Current Medicinal Chemistry (v.22, #10)

Meet the Editorial Board: by Alessandro Serretti (1169-1169).

Ion Transporters in Brain Tumors by Damin Cong, Wen Zhu, John S. Kuo, Shaoshan Hu, Dandan Sun (1171-1181).
Ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions. They have recently emerged as important players in cancer progression. In this review, we discussed two important ion transporter proteins, sodiumpotassium- chloride cotransporter isoform 1 (NKCC-1) and sodium-hydrogen exchanger isoform 1 (NHE-1) in Glioblastoma multiforme (GBM) and other malignant tumors. NKCC-1 is a Na+- dependent Cl- transporter that mediates the movement of Na+, K+, and Cl- ions across the plasma membrane and maintains cell volume and intracellular K+ and Cl- homeostasis. NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pHi) and extracellular pH (pHe) homeostasis and cell volume. Here, we summarized recent pre-clinical experimental studies on NKCC-1 and NHE-1 in GBM and other malignant tumors, such as breast cancer, hepatocellular carcinoma, and lung cancer cells. These studies illustrated that pharmacological inhibition or down-regulation of these ion transporter proteins reduces proliferation, increases apoptosis, and suppresses migration and invasion of cancer cells. These new findings reveal the potentials of these ion transporters as new targets for cancer diagnosis and/or treatment.

Progressive Supranuclear Palsy: What Do We Know About it? by Ling Long, Xiao-Dong Cai, Xiao-Bo Wei, Jin-Chi Liao, Yun-Qi Xu, Hui-Min Gao, Xiao-Hong Chen, Qing Wang (1182-1193).
Progressive supranuclear palsy (PSP) is a progressive tauopathy characterized by supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, axial rigidity, frontal lobe dysfunction, and dementia. The typical pathology includes neuronal loss, gliosis and microtubule-associated protein tau (MAPT)-positive inclusions in neurons and glial cells, primarily in basal ganglia, brainstem and cerebellum. The pathogenesis of PSP is not yet completely understood; however, there are several hypotheses. This article reviews the present knowledge about PSP, and the concepts underlying mitochondrial dysfunction, lipoperoxidation, and gene mutations. The clinical features of PSP are also discussed; these include vertical gaze palsy, pseudobulbar palsy, aphasia, dysarthria, axial rigidity, and neuropsychiatric symptoms, such as amnesia, irritability, loss of interest, and dementia. In terms of diagnosis, there is considerable interest in neuroimaging for detecting PSP; therefore, neuroimaging techniques such as magnetic resonance imaging (MRI) and [18F]- fluorodeoxyglucose positron-emission tomography (FDG-PET) are reviewed. A definitive diagnosis of PSP depends on pathology, and the introduction of new clinical subtypes challenges presents the widely adopted diagnosis criteria. PSP treatments such as serotonin antagonists, ?2 receptor antagonists, and coenzyme Q10 are also discussed. There is no curative therapy for PSP; all of the available treatments are palliative.

Neuroprotective Mechanisms of Oxygen and Ethanol: A Potential Combination Therapy in Stroke by Sweena Parmar, Shannon Moore-Langston, Vance Fredrickson, Jung-Min Kim, Radhika Rastogi, Omar Elmadoun, Yuchuan Ding (1194-1204).
Currently, stroke researchers are racing to develop neuroprotective strategies that shield the brain from ischemia-induced injury. To date, neuroprotective agents that have shown promise in animal studies have failed in clinical trials. Since the pathophysiology of ischemic stroke exploits numerous pathways leading to cellular injury, a combination of neuroprotective agents may offer substantially better results than a single agent alone - by intervening in multiple mechanisms. In this paper, we consider an approach using combination therapy with normobaric oxygen (NBO) and ethanol. Studies indicate that NBO therapy improves tissue oxygenation, thereby reducing the extent of hypoxic injury and decelerating the development of tissue necrosis when administered early after stroke onset. Studies have also demonstrated that low to moderate levels of ethanol not only decrease the risk of stroke, but also reduce post-ischemic sequelae. This article reviews the history of NBO and ethanol therapies, their mechanisms of action, the results of key clinical trials, and the rationale for their use as a combination therapy in the context of stroke treatment.

Erythropoietin in Stroke Therapy: Friend or Foe by Rhonda Souvenir, Desislava Doycheva, John H Zhang, Jiping Tang (1205-1213).
Recombinant human erythropoietin (rhEPO), over the past decade, was hailed as an auspicious therapeutic strategy for various types of brain injuries. The promising results from experiments conducted in animal models of stroke led to a hurried clinical trial that was swiftly aborted in Phase II. The multiple neuroprotective modalities of rhEPO failed to translate smoothly to human adult ischemic brain injury and provided limited aid to neonates. In light of the antithetical results, several questions were raised as to why and how this clinical trial failed. There was bolstering evidence from the preliminary studies that pointed to a bright future. Therefore, the objective of this review is to address these questions by discussing the signaling pathways of rhEPO that are reported to mediate the neuroprotective effect in various animal models of brain injury. Major biomedical bibliographical databases (MEDLINE, ISI, PubMed, and Cochrane Library) were searched with the use of keywords such as erythropoietin, stroke, neonatal hypoxia ischemia, intracerebral hemorrhage, etc. This article will discuss the confounding factors that influence the efficacy of rhEPO treatment hence challenging its clinical translatability. Lastly, rhEPO may still be a promising therapeutic candidate for neonates in spite of its shortcoming in clinical trial if caution is taken with the dose and duration of its administration.

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network by Tim Lekic, Damon Klebe, Roy Poblete, Paul R. Krafft, William B. Rolland, Jiping Tang, John H. Zhang (1214-1238).
Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

NAD+/NADH Metabolism and NAD+-Dependent Enzymes in Cell Death and Ischemic Brain Injury: Current Advances and Therapeutic Implications by Yingxin Ma, Hui Nie, Heyu Chen, Jiefu Li, Yunyi Hong, Ban Wang, Caixia Wang, Jie Zhang, Wei Cao, Mingchao Zhang, Yongning Xu, Xianting Ding, Shan Kai Yin, Xinkai Qu, Weihai Ying (1239-1247).
NAD+ and NADH play crucial roles in a variety of biological processes including energy metabolism, mitochondrial functions, and gene expression. Multiple studies have indicated that NAD+ administration can profoundly decrease oxidative cell death as well as ischemic and traumatic brain injury, suggesting NAD+ metabolism as a promising therapeutic target for cerebral ischemia and head injury. Cumulating evidence has suggested that NAD+ can produce its protective effects by multiple mechanisms, including preventing mitochondrial alterations, enhancing energy metabolism, preventing virtually all forms of cell death including apoptosis, necrosis and autophagy, inhibiting inflammation, directly increasing antioxidation capacity of cells and tissues, and activating SIRT1. Increasing evidence has also suggested that NADH metabolism is a potential therapeutic target for treating several neurological disorders. A number of studies have further indicated that multiple NAD+-dependent enzymes such as sirtuins, polymerase(ADP-ribose) polymerases (PARPs) and CD38 mediate cell death and multiple biological processes. In this article, an overview of the recent findings regarding the roles of NAD+/NADH and NAD+- dependent enzymes in cell death and ischemic brain injury is provided. These findings have collectively indicated that NAD+/NADH and NAD+-dependent enzymes play fundamental roles in oxidative stress-induced cell death and ischemic brain injury, which may become promising therapeutic targets for brain ischemia and multiple other neurological disorders.

Zinc (Zn2+) is one of the most important trace metals in the body. It is necessary for the normal function of a large number of protein s including enzymes and transcription factors. While extracellular fluid may contain up to micromolar Zn2+, intracellular Zn2+ concentration is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn2+ extrusion by Zn2+ transporting systems. Interestingly, systematic investigation has revealed that activities, previously believed to be dependent on calcium (Ca2+), may be partially mediated by Zn2+. This is also supported by new findings that some Ca2+-permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA-Rs) are also permeable to Zn2+. Thus, the importance of Zn2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn2+- permeable membrane molecules, especially Zn2+-permeable ion channels, in intracellular Zn2+dynamics and Zn2+ mediated physiology/pathophysiology.

Inflammatory Responses in Brain Ischemia by Masahito Kawabori, Midori A. Yenari (1258-1277).
Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke.

Catalpol: A Potential Therapeutic for Neurodegenerative Diseases by B. Jiang, R.F. Shen, J. Bi, X.S. Tian, T Hinchliffe, Y. Xia (1278-1291).
Neurodegenerative disorders, e.g., Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the progressive loss of neurons and subsequent cognitive decline. They are mainly found in older populations. Due to increasing life expectancies, the toll inflicted upon society by these disorders continues to become heavier and more prominent. Despite extensive research, however, the exact etiology of these disorders is still unknown, though the pathophysiological mechanisms have been attributed to oxidative, inflammatory and apoptotic injury in the brain. Moreover, there is currently no promising therapeutic agent against these neurodegenerative changes. Catalpol, an iridoid glucoside contained richly in the roots of the small flowering plant species Rehmannia glutinosa Libosch, has been shown to have antioxidation, anti-inflammation, anti-apoptosis and other neuroprotective properties and plays a role in neuroprotection against hypoxic/ischemic injury, AD and PD in both in vivo and in vitro models. It may therefore represent a potential therapeutical agent for the treatment of hypoxic/ischemic injury and neurodegenerative diseases. Based on our studies and those of others in the literature, here we comprehensively review the role of Catalpol in neuroprotection against pathological conditions, especially in neurodegenerative states and the potential mechanisms involved.

Effects of Hypoxia and Ischemia on MicroRNAs in the Brain by Yilin Yang, Harleen K Sandhu, Feng Zhi, Fei Hua, Min Wu, Ying Xia (1292-1301).
Hypoxia and ischemia play a major role in the pathogenesis of cerebrovascular diseases such as stroke. However, the protective strategies against hypoxic and ischemic insults are very limited in clinical settings. This has reinforced the need to improve our understanding of the hypoxic and ischemic cascades and explore novel solutions of hypoxic/ ischemic injury. Recent research has identified the crucial role of microRNAs in regulation of gene expression under hypoxic/ischemic conditions. These 19-24 ribonucleotide non-coding RNA molecules function as inhibitory modulators of gene expression, by targeting mRNAs and promoting either RNA degradation or translational repression. They are differentially regulated in the brain as well as other organs under hypoxic and ischemic conditions. Targeting microRNA expression/activity offers a potentially effective way to intervene against hypoxic and ischemic injury. In this review, we highlight recent updates with summary of our recent work, which provides an insight into the roles and mechanisms of microRNA-induced regulation of cellular and molecular processes in response to hypoxic and/or ischemic stress.

New Missions for an Old Agent: Granulocyte-Colony Stimulating Factor in the Treatment of Stroke Patients by Ihsan Solaroglu, Murat Digicaylioglu, G. Evren Keles, John H. Zhang (1302-1309).
Granulocyte-colony stimulating factor (G-CSF) has a multimodal neuroprotective profile and the cumulative preclinical data from numerous translational studies statistically confirmed the efficacy of G-CSF as a treatment option in ischemic stroke. G-CSF activates anti-apoptotic, antioxidative, and anti-inflammatory signaling pathways and stimulates angiogenesis and neurogenesis. In this review, we summarize the role of G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection and discuss its potential as a new drug for stroke treatment.