory discharge. The CB has a high blood flow and an elevated metabolism that correlate to its oxygen-sensing function. Thus, vasoactive molecules produced within the CB may modulate the chemosensory process by controlling the CB blood flow and tissue PO2. In this review, we examine recent evidence supporting the idea that endothelins (ETs) and nitric oxide (NO) modulate the CB function acting upon chemoreceptor cells and chemosensory neurons or by regulating the blood flow through the CB parenchyma.