Current Neurovascular Research - Volume 2, Issue 4, 2005

Understanding the role of nicotinamide (NIC) in different cell systems represents a significant challenge in several respects. Recently, NIC has been reported to have diverse roles during cell biology. In the absence of NIC, sirtuin protein activity is enhanced and pyrazinamidase/nicotinamidase 1 (PNC1) expression, an enzyme that deaminates NIC to convert NIC into nicotinic acid, is increased to lead to lifespan extension during calorie restriction, at least in yeast. Yet, NIC may be critical for cell survival as well as the modulation of inflammatory injury during both experimental models as well as in clinical studies. We therefore investigated some of the underlying signal transduction pathways that could be critical for the determination of the neuroprotective properties of NIC. We examined neuronal injury by trypan blue exclusion, DNA fragmentation, phosphatidylserine (PS) exposure, Akt1 phosphorylation, Bad phosphorylation, mitochondrial membrane potential, caspase activity, cleavage of poly(ADP-ribose) polymerase (PARP), and mitogen-activated protein kinases (MAPKs) phosphorylation. Application of NIC (12.5 mM) significantly increased neuronal survival from 38 ± 3% of anoxia treated alone to 68 ± 3%, decreased DNA fragmentation and membrane PS exposure from 67 ± 4% and 61 ± 5% of anoxia treated alone to 30 ± 4% and 26 ± 4% respectively. We further demonstrate that NIC functions through Akt1 activation, Bad phosphorylation, and the downstream modulation of mitochrondrial membrane potential, cytochrome c release, caspase 1, 3, and 8 - like activities, and PARP integrity to prevent genomic DNA degradation and PS externalization during anoxia. Yet, NIC does not alter the activity of either the MAPKs p38 or JNK, suggesting that protection by NIC during anoxia is independent of the p38 and JNK pathways. Additional investigations targeted to elucidate the cellular pathways responsible for the ability of NIC to modulate both lifespan extension and cytoprotection may offer critical insight for the development of new therapies for nervous system disorders.

Evidence for a protective role of estradiol in neurodegenerative diseases has steadily increased over the past decade, though the mechanisms of action and the participation of true estrogen receptors (ERs) have proven a complex score. The protective effects of estrogens take place partly through pathways involving canonical ER activation, which is constitutively expressed in many brain regions and is able to initiate gene transcription after specifically binding to estradiol. In addition, non-genomic (or alternative) signalling pathways, involving extranuclear ERs, respond to physiological concentration of estrogens to elicit neuroprotection. Often, rapid activation of intracellular signallers such as mitogenactivated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) underlie alternative estrogen-induced neuroprotection upon activation of specific binding sites at the plasma membrane. Although the molecular characteristics of these unconventional ERs are still largely unknown, the generally held view maintains that plasma membrane ER (mER) originates from, or is related to, classical nuclear ERs. The present article will review some of the most recent evidence revealing the relevance of alternative mechanisms in estrogen-dependent neuroprotection. Special emphasis will be paid to cellular models of amyloid-β toxicity where classical and alternative pathways activated by estrogens seem to coexist to orchestrate neuroprotection.

The sympathetic nervous system (SNS) is the first line of defense in the response to environmental stress through its regulation of second-to-second changes in blood pressure (BP). Both the activity of the SNS and the therapeutic responses to SNS agonists and antagonists are known to be highly variable in the population. "Small" changes caused by single nucleotide polymorphisms (SNPs) of SNS genes may have considerable impact on SNS function and individualized hypertension treatment. In this review, we first describe the physiology of the SNS and its influence on cardiovascular and renal mechanisms of BP regulation. A thorough review of the role of genetic variability of various SNS genes in relation to the development of BP and essential hypertension (EH) follows. Given the vast number of SNS components, evaluations of multiple SNPs from multiple SNS genes are necessary for future association studies of BP and EH. One way to surpass the limitations and inconsistencies of previous association studies is to use a gene-based approach also referred to as indirect association, which takes all common variation within a candidate gene into account. In order to determine how SNS genes are differentially expressed or silenced, activated or inactivated against various environmental backgrounds, it is important to assess not only environmental and lifestyle risk factors such as diet, climate, chronic stress, but also personality characteristics such as hostility and coping styles. Uncovering relevant gene-gene and geneenvironment interactions within the SNS cascade will not only enable early detection of EH risk but will also aid in the treatment of hypertensives through both non-pharmacological and pharmacological means.

This review extrapolates the functions of SDF-1α and its receptor, CXCR4, as regulators of hematopoietic stem cells and discusses their potential roles in the development and regeneration of tissues. The discussion focuses on the repair of neural tissues while parallels are made with bone marrow hematopoietic stem cells. Overall, the organization links the basic biology of SDF-1α and CXCR4 to topics in medicine and show how any disease processes involving the SDF- 1α-CXCR4 system could be central points in medicine. Discussions focused on potential therapies for SDF-1 and CXCR4 in clinical disorders. Breast and prostate cancers are selected as examples of solid tumors while leukemia is discussed as an example of hematological malignancies. Diffuse macular edema is discussed as potential therapy for a non-malignant disease.

Wnt proteins are cysteine-rich glycosylated proteins named after the Drosophilia Wingless (Wg) and the mouse Int-1 genes that play a role in embryonic cell patterning, proliferation, differentiation, orientation, adhesion, survival, and programmed cell death (PCD). Wnt proteins involve at least two intracellular signaling pathways. One pathway controls target gene transcription through β-catenin, generally referred to as the canonical pathway and a second pathway pertains to intracellular calcium (Ca2+) release which is termed the non-canonical or Wnt/ Ca2+ pathway. The majority of Wnt proteins activate gene transcription through the canonical signaling pathway regulated by pathways that include the Frizzled transmembrane receptor and the co-receptor LRP-5/6, Dishevelled, glycogen synthase kinase-3β (GSK-3β), adenomatous polyposis coli (APC), and β-catenin. In contrast, the noncanonical Wnt signaling pathway has two intracellular signaling cascades that consist of the Wnt/ Ca2+ pathway with protein kinase C (PKC) and the Wnt/PCP pathway involving Rho/Rac small GTPase and Jun N-terminal kinase (JNK). Through a series of signaling pathways, Wnt proteins modulate cell development, proliferation, and cell fate. In regards to cell survival and fate through PCD, Wnt may be critical for the prevention of tissue pathology that involves cytokine and growth factor control during disorders such as neuropsychiatric disease, retinal disease, and Alzheimer's disease. Elucidation of the vital elements that shape and control the Wnt-Frizzled signaling pathway may provide significant prospects for the treatment of disorders of the nervous system.

Alzheimer's disease is a progressive brain disorder that gradually destroys a patient's memory function and ability to carry out daily activities. According to the prevailing amyloid cascade hypothesis, Alzheimer's disease is initiated by amyloid ß-peptide accumulation leading to neuronal toxicity. The neurofibrillary tangle deriving from hyperphosphorylated tau and synapse loss are also key features for Alzheimer's disease. Recent studies revealed a significant comorbidity of Alzheimer's disease and cerebrovascular disease suggesting that cerebrovascular dysregulation is an important feature of Alzheimer's disease. This mini-review will discuss the hypothesis that a dysfunction of the vascular system may result in damage of the neurovascular unit, initiating a cascade of events. An overlap with other forms of cognitive impairment, such as mild cognitive impairment, or vascular dementia will be discussed.

Multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE) are debilitating paralytic diseases caused by inflammation, demyelination and axonal degeneration of the central nervous system (CNS). Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. As opposed to the majority of MS patients, which exhibit a relapsing-remitting course of the disease, only a handful of available EAE models displays relapsingremitting course. In this review, we will summarize differences in regulation of acute and relapsing disease with emphasis on relapsing-remitting EAE models, and outline advantages and limitations of available relapsing EAE models pertinent for studies of relapsing human disease. We will discuss current concepts of relapse regulation by focusing on immune and molecular mechanisms of neuroinflammation, oligodendrocyte damage, myelin loss and axonal degeneration. This review will compare our present understanding of relapse regulation in human versus experimental autoimmune disease. Translation of mechanisms learned from relapsing EAE into development of new therapies for MS will be evaluated. Finally, perspectives in further optimization and development of more suitable experimental models to study human relapsingremitting MS will be discussed.