Brain renin-angiotensin--a new look at an old system

The classic renin-angiotensin system (RAS) is described as a circulating hormone system focused on cardiovascular and body water regulation, with angiotensin II as its major effector. Detlef Ganten's discovery some years ago of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2) and AT(4) receptor proteins. We discuss the characterization and distribution of the AT(1) and AT(2) receptor subtypes and the current controversy over the identity of the AT(4) receptor subtype. Research findings favoring the candidates insulin-regulated aminopeptidase (IRAP) and the type 1 tyrosine kinase receptor c-Met, are presented. Next, we summarize current research efforts directed at the use of angiotensin analogues in the treatment of clinical disorders such as memory dysfunction, cerebral blood flow and cerebroprotection, stress, depression, alcohol consumption, seizure, Alzheimer's and Parkinson's diseases, and diabetes. The use of ACE inhibitors, and AT(1) and/or AT(2) receptor blockers, has shown promise in the treatment of several of these pathologies. The development of blood-brain barrier penetrant AT(4) receptor agonists and antagonists is of major importance regarding the continuing evaluation of the efficacy of new treatment approaches.     

Correlation of iron deposition and change of gliocyte metabolism in the basal ganglia region evaluated using magnetic resonance imaging techniques: an in vivo study

Introduction

We assessed the correlation between iron deposition and the change of gliocyte metabolism in healthy subjects’ basal ganglia region, by using 3D-enhanced susceptibility weighted angiography (ESWAN) and proton magnetic resonance spectroscopy (¹H-MRS).

Material and methods

Seventy-seven healthy volunteers (39 female and 38 male subjects; age range: 24–82 years old) were enrolled in the experiment including ESWAN and proton MRS sequences, consent for which was provided by themselves or their guardians. For each subject, the mean phase value gained by ESWAN was used to evaluate the iron deposition; choline/creatine (Cho/Cr) and mI/Cr ratios gained by ¹H-MRS were used to evaluate gliocyte metabolism in the basal ganglia region of both sides. The paired t test was used to test the difference between the two sides of the basal ganglia region. Linear regression was performed to evaluate the relation between mean phase value and age. Pearson''s correlation coefficient was calculated to analyze the relationship between the result of ESWAN and ¹H-MRS.

Results

There was no difference between the two sides of the basal ganglia region in the mean phase value and Cho/Cr. But in mI/Cr the mean phase value of each nucleus in bilateral basal ganglia decreased with increasing age. There are 16 r-values between the mean phase value and Cho/Cr and mI/Cr in bilateral basal ganglia region. And each of all p-values is less than 0.001 (p < 0.001).

Conclusions

Iron deposition in the bilateral basal ganglia is associated with the change of gliocyte metabolism with increasing age. Iron deposition in each nucleus of the basal ganglia region changes with age.     

Involvement of the brain histaminergic system in addiction and addiction-related behaviors: A comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence.     

Human epidermal growth factor receptor 2, Na+/H+ exchanger regulatory factor 1, and breast cancer susceptibility gene-1 as new biomarkers for familial breast cancers

The aim of this study is to evaluate the analysis of markers related with progression, to further characterize familial breast cancers. Here, we investigated the expression of breast cancer susceptibility gene-1, hypoxia-inducible factor-1α, vascular endothelial growth factor receptor 1, and Na+/H+ exchanger regulatory factor 1 in 187 microarrayed breast carcinomas from 94 familial and 93 sporadic breast cancer patients by immunohistochemical staining. Furthermore, the expression levels of these biomarkers were compared with triple-negative phenotype. Familiarity was significantly associated with younger age (P < .000), higher tumor grade (P = .038), negative estrogen receptor hormonal status (P = .036), and high proliferative activity (P = .029). The familial cancers were immunonegative for membranous Na+/H+ exchanger regulatory factor 1 expression compared with sporadic cancers (P = .001); notably, vascular endothelial growth factor receptor 1 staining correlated with cytoplasmic Na+/H+ exchanger regulatory factor 1 expression in familial tumors (P = .009). In multivariate analysis, the "new biomarkers," including negative human epidermal growth factor receptor 2 status (odds ratio, 4.538; 95% confidence interval, 1.756-11.728), negative membranous Na+/H+ exchanger regulatory factor 1 expression (odds ratio, 7.686; 95% confidence interval, 1.876-31.483) and positive nuclear breast cancer susceptibility gene-1 (odds ratio, 0.3982; 95% confidence interval, 0.169-0.936), significantly correlated with family history of breast cancer. We hypothesize that the evaluation of human epidermal growth factor receptor 2, Na+/H+ exchanger regulatory factor 1, and breast cancer susceptibility gene-1 could be clinically useful to identify familial breast tumors and to select patients candidate to breast cancer susceptibility genes 1/2 gene sequencing.     

Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies

Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.     

The effects of angiotensin-II receptor blockers on podocyte damage and glomerular apoptosis in a rat model of experimental streptozotocin-induced diabetic nephropathy

The aim of the study was to determine in a rat model of streptozotocin-induced diabetic nephropathy the expression of: WT-1 (for podocyte loss in the glomerulus), TGF-beta 1 (for tissue damage), caspase-3 and bax (for glomerular apoptosis) and the possible protective effects of an angiotensin II type 1 receptor blocker. Three groups of male Wistar albino rats were used. The first group consisted of non-diabetic control rats. The second group was the untreated diabetic rats. The third group consisted of diabetic rats treated with Irbesartan, which is an angiotensin II receptor antagonist, widely used in treatment for hypertension. Immunohistochemical stainings for TGF-beta 1, bax, caspase-3 and WT-1 were performed. The microalbuminuria levels of the Irbesartan-treated diabetic group were lower than those of the untreated diabetic group (P < 0.01). The immunostaining of TGF-beta 1, bax and caspase-3 was decreased in glomeruli of the Irbesartan-treated diabetic group compared to the untreated diabetic group. WT-1 immunopositive podocyte numbers were found to be significantly lower in the untreated diabetic group than in the other groups (P < 0.01). In the Irbesartan-treated diabetic group, the WT-1 immunopositive cell numbers were higher compared to the untreated diabetic group (P < 0.01). We conclude that the decrease in the number of podocytes is an early marker of diabetic nephropathy, AT1 receptor blocker has renoprotective effects on the regulation of renal hemodynamics and on the control of tissue damage by preventing podocyte loss, which leads to decrease of bax and caspase-3 expressions of apoptosis related proteins, and may prevent glomerular cell apoptosis via angiotensin II.     

Effect of the two new calcium channel blockers mebudipine and dibudipine on vascular flow of isolated kidney of normal and diabetic rats

Background and aims: Calcium channel blockers (CCBs) are powerful drugs in the treatment of hypertension. These agents also preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. There is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. In previous researches mebudipine and dibudipine two newly synthesized CCBs, improved normal rat kidney perfusion. The study was designed to investigate the effects of these new drugs on vascular flow of isolated kidney from diabetic rats comparing to nifedipine, also to test that the effects of the new DHPs and nifedipine on renal blood flow in the isolated perfused kidney might be altered in experimental diabetic rats. Methods: In this study normal and STZ-induced 6- to 7-week diabetic rats were used. Following the establishment of renal perfusion with a constant baseline pressure of 85-95 mmHg, the renal vasculature was constricted by phenylephrine (PE) injection. Changes in the baseline perfusion pressure were recorded. Then DHP CCBs prepared in perfusion medium was fed to the kidney for 30 min. Finally alterations in the baseline pressure arising from PE administrations in the presence of DHPs were recorded and data analyses were done. Results: Mebudipine and dibudipine (1-10 μM) were more effective in the inhibition of phenylephrine (PE)-induced perfusion pressure in isolated kidney of diabetic rats compared to nifedipine at similar concentrations. Based on the obtained EC₅₀ values for DHPs-induced inhibition of prefusion pressure, it is referred that lower concentrations of mebudipine and dibudipine are needed to inhibit PE-evoked increments of renal perfusion pressure in diabetic rats. Conclusion: Mebudipine and dibudipine have more potency in inhibiting PE-elicited perfusion pressure in isolated kidney from diabetic rats compared to normal rats.     

Biological metals and Alzheimer's disease: Implications for therapeutics and diagnostics

The equilibrium of metal ions is critical for many physiological functions, particularly in the central nervous system, where metals are essential for development and maintenance of enzymatic activities, mitochondrial function, myelination, neurotransmission as well as learning and memory. Due to their importance, cells have evolved complex machinery for controlling metal-ion homeostasis. However, disruption of these mechanisms, or absorption of detrimental metals with no known biological function, alter the ionic balance and can result in a disease state, including several neurodegenerative disorders such as Alzheimer's disease. Understanding the complex structural and functional interactions of metal ions with the various intracellular and extracellular components of the central nervous system, under normal conditions and during neurodegeneration, is essential for the development of effective therapies. Accordingly, assisting the balance of metal ions back to homeostatic levels has been proposed as a disease-modifying therapeutic strategy for Alzheimer's disease as well as other neurodegenerative diseases.     

Glycine and glycine receptor signaling in hippocampal neurons: Diversity,function and regulation

Glycine is a primary inhibitory neurotransmitter in the spinal cord and brainstem. It acts at glycine receptor (GlyR)-chloride channels, as well as a co-agonist of NMDA receptors (NMDARs). In the hippocampus, the study of GlyRs has largely been under-appreciated due to the apparent absence of glycinergic synaptic transmission. Emerging evidence has shown the presence of extrasynaptic GlyRs in the hippocampus, which exert a tonic inhibitory role, and can be highly regulated under many pathophysiological conditions. On the other hand, besides d-serine, glycine has also been shown to modulate NMDAR function in the hippocampus. The simultaneous activation of excitatory NMDARs and inhibitory GlyRs may provide a homeostatic regulation of hippocampal network function. Furthermore, glycine can regulate hippocampal neuronal activity through GlyR-mediated cross-inhibition of GABAergic inhibition, or through the glycine binding site-dependent internalization of NMDARs. Therefore, hippocampal glycine and its receptors may operate in concert to finely regulate hippocampus-dependent high brain function such as learning and memory. Finally, dysfunction of hippocampal glycine signaling is associated with neuropsychiatric disorders. We speculate that further studies of hippocampal glycine-mediated regulation may help develop novel glycine-based approaches for therapeutic developments.     

Neurochemical pathways involved in the protective effects of nicotine and ethanol in preventing the development of Parkinson's disease: potential targets for the development of new therapeutic agents

In this short review, neurochemical targets are identified where nicotine, and possibly ethanol, may interact to prevent the occurrence of Parkinson's disease. These are (a) the nicotinic acetycholine receptors present in the nigrostriatal area or on the surface of microglia, (b) monoamine oxidases and (c) inducible nitric oxide synthase. If such induced changes can be verified in clinical studies, this may help in the design of new therapeutic drugs which may be of relevance to diminish the incidence and perhaps the progression of the debilitating condition of Parkinson's disease.     

Oxytocin: The great facilitator of life

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review.     

Early coupled up-regulation of interleukin-12 receptor beta-1 in CD8+ central memory and effector T cells for better clinical outcomes in liver transplant recipients

This study aimed to investigate the role of initial priming of interleukin (IL)-12 receptor beta-1 in CD8⁺central memory T cells (initial IL-12RT_CM priming) and CCR7-negative subsets (CNS) in effector cell expansion and clinical outcome after living donor liver transplantation (LDLT). One hundred and six patients who underwent LDLT were classified into the following three groups according to hierarchical clustering of CD8⁺CD45 isoforms before LDLT: I, naive-dominant; II, effector memory-dominant; and III, effector-dominant. The pre-existing CD8⁺effector cells (T_E) and activated immune status increased progressively from group I to group II to group III. Groups I, II and III received tacrolimus (Tac)/glucocorticoid (GC) regimens. Eighteen group III recipients received Tac/mycophenolate mofetil (MMF) and were defined as group IV. Initial IL-12RT_CM priming was slightly, moderately and markedly decreased in droups I, II, and III, respectively. Initial priming of IL-12Rβ1 in CNS was decreased markedly in the three groups with marked decreases of T_E, perforin and interferon (IFN)-γ; all parameters were restored by up-regulation of IL-12Rβ1⁺T_CM through the self-renewal of T_CM. The lag time required until coupled up-regulation of IL-12Rβ1 of T_CM and CNS to above baseline was 12, 20 and 32 days in groups I, II and III, respectively. Inferior clinical outcomes were associated with increasing lag time. In contrast, the initial priming of IL-12Rβ1 in T_CM and CNS remained above baseline in group IV due to MMF-mediated increase of IL-12Rβ1. Early coupled up-regulation of T_CM and CNS leads to efficient T_E differentiation and optimal clinical outcomes.     

Glutamate receptor activation in cultured cerebellar granule cells increases cytosolic free Ca2+ by mobilization of cellular Ca2+ and activation of Ca2+ influx

Summary The Ca²⁺ sensitive fluorescent probe, fura-2 has been used to monitor cytosolic free calcium levels in mature primary cultures of cerebellar granule cells during exposure to L-glutamate and other excitatory amino acids: quisqualate (QA), kainate (KA) and N-methyl-D-aspartate (NMDA). Glutamate at micromolar concentrations produced a prompt and dose-related increase in the intracellular concentration of free Ca²⁺, ([Ca²⁺]_i), whereas QA, KA and NMDA had no effect. This increase was also seen in the absence of extracellular Ca²⁺, suggesting that L-glutamate promotes mobilization of Ca²⁺ from intracellular stores. In the presence of extracellular calcium, the elevation of [Ca²⁺]_i was, in part, mediated by an increase in the plasma membrane permeability to Ca²⁺. This Ca²⁺ influx was not affected by the Ca²⁺-channel antagonist 1-Verapamil. However, L-Verapamil did block the increase in [Ca²⁺]_i seen after depolarization of the cells with potassium. The Ca²⁺ response elicited by glutamate was partially blocked by the excitatory amino acid antagonist glutamate diethyl ester (GDEE). Furthermore, glutamate stimulated the formation of inositol mono-, bis-, tris and tetrakisphosphates (IP1, IP2, IP3, and IP4) suggesting a role for these compounds for the increase in [Ca²⁺]_i.     

Small conductance calcium-activated potassium channels: From structure to function

The cloning of K_Ca2 channels revealed three subtypes, with each displaying distinct but partially overlapping expression distributions in the mammalian CNS and periphery. Activation of K_Ca2 channels leads to membrane hyperpolarization and inhibition of action potential firing. Block of K_Ca2 channels has been suggested as a novel target for cognitive enhancement, depression, myotonic muscular dystrophy and heart arrhythmias. It is clear however, that blockers selective for individual K_Ca2 channel subtypes would be required to be therapeutically useful. K_Ca2 channel current is blocked by apamin, with the bee venom toxin being unusual in displaying some selectivity between K_Ca2 channel subtypes. This suboptimal selectivity is not sufficient to be therapeutically useful and the toxin has been shown in vivo to have a very narrow therapeutic window. Mutational and molecular modelling studies of the K_Ca2 channels are beginning to determine how selective block might be achieved. Mutagenesis has indicated the importance of the outer pore region and the extracellular loop between transmembrane domains S3 and S4 for block of K_Ca2 current by apamin. Mapping the sequence of transmembrane domains S5, pore helix and S6 onto the crystal structures of KcsA, MthK and Kv1.2 has provided an approximation of the pore structure. This approach has allowed structural modelling of the interactions between toxins and channel, demonstrating that the toxins that show little discrimination between K_Ca2 channel subtypes interact with the outer pore and around the K⁺ selectivity filter. We present the structural modelling of the interaction of apamin and K_Ca2.2, which is superimposed onto the crystal structure of Kv1.2. This has shown that apamin interacts only with the outer pore and does not come into contact with channel's selectivity filter. It is clear that by comparing how different toxins interact with each K_Ca2 channel subtype, a detailed picture will be generated that will aid the development of more specific K_Ca2 channel blockers.     

Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis

Dopamine plays an important role in fear and anxiety modulating a cortical brake that the medial prefrontal cortex exerts on the anxiogenic output of the amygdala and have an important influence on the trafficking of impulses between the basolateral (BLA) and central nuclei (CeA) of amygdala. Dopamine afferents from the ventral tegmental area innervate preferentially the rostrolateral main and paracapsular intercalated islands as well as the lateral central nucleus of amygdala activating non-overlapping populations of D1- and D2-dopamine receptors located in these structures. Behaviorally, the intra-amygdaloid infusion of D1 agonists and antagonists elicits anxiogenic and anxiolytic effects respectively on conditioned and non-conditioned models of fear/anxiety suggesting an anxiogenic role for D1 receptors in amygdala. The analysis of the effects of D2 agonists and antagonists suggest that depending of the nature of the threat the animal experiences in anxiety models either anxiogenic or anxiolytic effects are elicited. It is suggested that D1- and D2-dopamine receptors in the amygdala may have a differential role in the modulation of anxiety. The possibility is discussed that D1 receptors participate in danger recognition facilitating conditioned–unconditioned associations by the retrieval of the affective properties of the unconditioned stimuli, and in the control of impulse trafficking from cortical and BLA regions to BLA and CeA nuclei respectively whereas D2 receptors have a role in setting up adaptive responses to cope with aversive environmental stimuli.     

Axonal ion channels from bench to bedside: A translational neuroscience perspective

Over recent decades, the development of specialised techniques such as patch clamping and site-directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states.     

Influence of the NR3A subunit on NMDA receptor functions

Various combinations of subunits assemble to form the NMDA-type glutamate receptor (NMDAR), generating diversity in its functions. Here we review roles of the unique NMDAR subunit, NR3A, which acts in a dominant-negative manner to suppress receptor activity. NR3A-containing NMDARs display striking regional and temporal expression specificity, and, unlike most other NMDAR subtypes, they have a low conductance, are only modestly permeable to Ca²⁺, and pass current at hyperpolarized potentials in the presence of magnesium. While glutamate activates triheteromeric NMDARs composed of NR1/NR2/NR3A subunits, glycine is sufficient to activate diheteromeric NR1/NR3A-containing receptors. NR3A dysfunction may contribute to neurological disorders involving NMDARs, and the subunit offers an attractive therapeutic target given its distinct pharmacological and structural properties.     

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans.Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci., 45, 599–606.]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization.To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors.While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons.The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.