Current Neurovascular Research - Volume 4, Issue 3, 2007

“These chemical messengers, however, or hormones (from [the Greek word] I excite or arouse), as we might call them, have to be carried from the organ where they are produced to the organ which they affect by means of the blood stream and the continually recurring physiological needs of the organism must determine their repeated production and circulation throughout the body.” As part of his second Croonian lecture to the Royal College of Surgeons in 1905 entitled “The chemical control of the functions of the body”, Ernest Starling surprisingly introduces the term “hormones” to describe chemicals that can be set into action in the blood stream to elicit activity in different organs of the body. The selection of the term “hormone” by Starling is not entirely clear, but may have developed in conversations with William Hardy and the Greek poet scholar W. T. Vesey to use the Greek verb “ormao” for “arouse” or “excite”. Yet, despite the absence, or at least the minimal use of the term “hormone” in the scientific arena prior to this point, early work during the mid-nineteenth century, such as by Claude Bernard, depicted processes responsible for internal secretion of chemicals as described with the release of glucose from glycogen in the liver. During this period, other pioneers such as Arnold Adolphe Berthold spoke of the interaction and communication between the different organs in the body. As these concepts became more accepted, physicians later in the nineteenth century reported the use of extracts of animal thyroid, pancreas, and even adrenal glands to treat patients suspected of suffering from the loss of circulating chemicals. By the early twentieth century, Starling and William Bayliss demonstrated that the duodenum, when stimulated with acid through local application, could lead to pancreatic secretion. They furthered these results by illustrating that duodenal extracts injected into the blood stream in animals also resulted in pancreatic secretion. From these studies, Starling and Bayliss suggested that the agent released from the duodenum should be termed “secretin”. The Nobel Laureate Pavlov was initially impressed with these results that had suggested the presence of several mechanisms in the control of the digestive system, but later stood firm to promote his personal concepts that pancreatic secretion and the organs of the gut were controlled principally by innervation of the nervous system during his acceptance of the Nobel Peace Prize for his work in 1904. Politics aside, investigations since the work of early pioneers in endocrinology and the study of hormones have fostered the development of numerous fields that involve vascular biology, neuroscience, physiology, genetics, metabolomics, development, cancer, and molecular medicine. Clinically, the advances from these fields that rely upon the understanding of the chemistry of hormones have resulted in remarkable strides for treatment protocols that involve the care and management of diabetes, the replenishment of hormone deficiencies with recombinant proteins that eliminate potential toxicity from the use of animal or human sources, and the success of fertility treatments that utilize in vitro fertilization. Furthermore, our progressive knowledge of the cellular and molecular processes that involve hormones have alerted us to the intimate relationship we hold with the environment and its accumulation of synthetic chemicals that can ultimately be detrimental to the endocrine system of both animals and humans. This issue of Current Neurovascular Research highlights the complexity of hormones and the cellular pathways they govern that ultimately regulate clinical health and disease. Ahmadi et al. provides exciting evidence that administration of a bone marrow cell population containing multipotent stem cells is not only non-toxic in patients who have suffered myocardial infarction, but also may result in clinical cardiac improvement with potential myogenesis and angiogenesis. However, hormonal systems may not always be beneficial during illness as illustrated by Makikallio et al. In their paper, they examined the hypothalamus-pituitary-adrenal axis in patients suffering from ischemic stroke over time and report that elevated cortisol and natriuretic peptide levels may be detrimental to the eventual recovery from stroke, suggesting that targeting this hormone system may offer treatment for acute cerebral ischemia.....

The CD133+ bone marrow cell (BMC) population includes primitive multipotent stem cells which induce neoangiogenesis. Studies suggested transplantation of these cells to infarcted myocardium can have a favorable impact on tissue perfusion and contractile performance. We assessed the feasibility, safety and functional outcomes of autologus CD133+ BMC transplantation during coronary artery bypass grafting (CABG) in patients with recent myocardial infarction. In a prospective, nonrandomized, open-label study, 27 patients with recent myocardial infarction underwent CABG and intramyocardial injection of autologous bone marrow-derived CD133+ cells (18 patients, BMC group) or CABG alone (9 patients, control group). At 6 months after CABG, the Wall Motion Score Index (WMSI) was significantly reduced for akinetic/dyskinetic segments treated with CD133+ cells compared with the control group (P<0.006). Likewise, comparison between baseline and follow up results of dobutamine stress echocardiography and myocardial perfusion scintigraphy showed improvement of myocardial viability and local perfusion of the infarcted zone of the BMC group compared with the control group. No complications related to CD133+ cell transplantation were noted, either procedurally or during postoperative at a mean of 14 months follow up. In patients with recent myocardial infarction, transplantation of CD133+ cells to the peri-infarct zone during CABG surgery is feasible and safe, with no evidence of early or late adverse events. Moreover, these cells might restore tissue viability and improve perfusion of the infarcted myocardium, suggesting that they may induce myogenesis as well as angiogenesis.

We sought to evaluate the influence of specific vasoactive gene knockouts on the process of intracranial aneurysm formation in mice. Thirty wild type, 7 nitric oxide synthase (NOS)-2 knockout, 6 NOS-3 knockout, and 8 plasminogen activator inhibitor (PAI)-1 knockout female mice underwent left common carotid artery ligation at 2 to 6 months of age. After a survival period (average 20.4 months ± 1.5 months), the brains were perfusion fixed with 10% buffered formalin for 10 minutes and then perfused with India ink. Brain and intact cerebral circulation were surgically removed and further fixed in 10% buffered formalin for 4 additional days. The basal cerebral circulation of each brain was examined for the presence of intracranial aneurysms under a surgical microscope (3x-21x). Suspected aneurysms were further dissected for histological analysis. Specimens were embedded in epoxy resin, cut into 0.5 and 1.0 micron sections, and stained with Toluidine blue. A neuropathologist blinded to genotype and surgical microscopy results examined the slides for evidence of aneurysmal pathology. Two intracranial aneurysms in 2 NOS-3 knockout mice were confirmed by histology. No intracranial aneurysms were confirmed in any wild type, NOS-2 knockout, or PAI-1 knockout mice. Histological analysis of aneurysms revealed loss of elastica, subendothelial collagen deposition, and perivascular lymphocytic infiltration. Our results suggest that NOS-3 knockout, but not PAI-1 or NOS-2 knockout, predisposes to the formation of intracranial aneurysms in mice subjected to unilateral carotid artery ligation. Due to small sample sizes however, selection bias cannot be excluded and further investigation is necessary to confirm our results.

A stress response consisting of elevated levels of cortisol and catecholamines is common after acute stroke. The plasma levels of natriuretic peptides are known to be elevated after ischemic stroke, but the relations of these neurohormonal systems in the acute phase of stroke and their impact on long-term prognosis have not been studied previously. A series of 51 consecutive patients (mean age 68±11years) with an ischemic first-ever stroke underwent a comprehensive clinical investigation, scoring of their neurologic deficit by Scandinavian Stroke Scale (SSS), Barthel Index (BI) and Modified Ranking Scale (MRS) as well as measurements of plasma cortisol, norepinephrine, epinephrine, ACTH and atrial (N-ANP) and brain (N-BNP) natriuretic peptides on the 2nd and 7th days after ischemic stroke. The patients were followed up for 44±21 months. Higher levels of cortisol, ACTH and natriuretic peptides were observed in the stroke patients who died (n=22) during the follow-up than in the stroke survivors. Cortisol levels associated significantly with the 2nd and 7th day N-ANP and N-BNP levels, catecholamine levels (r= 0.55- 0.94, p<0.01 for all) and measures of neurologic deficit (r= 0.36 - -0.44, p<0.05). High acute phase cortisol levels assessed either in the morning (RR=5.4, p<0.05) or in the evening (RR=5.8, p<0.05) predicted long-term mortality after stroke in multivariate analysis. Activation of the hypothalamus-pituitary-adrenal axis in ischemic stroke is associated with elevated levels of natriuretic peptides. High cortisol and natriuretic peptide values predict long-term mortality after ischemic stroke, suggesting that this profound neurohumoral disturbance is prognostically unfavourable.

The present study was designed to investigate whether the neuroprotective effect of nimesulide was mediated by inhibiting expression of matrix metalloproteinase-9 (MMP-9) and/or matrix metalloproteinase-2 (MMP-2) in a rat model of thrombolytic reperfusion after the embolic focal cerebral ischemia (FCI). It was found that nimesulide at therapeutically relevant doses (3, 6 and 12 mg/kg) decreased neurological deficits, infarct volume, brain index and brain water content in a dose-dependent manner. Hemorrhagic transformation was reduced by 64% with treatment of 12 mg/kg nimesulide. Quantitative analysis of immunohistochemical staining of brain slices showed that the neuron number expressing MMP-9 and MMP-2 increased in the model animals treated with vehicle (p<0.01 vs sham group), and significantly decreased in nimesulide-treated animals (p<0.05 or p<0.01 vs vehicle group). Our results demonstrate that nimesulide significantly reduces the degree of neuronal injury and hemorrhage transformation caused by thrombolytic reperfusion after the embolic FCI, and that inhibition of MMP-9 and MMP-2 expression contributes at least in part to the neuroprotection.

Thyroid hormones (THs), including triiodothyronine (T3) and tetraiodothyronine (T4), are recognized as key metabolic hormones of the body. THs are essential for normal maturation and function of the mammalian central nervous system (CNS) and its deficiency, during a critical period of development, profoundly affects cognitive function. Sodiumpotassium adenosine 5'-triphosphatase (Na+, K+-ATPase) is a crucial enzyme responsible for the active transport of sodium and potassium ions in the CNS necessary to maintain the ionic gradient for neuronal excitability. Studies suggest that Na+, K+-ATPase might play a role on memory formation. Moreover, THs were proposed to stimulate Na+, K+-ATPase activity in the heart of some species. In this work we investigated the effect of a chronic administration of L-thyroxine (LT4) or propylthiouracil (PTU), an antithyroid drug, on some behavioral paradigms: inhibitory avoidance task, open field task, plus maze and Y-maze, and on the activity of Na+, K+-ATPase in the rat parietal cortex and hippocampus. By using treatments which have shown to induce alterations in THs levels similar to those found in hyperthyroid and hypothyroid patients, we aimed to understand the effect of an altered hyperthyroid and hypothyroid state on learning and memory and on the activity of Na+, K+-ATPase. Our results showed that a hyper and hypothyroid state can alter animal behavior and they also might indicate an effect of THs on learning and memory.

Impacting a significant portion of the world's population with increasing incidence in minorities, the young, and the physically active, diabetes mellitus (DM) and its complications affect approximately 20 million individuals in the United States and over 100 million individuals worldwide. In particular, vascular disease from DM may lead to some of the most serious complications that can extend into both the cardiac and nervous systems. Unique strategies that can prevent endothelial cell (EC) demise and elucidate novel cellular mechanisms for vascular cytoprotection become vital for the prevention and treatment of vascular DM complications. Here, we demonstrate that erythropoietin (EPO), an agent that has recently been shown to extend cell viability in a number of systems extending beyond hematopoietic cells, prevents EC injury and apoptotic nuclear DNA degradation during elevated glucose exposure. More importantly, EPO employs Wnt1, a cysteine-rich glycosylated protein involved in gene expression, cell differentiation, and cell apoptosis, to confer EC cytoprotection and maintains the integrity of Wnt1 expression during elevated glucose exposure. In addition, application of anti-Wnt1 neutralizing antibody abrogates the protective capacity of both EPO and Wnt1, illustrating that Wnt1 is an important component in the cytoprotection of ECs during elevated glucose exposure. Intimately linked to this cytoprotection is the downstream Wnt1 pathway of glycogen synthase kinase (GSK-3β) that requires phosphorylation of GSK-3β and inhibition of its activity by EPO. Interestingly, inhibition of GSK-3β activity during elevated glucose leads to enhanced EC survival, but does not synergistically improve protection by EPO or Wnt1, suggesting that EPO and Wnt1 are closely tied to the blockade of GSK-3β activity. Our work exemplifies an exciting potential application for EPO in regards to the treatment of DM vascular disease complications and highlights a previously unrecognized role for Wnt1 and the modulation of the downstream pathway of GSK-3β to promote vascular cell viability during DM.

Na+/H+ exchangers (NHEs) conduct the electroneutral exchange of proton (H+) and sodium (Na+) ions across cellular membranes down their concentration gradients. To date, nine NHE family members have been cloned from mammals and share a common secondary structure. The ubiquitous exclusive plasma membrane NHE isoform 1 (NHE1) is a major membrane transport mechanism in regulation of intracellular pH (pHi) and volume. In addition to its role in regulation of ionic homeostasis, NHE1 can directly interact with other regulatory cellular signaling pathways, including modulation of the activity of mitogen-activated protein kinases (MAPKs) and Akt/protein kinase B (PKB). Thus, NHE1 is a multifaceted regulator of cell migration, proliferation, and cell death. NHE1 also plays pivotal roles under a number of pathophysiological conditions such as osmotic stress, acidosis, and mechanical stress. NHE1 is the most abundant NHE isoform in the rat central nervous system (CNS). This review discusses distribution and regulation of NHE1, and its physiological roles in the CNS. Moreover, it includes an extensive presentation of studies on activation of NHE1 under ischemic conditions in the CNS and its impact on Na+ and Ca2+ ionic homeostasis as well as on cell survival and damage.

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only recently coming to light. Potential mechanisms include changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Behaviorally, aged rats are more severely impaired by stroke than are young rats, and they also show diminished functional recovery. Infarct volume does not differ significantly in young and aged animals, but critical differences are apparent in the cytological response to stroke, most notably an age-related acceleration of the establishment of the glial scar. The early infarct in older rats is associated with a premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration, and accelerated apoptosis. Regeneration-associated mechanisms in the rat brain are active thoughout life, albeit at lower levels in the aged animals. However; after stroke in aged rats, neuroepithelial marker-positive cells emanating largely from capillaries did not make a significant contribution to neurogenesis in the infarcted cortex of aged animals. Furthermore, the expression of plasticity-associated proteins, such as MAP1B, was delayed in aged rats. Tissue recovery was further delayed by the upregulation of Nogo, ephrin-A5 and MAG, which exert a powerful negative effect on axonal sprouting in the aged peri-infarct cortex, and by an age-related increase in the amount of the neurotoxic C-terminal fragment of the β-amyloid precursor protein (βAPP) at 2 wks post-stroke. Our findings indicate that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis of this phenomenon in the aging brain could yield novel approaches to neurorestoration following stroke or head injury in the elderly.