Glutamate receptors in glia: new cells, new inputs and new functions

Functional glutamate receptors are expressed on the majority of glial cell types in the developing and mature brain. Although glutamate receptors on glia are activated by glutamate released from neurons, their physiological role remains largely unknown. Potential roles for these receptors in glia include regulation of proliferation and differentiation, and modulation of synaptic efficacy. Recent anatomical and functional evidence indicates that glutamate receptors on immature glia are activated through direct synaptic inputs. Therefore, glutamate and its receptors appear to be involved in a continuous crosstalk between neurons and glia during development and also in the mature brain.     

Drug transport across the blood-brain barrier

This is the third part of a review on the transport of drugs across the blood-brain barrier. In the first two parts, the anatomical and physiological aspects and the various techniques that can be used to study blood-brain transport have been discussed and reviewed. This third part focuses specifically on the mechanisms that are involved in drug transport across the blood-brain barrier. In addition, the opportunities to improve drug transport into the brain will be reviewed. Emphasis is on the transport of peptides.     

Physiological pharmacokinetic and pharmacodynamic model of physostigmine in the rat.

A physiological model for physostigmine disposition was developed in the rat which incorporated anatomical, physiological, and biochemical parameters, i.e. tissue volume, plasma flow rates, drug metabolism, and tissue-to-plasma partition coefficients. Predicted concentrations of physostigmine in different tissue compartments were consistent with the experimental observations in the rat following an iv dose. Part of this study also compared the time course changes in measured effect, as percentage change in cholinesterase activity in brain, and related these changes to the plasma or brain drug level in either a combined pharmacokinetic-pharmacodynamic (plasma physostigmine-effect relationship) or a dynamic model (brain physostigmine-effect relationship). Fitting the time course of the effect in a pharmacokinetic-pharmacodynamic model required an effect compartment with the equilibration rate constant between it and the plasma compartment. Both models help to understand whether the cholinesterase activity is homogeneous or heterogenous in the brain.     

Sensing of glucose in the brain

The brain, and in particular the hypothalamus and brainstem, have been recognized for decades as important centers for the homeostatic control of feeding, energy expenditure, and glucose homeostasis. These structures contain neurons and neuronal circuits that may be directly or indirectly activated or inhibited by glucose, lipids, or amino acids. The detection by neurons of these nutrient cues may become deregulated, and possibly cause metabolic diseases such as obesity and diabetes. Thus, there is a major interest in identifying these neurons, how they respond to nutrients, the neuronal circuits they form, and the physiological function they control. Here I will review some aspects of glucose sensing by the brain. The brain is responsive to both hyperglycemia and hypoglycemia, and the glucose sensing cells involved are distributed in several anatomical sites that are connected to each other. These eventually control the activity of the sympathetic or parasympathetic nervous system, which regulates the function of peripheral organs such as liver, white and brown fat, muscle, and pancreatic islets alpha and beta cells. There is now evidence for an extreme diversity in the sensing mechanisms used, and these will be reviewed.     

Physiological and neuropharmacological aspects of the central respiratory mechanisms

The present physiological and neuropharmacological views and the essentials of the experimental results on the anatomical localization, functional and neuronal organization of the central respiratory mechanisms, classically expressed as the respiratory centers, in the brain stem were reviewed and discussed. The brain stem neural mechanism for central regulation of breathing is regarded as a complex neuronal mechanism consisting of several functional subsystems subserving different functions. One of its functions is the generation of respiratory rhythm. The subsystem for respiratory rhythm-generating mechanisms is located in the medullary reticular formation outside the DRG and VRG regions, which are thought to be premotor neuron pools. Rhythmic activity originating in the medulla is dominant in terms of the spontaneity over other rhythmic activity in the pontine and spinal cord mechanisms. Evidences for heterogeneity of the functional properties of brain stem respiratory neurons have been demonstrated. Neuronal mechanisms involving respiratory neurons identified as members of the primary respiratory neuron population or neuronal networks consisting of different types of respiratory neurons located in the lateral region of the bulbar reticular formation may play important roles in the generation of respiratory rhythms. These aspects contribute to the understanding of the neurophysiological basis, providing important prerequisites for further neuropharmacological studies on neurotransmission within the neuronal network of the central respiratory mechanisms.     

经鼻递脑机制及基于EPR效应的脑靶向脂质体的研究进展

鼻腔与脑在解剖生理结构上的独特联系使得鼻腔给药作为脑内递药途径成为可能,而作为特殊给药系统的脂质体具有鼻腔给药的诸多特点,经鼻腔给药并且利用肿瘤的长滞留效应（EPR效应）或"炎症靶向"达到脑靶向作用,可增加药物的脑内递送。近年来经鼻递药结合EPR效应的策略越来越受到关注,本文归纳总结了近些年国内外有关经鼻递脑途径的机制、影响因素,探讨了经鼻给药结合EPR效应的脑靶向脂质体在中枢神经系统疾病方面的相关研究。     

Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology

At present, brain tumor is among the most challenging diseases to treat and the therapy is limited by the lack of effective methods to deliver anticancer agents across the blood-brain barrier (BBB). BBB is a selective barrier that separates the circulating blood from the brain extracellular fluid. In its neuroprotective function, BBB prevents the entry of toxins, as well as most of anticancer agents and is the main impediment for brain targeted drug delivery approaches. Nanotechnology-based delivery systems provide an attractive strategy to cross the BBB and reach the central nervous system (CNS). The incorporation of anticancer agents in various nanovehicles facilitates their delivery across the BBB. Moreover, a more powerful tool in brain tumor therapy has relied surface modifications of nanovehicles with specific ligands that can promote their passage through the BBB and favor the accumulation of the drug in CNS tumors. This review describes the physiological and anatomical features of the brain tumor and the BBB, and summarizes the recent advanced approaches to deliver anticancer drugs into brain tumor using nanobiotechnology-based drug carrier systems. The role of specific ligands in the design of functionalized nanovehicles for targeted delivery to brain tumor is reviewed. The current trends and future approaches in the CNS delivery of therapeutic molecules to tumors are also discussed.     

Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate

Recent physiological, pharmacological and anatomical studies provide evidence that one of the main roles of the endocannabinoid system in the brain is the regulation of gamma-aminobutyric acid (GABA) and glutamate release. This article aims to review this evidence in the context of its implications for pain. We first provide a brief overview of supraspinal regulation of nociception, followed by a review of the evidence that the brain's endocannabinoid system modulates nociception. We look in detail at regulation of supraspinal GABAergic and glutamatergic neurons by the endocannabinoid system and by exogenously administered cannabinoids. Finally, we review the evidence that cannabinoid-mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions.     

PET studies with carbon-11 radioligands in neuropsychopharmacological drug development.

A basic problem in the discovery and development of novel drugs to be used in the treatment of neurological and psychiatric disorders is the absence of relevant in vitro or in vivo animal models that can yield results which can be extrapolated to man. Drug research now benefits from the fast development of functional imaging techniques such as positron emission tomography (PET) which trace radiolabelled molecules directly in the human brain. PET uses molecules that are labelled with short-lived radionuclides and injected intravenously into experimental animals, human volunteers or patients. The most frequent approach is to study how an unlabelled drug inhibits specific binding of a well characterised selective PET radioligand. The alternative direct approach is to radiolabel a new potential drug and to trace its uptake, anatomical distribution and binding in brain. Furthermore, the effects of a novel drug on physiological-biochemical parameters, such as glucose metabolism or blood flow, can also be assessed. The demonstration of quantitative relationships between drug binding in vivo and drug effects in patients is used to validate targets for drug action, to correlate pharmacological and physiological effects, and to optimise clinical treatment.     

Advances in brain drug targeting and delivery: limitations and challenges of solid lipid nanoparticles

Introduction: With the advancement in the field of medical colloids and interfacial sciences, the life expectancy has been greatly improved. In addition, changes in the human lifestyle resulted in development of various organic and functional disorders. Central nervous system (CNS) disorders are most prevalent and increasing among population worldwide. The neurological disorders are multi-systemic and difficult to treat as portal entry to brain is restricted on account of its anatomical and physiological barrier.

Areas covered: The present review discusses the limitations to CNS drug delivery, and the various approaches to bypass the blood brain barrier (BBB), focusing on the potential use of solid lipid nanoparticles (SLN) for drug targeting to brain. The methods currently in use for SLN production, physicochemical characterization and critical issues related to the formulation development suitable for targeting brain are also discussed.

Expert opinion: The potential advantages of the use of SLN over polymeric nanoparticles are due to their lower cytotoxicity, higher drug loading capacity and scalability. In addition, their production is cost effective and the systems provide a drug release in a controlled manner up to several weeks. Drug targeting potential of SLN can be enhanced by attaching ligands to their surface.     

Brain neuronal mechanisms of circadian rhythms in mammalians]

It is now widely accepted that the suprachiasmatic nucleus (SCN) of the hypothalamus is a circadian pacemaker in the mammalians. This conclusion is based on three principal lines of the following evidence. First, ablation of the SCN results in a loss of circadian rhythms in rodents. Second, the SCN exhibits rhythms in neuronal activity and glucose metabolism both in vivo and in vitro experiments. Third, the transplantation of fetal SCN to the third ventricle of animals rendered arrhythmic++ by SCN ablation restores circadian function. In this review the anatomical, physiological and pharmacological characteristics of SCN neurons in vitro are discussed by focusing especially upon the roles of various neurotransmitters and modulators in the circadian system of mammals, in relation to the function of SCN.     

Paediatric pharmacokinetics: key considerations

A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials.     

Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease

Deprenyl, a monoamine oxidase (MAO) inhibitor with selective effects on MAO type-B at low doses, was administered to 13 patients with dementia of the Alzheimer type (DAT), a disorder reported to be associated with increased brain MAO-B activity. Cerebrospinal fluid was obtained for measurement of three monoamine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), by high pressure liquid chromatography with electrochemical detection. Deprenyl treatment (10 mg/day) for 3–4 weeks was associated with small but statistically significant reductions in HVA (21%) and 5-HIAA (15%) compared to baseline values. Subsequent administration of deprenyl at the higher dose of 40 mg/day for 3–4 more weeks led to greater reductions in HVA (40%) and MHPG (43%) than 5-HIAA (20%). These dose-dependent reductions are consistent with in vitro biochemical and anatomical data from primate brain suggesting that at low doses of deprenyl, MAO-B inhibition might be expected to selectively affect dopamine and serotonin-containing neurons, while at higher doses (which lead to MAO-A as well as MAO-B inhibition), noradrenergic neurons may become relatively more affected by the drug.     

Self-administered and passive cocaine infusions produce different effects on corticosterone concentrations in the medial prefrontal cortex (MPC) of rats

Although our lab, as well as several others, has demonstrated a role for corticosterone in cocaine self-administration, there are no studies of the central dynamics of this hormone over the course of a behavioral session when rats are self-administering cocaine or receiving passive injections. The assay of corticosterone in microdialysates collected during such sessions allows for determinations of changes in brain corticosterone during drug-taking behavior. By using the combination of microdialysis in terminal fields for the mesocorticolimbic dopaminergic system and the yoked-triad model, one can distinguish between the direct cocaine-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis from the activation of the HPA axis related to drug-taking. In these experiments, we measured corticosterone in microdialysis samples collected from probes aimed at the medial prefrontal cortex, nucleus accumbens and basolateral amygdala in rats self-administering cocaine and receiving identical, passive infusions of cocaine or saline. While corticosterone was increased in all three brain regions in rats receiving cocaine, medial prefrontal cortex corticosterone was increased significantly more in rats receiving non-contingent infusions of the drug compared to rats self-administering cocaine. The results of these experiments demonstrate that control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the central nervous system. These results also provide evidence of the role steroid hormones play in shaping the functional activity of the brain.     

Voltage gated ion channels: targets for anticonvulsant drugs

Epilepsy is one of the most prevalent neurological syndromes in the world today. Epilepsy describes a group of brain disorders whose symptoms and causes are diverse and complicated, but all share a common behavioural manifestation: the seizure. Seizures result from the abnormal discharge of groups of neurons within the brain, usually within a focal point, that can result in the recruitment of large brain regions into epileptiform activity. Although the range of explanations for the development of seizures can be as varied as genetic composition to acute head trauma, the net result is often similar. The excitability of neurons is governed by the input they receive from their neighbours and the intrinsic excitability of the neuron. In this review we focus on elements that are crucial to determining the intrinsic excitability of neurons in the CNS, the voltage gated ion channels (VGICs). VGICs as well as being important for physiological function are critical in producing hyperexcitability such as that associated with seizure discharges. Many drugs routinely used in the clinical setting, as well as several novel experimental drugs, have shown interactions with VGICs that underpin, at least in part, their anticonvulsant action. We review the physiological roles of voltage gated ion channels that are selective for sodium, potassium and calcium conductance and attempt to highlight their role in the pathology of epilepsy. This is supplemented by the mechanisms of drug action at these important anticonvulsant targets for classical and clinically relevant compounds (e.g. phenytoin, ethosuximide) as well as some important second generation drugs (e.g. gabapentin, levetiracetam) and novel experimental agents (e.g. retigabine, losigamone, safinamide). We also briefly discuss the urgent need for new drugs in this arena and the potential of combinatorial methods and recombinant screening to identify leads.     

Gene therapy for Parkinson's disease: current status and future potential

Parkinson's disease appears to be a good candidate for gene therapy. The primary biochemical defect associated with the disease has been clearly determined as an absence of dopamine in the caudate-putamen, and the anatomical region where the neuropathologic hallmark of the disease, death of the nigral dopamine-producing neurons, occurs, remains circumscribed. Based on the biochemical and anatomical information gathered on Parkinson's disease, different gene therapy strategies have been devised to treat it. The first, and most explored strategy so far, consists in engineering cells to produce levodopa or dopamine so they will replace dopaminergic neurotransmission. Several types of cells have been employed in these experiments, and behavioral recovery has been reported in animal models of the disease. However, this approach cannot prevent neuronal death, nor reconstruct brain circuits. Another strategy is to protect cells by transferring genes that encode neurotrophic factors. Effort is now being concentrated into this research area, and promising results have recently been reported. Finally, an additional strategy aims at generating cells with a dopaminergic phenotype so they will be capable of replacing the missing dopaminergic neurons in biochemical, anatomical and functional terms. This has the potential to become an important constituent for an effective cure. Gene therapy holds significant promise for the treatment of neurodegenerative disorders, and Parkinson's disease treatment will benefit greatly from the knowledge and information arising from gene therapy research.     

Biological Mechanisms,Cerebrovascular Alterations and Pharmacological Targets in the Pathology of Dementia

In response to stimulation, information is stored in the brain when synapses are simultaneously active. Interestingly, a physiological continuum may exist between processes of memory formation and brain injury, as many of the molecular mechanisms involved in memory encoding are the same as those activated during excitotoxic events in neurons. However, how brain injury leads to long lasting impairments in memory and/or dementia is still open for debate. Furthermore, evidence now suggests that cerebrovascular alterations and the pathology seen in dementia from Alzheimer's disease are mechanistically linked. Investigations have generated a wealth of information on mechanisms that become disturbed in dementia. However, there is still no cure for dementia of the Alzheimer's type. Undaunted by failures or drugs that have only modest effects, hundreds of drug discovery programs across the world continue to look for promising and more effective treatments for the disease. (c) 2002 Prous Science. All rights reserved.     

A review of the applications of physiologically based pharmacokinetic modeling

The physiological pharmacokinetic approach to the modeling of drug distribution is reviewed. These models allow extrapolation outside the range of data with some confidence if the dominant mechanisms of transport are sufficiently well understood. In addition, it is possible to extrapolate to other species. Compartments correspond to anatomical spaces so that biochemical interactions (including drug effect or pharmacodynamics) can be incorporated in the model. The articles summarized in this review are limited to models dealing with drug application.     

Cyclin-dependent kinase 5 (Cdk5): a potential therapeutic target for the treatment of neurodegenerative diseases and diabetes mellitus

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39 expressed predominantly in neurons. Cdk5 is indispensable for the development of the central nervous system through regulation of neuronal migration. In mature neurons, Cdk5 has been implicated in various signaling transduction pathways, which contribute to functional neuronal activity. It has been widely accepted that aberrant Cdk5 activity induced by the conversion of p35 to p25 plays roles in the pathogenesis of neurodegenerative diseases. Cdk5 also contributes to adaptive changes in the brain related to drug addiction. Moreover, recent studies suggest that Cdk5 plays crucial roles in physiological functions in non-neuronal cells such as glucose-stimulated insulin secretion in pancreatic -cells. The present evidence indicates that Cdk5 might be a potential drug target for the treatment of neurodegenerative diseases, drug abuse and diabetes mellitus. This review focuses on the implication of Cdk5 in the signaling pathways of both neurodegenerative diseases and drug abuse, and the mechanism of Cdk5 involvement in insulin secretion. This review also discusses the possibility of using Cdk5 inhibitors as therapeutic drugs.