Current Drug Targets (v.13, #2)

New Mechanisms of Neuronal Injury and Neuroprotection Neurological diseases, including such devastating illnesses as stroke, Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury and brain tumors, belong to the major diseases that have caused the greatest number of death and disability around the world. A large number of studies have exposed many mechanisms of the illnesses. However, our understanding regarding the diseases is still significantly deficient, and effective therapies are absent for most of the illnesses. For example, over one hundred clinical trials on drug treatment of stroke have failed in the recent years. There may be multiple reasons underlying the numerous failures in developing effective therapies for treating neurological diseases: 1) Our understanding regarding the pathology of neurological diseases is still far from complete; 2) a major portion of our understanding on the mechanisms of neurological diseases has come from the studies using animal models of the diseases; however, there could be significant differences between the pathology of certain neurological diseases and that of the animal models of the diseases; and 3) the blood-brain barriers (BBB) constitute a major barrier for most drugs to enter the brain. Considering that the brain may be one of the most complex systems that have evolved in the universe, it is not unexpected that we have not had sufficient knowledge and capacity to conquer the devastating threats that are produced by neurological diseases. However, we can be reasonably optimistic that the rapid development of science and technology of human being would enable us to eventually conquer the seemingly intractable neurological diseases in the future. To overcome the critical obstacles in our long march toward the cure of neurological illnesses, future studies in the following directions may be of particular significance: 1) To strengthen translational studies on neurological diseases, by increasing the number of clinical trials on the therapeutic effects of new treatment strategies and by increasing studies on the pathological changes of the patients of neurological diseases; 2) to enhance the studies on novel therapeutic strategies, such as stem cell therapy, for treating neurological diseases; 3) to increase the studies on new strategies to enhance the drug delivery across the BBB to enter the brain; and 4) to increase the applications of interdisciplinary approaches, particularly medical imaging techniques and nanotechnology, to improve the diagnosis and monitoring of the illnesses. In order to establish new effective therapeutic strategies for neurological diseases, it is pivotal to further investigate the mechanisms underlying the etiology and pathology of the illnesses. A renowned Chinese expression is: ‘Reviewing what you have learned is essential for you to learn new things’. In this special issue, multiple important topics regarding neurological diseases are reviewed. Several reviews have focused on the promising specific therapeutic targets for neurological diseases: The review of Cairns et al. provides a comprehensive overview of the roles of NADPH oxidase in ischemic brain damage; Chu et al. have reviewed the current advances regarding the mechanisms underlying the roles of acid-sensing ion channels (ASICs) in neurological disorders; Xia et al. provides an overview regarding the roles of opiod receptors as a treatment target for neurological diseases; Shao et al. have reviewed the advances regarding the roles of estrogen and estrogen receptors in neurological diseases; the article of Ma et al. provides an overview of the roles of NAD+ and NAD+-dependent enzymes in neurological diseases as well as the potential of these factors as therapeutic targets; Wang et al. have reviewed the information regarding the roles of chemokine CXCL12 and its receptors in ischemic stroke; and Li et al. provides an overview of the recent progress regarding the participation of synaptic and extrasynaptic NMDA receptors in multiple neurologic diseases. There are also a few reviews regarding the general therapeutic strategies for neurological diseases: The article of Dornbos and Ding provides an overview regarding the mechanisms underlying the neuroprotective effects of exercises; the review of Liu et al. provides an overview of the roles of protein aggregation in neurological diseases; and the review of Zhao provides an overview of the protective mechanisms underlying post-conditioning. I would like to express my sincere gratitude to the authors of the reviews in this special edition for their excellent work. I would also like to thank the Assistant Editor of this issue --- Dr. Weiliang Xia of Med-X Research Institute, Shanghai Jiao Tong University --- for his careful editing work. I would also like to express my gratitude to the editorial assistants of this special issue, Ms. Yingxin Ma and Mr. Heyu Chen, for their valuable editorial support.....

There are two major routes for clearance of aberrant cellular components: (i) the ubiquitin-proteasomal system (UPS); and (ii) the autophagy pathway. The UPS degrades individual abnormal proteins, whereas the autophagy pathway is the chief route for bulk degradation of large abnormal protein aggregates and aberrant organelles. Impairments of the protein degradation pathways are closely tied with many human diseases. Brain ischemia leads to protein misfolding and aggregation, resulting in overproduction of protein aggregate-associated organelles. Brain ischemia also damages protein degradation pathways. This chapter will discuss molecular mechanisms underlying the impairments of the UPS and autophagy pathways and how such impairments lead to multiple organelle failure and delayed neuronal death after brain ischemia.

Chemokine CXC ligand 12 (CXCL12), originally named stromal cell-derived factor-1 (SDF-1), is a member of the CXC chemokine subfamily. CXCL12 is found to be expressed by all cell types that are presented in the central nervous system (CNS). It works in conjunction with the G-protein coupled receptor CXCR4, which is found at the surface of a variety of cells including neurons, astrocytes, microglia, bone marrow-derived cells, as well as other progenitor cells. Recent studies revealed that CXCL12 could also bind and signal through receptor CXCR7. CXCL12 and CXCR4 are constitutively expressed in the brain but are up-regulated in the ischemic penumbra regions following ischemic stroke. CXCL12/CXCR4 play important roles in multiple processes after ischemic stroke, which include inflammatory response, focal angiogenesis, and the recruitment of bone marrow-derived cells (BMCs) and neural progenitor cell (NPC) to injury. In addition to its roles in stroke pathology, CXCL12 is also thought to be a key regulator in stroke repairing. This review will focus on the function of CXCL12/CXCR4 in post-stroke inflammation and neurovascular repairing. The potential application of CXCL12 modulation in clinical stroke treatment is also discussed.

Ischemic postconditioning is a concept originally defined to contrast with that of ischemic preconditioning. While both preconditioning and postconditioning confer a neuroprotective effect on brain ischemia, preconditioning is a sublethal insult performed in advance of brain ischemia, and postconditioning, which conventionally refers to a series of brief occlusions and reperfusions of the blood vessels, is conducted after ischemia/reperfusion. In this article, we first briefly review the history of preconditioning, including the experimentation that initially uncovered its neuroprotective effects and later revealed its underlying mechanisms-of-action. We then discuss how preconditioning research evolved into that of postconditioning - a concept that now represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, remote postconditioning - and its underlying protective mechanisms involving the Akt, MAPK, PKC and KATP channel cell-signaling pathways. Because the concept of postconditioning is so closely associated with that of preconditioning, and both share some common protective mechanisms, we also discuss whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone.

Stroke is the third most common cause of death, particularly of the elderly. Despite considerable advances in knowledge about the mechanisms of cell death after stroke, a treatment for stroke remains exclusive. For a long time, estrogen was thought of only as a “sex hormone”. Studies have documented that estrogen plays an important role in regulating behavioral and physiological events beyond the reproductive system. Most animal studies have shown that estrogens exert neuroprotective and neurogenesis effects in vivo and in vitro after ischemic stroke. However, clinical and epidemiological evidence shows that estrogen increases the risk of coronary heart disease, stroke, and breast cancer. The discrepancy between animal studies and clinical data emphasizes the importance of performing further investigations using appropriate animal models, and gaining a deeper understanding of the mechanisms of estrogen-mediated neuroprotection and neurogenesis. This review focuses on recent advances in estrogen-mediated neuroprotection and neurogenesis after ischemic stroke, highlighting its potential molecular and cellular mechanisms

NADPH oxidase was originally identified in immune cells as playing an important microbicidal role. In neurodegenerative and cerebrovascular diseases, inflammation is increasingly being recognized as contributing negatively to neurological outcome, with NADPH-oxidase as an important source of superoxide. Recently, several forms of this oxidase have been found in a variety of non-immune cells. Neuronal NADPH oxidase is thought to participate in longterm potentiation and intercellular signaling. However, excessive superoxide production is damaging and has been shown to play an important role in the progression of brain injury. NADPH oxidase is a multisubunit complex composed of membrane-associated gp91phox and p22phox subunits and cytosolic subunits, p47phox, p67phox, and p40phox and Rac. When NADPH oxidase is activated through phosphorylatoin of p47phox, cytosolic subunits translocate to the cell membrane and fuse with the catalytic subunit, gp91phox. The activated enzyme complex transports electrons to oxygen, thus producing the superoxide anion (O2

The N-methyl-D-aspartate (NMDA) receptor is a major type of ionotropic glutamate receptor. Many studies have shown that NMDA receptors play a pivotal role in the central nervous system (CNS) under both physiological and pathological conditions. The functional diversity of NMDA receptors can be mainly attributed to their different subunit compositions that perform multiple functions in various situations. Furthermore, recent reports have indicated that synaptic and extrasynaptic NMDA receptors have distinct compositions and couple with different signaling pathways: while synaptic NMDA receptors tend to promote cell survival, extrasynaptic NMDA receptors promote cell death. Currently, intensive efforts are being made to study the pathological role of extrasynaptic NMDA receptors in order to find a more effective approach for the treatment of neurologic disorders. Here we reviewed some recent progress on the participation of synaptic and extrasynaptic NMDA receptors in neurologic diseases including epilepsy, ischemia, schizophrenia, depression and some neurodegenerative diseases.

Numerous studies have indicated that four interacting factors, including oxidative stress, mitochondrial alterations, calcium dyshomeostasis and inflammation, play crucial pathological roles in multiple major neurological diseases, including stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). Increasing evidence has also indicated that NAD+ plays important roles in not only mitochondrial functions and energy metabolism, but also calcium homeostasis and inflammation. The key NAD+-consuming enzyme --- poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins --- have also been shown to play important roles in cell death and aging, which are two key factors in the pathology of multiple major age-dependent neurological diseases: PARP-1 plays critical roles in both inflammation and oxidative stress-induced cell death; and sirtuins also mediate the process of aging, cell death and inflammation. Thus, it is conceivable that increasing evidence has suggested that NAD+ metabolism and NAD+-dependent enzymes are promising targets for treating a number of neurological illnesses. For examples, the key NAD+-dependent enzymes SIRT1 and SIRT2 have been indicated to strongly affect the pathological changes of PD and AD; PARP-1 inhibition can profoundly reduce the brain injury in the animal models of multiple neurological diseases; and administration of either NAD+ or nicotinamide can also decrease ischemic brain damage. Future studies are necessary to further investigate the roles of NAD+ metabolism and NAD+-dependent enzymes in neurological diseases, which may expose novel targets for treating the debilitating illnesses.

The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The upregulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and antioxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.

The effects of exercise pre-conditioning on lessening the impact of ischemia/reperfusion injury provide pivotal information and potential targets for future pharmacological intervention. Exercise induces increased expression of neurotrophic factors, the extracellular matrix (ECM) proteins, integrins, angiogenic factors, as well as tumor necrosis factor (TNF-α) and heat shock proteins (Hsp-70). These factors all directly enhance the neurovascular unit and alleviate the harmful effects following ischemia/reperfusion injury. Furthermore, pre-conditioning decreases expression of matrix metalloproteinase (MMP-9) and Toll-like receptor-4, which ameliorates the inflammatory response and apoptosis following ischemic insult. Perhaps most importantly, exercise pre-conditioning shows a propensity to simultaneously favor cell survival mechanisms and inhibit apoptotic pathways via interactions between TNF-α and Hsp-70, which are regulated by extracellular signal-regulated kinases-1 and -2 (ERK1/2). Finally, chronic exercise preconditioning increases cerebral metabolism, effectively enhancing the neuronal response to increase ATP production following periods of hypoxia. The purpose of this review is to demonstrate the various effects of exercise pre-conditioning on the neural response to ischemia/reperfusion injury as a means of demonstrating potential targets for prevention and treatment of acute ischemic events

Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS.

Nitric oxide/peroxynitrite signaling is associated with manifold neurovascular pathogenic cascades that lead to neurodegenerative diseases, including ischemic stroke, Alzheimer's disease, and vascular dementia. Considerable evidence suggests that reactive nitrogen species as mediators of nitrosative stress could damage biomolecules and subsequently facilitate the breakdown of the highly-structured cellular machinery. Herein, we focus on nitrosative stress signaling, which is intimately associated with endothelial cell injury and blood-brain barrier damage in stroke and neurodegenerative diseases. Unraveling the detrimental role of nitrosative stress signaling in initiating and driving neurovascular pathogenesis may lead to the development of novel vasoprotective strategies via restorative therapies for brain diseases.

Cardiovascular complications are the leading cause of mortality, accounting for 50% of all deaths among patients with end-stage renal disease (ESRD). The majority of these deaths are from cardiac causes. The mechanisms underlying the enhanced susceptibility to myocardial ischaemia and subsequent morbidity in ESRD remain ill-defined. Numerous metabolic derangements accompany myocardial ischaemia and reperfusion and play a pivotal role in the development of concurrent myocardial dysfunction. Carnitine plays a critical role in myocardial energy metabolism, as the transporter of long chain fatty acyl intermediates across the inner mitochondrial membrane for β oxidation and as a central regulator of carbohydrate metabolism. Myocardial carnitine is significantly depleted during ischaemia and more particularly in uraemic patients and those on dialysis therapy. Carnitine treatment has cardiovascular benefits including modulation of myocardial metabolism, reduction in necrotic cell death and infarct size, decrease in the incidence of arrhythmias and preservation of mechanical function. This review details the profile of substrate metabolism in the uraemic heart and the impact of carnitine supplementation on metabolism and function of the reperfused heart and finally the experimental and clinical evidence for carnitine replacement therapy, in particular its impact on the uraemic heart via modulation of function and energetics.